Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database

Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database

 

Ryan A. Maddox, PhD1⇑ J. L. Blase, MPH1 N. D. Mercaldo, MS2,3 A. R. Harvey, MSPH1 L. B. Schonberger, MD1 W. A. Kukull, PhD3 E. D. Belay, MD1 1Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA 2Department of Biostatistics, Vanderbilt University, Nashville, TN, USA 3National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA Ryan A. Maddox, PhD, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop A-30, Atlanta, GA 30333, USA. Email: rmaddox@cdc.gov

 

Abstract Background: Brain tissue analysis is necessary to confirm prion diseases. Clinically unsuspected cases may be identified through neuropathologic testing.

 

Methods: National Alzheimer’s Coordinating Center (NACC) Minimum and Neuropathologic Data Set for 1984 to 2005 were reviewed. Eligible patients had dementia, underwent autopsy, had available neuropathologic data, belonged to a currently funded Alzheimer’s Disease Center (ADC), and were coded as having an Alzheimer’s disease clinical diagnosis or a nonprion disease etiology. For the eligible patients with neuropathology indicating prion disease, further clinical information, collected from the reporting ADC, determined whether prion disease was considered before autopsy.

 

Results: Of 6000 eligible patients in the NACC database, 7 (0.12%) were clinically unsuspected but autopsy-confirmed prion disease cases.

 

Conclusion: The proportion of patients with dementia with clinically unrecognized but autopsy-confirmed prion disease was small. Besides confirming clinically suspected cases, neuropathology is useful to identify unsuspected clinically atypical cases of prion disease.

 

prion disease Creutzfeldt–Jakob disease Alzheimer’s disease dementia diagnosis

 

http://aja.sagepub.com/content/early/2015/08/26/1533317515602218.abstract

 

***Miracles do happen. it just took 3 decades of denial from these authors cdc et al to finally come up with this conclusion...daaa...during that time period how many humans have been exposed due to their continued denial over those decades. $$$...just saying...terry

 

Subject: Re: Hello Dr. Manuelidis

 

Date: Fri, 22 Dec 2000 17:47:09 –0500

 

From: laura manuelidis

 

Reply-To: laura.manuelidis@yale.edu Organization: Yale Medical School

 

To: "Terry S. Singeltary Sr."

 

References: <39b5561a .87b84a28="" wt.net=""> <39b64574 .a4835745="" yale.edu=""> <39b680d8 .3872535b="" wt.net=""> <39b66ef1 .4ce25685="" yale.edu=""> <39bbb812 .425109f="" wt.net=""> <39be84cb .d7c0c16b="" yale.edu=""> <3a3ba197 .7f60d376="" wt.net="">

 

Dear Terry,

 

One of our papers (in Alzheimer's Disease Related Disord. 3:100-109, 1989) in text cites 6 of 46 (13%) of clinical AD as CJD. There may be a later paper from another lab showing the same higher than expected incidence but I can't put my hands on it right now. We also have a lot of papers from 1985 on stating that there are likely many silent (non-clinical) CJD infections, i.e. much greater than the "tip of the iceberg" of long standing end-stage cases with clinical symptoms. Hope this helps.

 

best wishes for the new year laura manuelidis

 

"Terry S. Singeltary Sr." wrote:

 

> > Hello again Dr. Manuelidis,

 

> > could you please help me locate the 2 studies that were

 

> done on CJD where it showed that up to 13% of the people

 

> diagnosed as having Alzheimer's actually had CJD.

 

> trying to find reference...

 

> > thank you,

 

> Terry S. Singeltary Sr.

 

TSS

 

===================

 

From: TSS (216-119-130-123.ipset10.wt.net)

 

Subject: CJD or Alzheimer's, THE PA STUDY...full text

 

Date: May 7, 2001 at 10:24 am PST

 

Diagnosis of dementia: Clinicopathologic correlations

 

Francois Boller, MD, PhD; Oscar L. Lopez, MD; and John Moossy, MD

 

Article abstract--Based on 54 demented patients consecutively autopsied at the University of Pittsburgh, we studied the accuracy of clinicians in predicting the pathologic diagnosis. Thirty-nine patients (72.2%) had Alzheimer's disease, while 15 (27.7%) had other CNS diseases (four multi-infarct dementia; three Creutzfeldt-Jakob disease; two thalamic and subcortical gliosis; three Parkinson's disease; one progressive supranuclear palsy; one Huntington's disease; and one unclassified). Two neurologists independently reviewed the clinical records of each patient without knowledge of the patient's identity or clinical or pathologic diagnoses; each clinician reached a clinical diagnosis based on criteria derived from those of the NINCDS/ADRDA. In 34 (63 %) cases both clinicians were correct, in nine (17%) one was correct, and in 11 (20%) neither was correct. These results show that in patients with a clinical diagnosis of dementia, the etiology cannot be accurately predicted during life.

 

NEUROLOGY 1989;39:76-79

 

Several recent papers and reports have addressed the problem of improving the clinician's ability to diagnose dementia. Notable among those reports are the diagnostic criteria for dementia of the American Psychiatric Association, known as DSM III,1 as well as the clinical and neuropathologic criteria for the diagnosis of Alzheimer's disease (AD).2,3 Other researchers have published guidelines for the differentiation of various types of dementia4 and for antemortem predictions about the neuropathologic findings of demented patients.5

 

Most studies on the accuracy of clinical diagnosis in patients with dementia, especially AD, have used clinicopathologic correlation,6-15 and have found a percentage of accuracy ranging from 43% to 87%. Two recent reports, however,16,17 have claimed an accuracy of 100%. These two reports are based on relatively small series and have consisted of very highly selected patient samples. In our own recent experience, several cases of dementia have yielded unexpected neuropathologic findings,18 and we hypothesized that, in larger series, there would be a significant number of discrepancies between clinical diagnoses and autopsy findings. The present paper reviews the neuropathologic diagnosis of 54 demented patients who were autopsied consecutively at the University of Pittsburgh over a 7-year period, and reports the ability of clinicians to predict autopsy findings.

 

Material and methods. We independently reviewed the pathologic data and clinical records of 54 consecutive patients who had had an autopsy at the University of Pittsburgh (Presbyterian University Hospital [PUH] and the Pittsburgh (University Drive) Veterans Administration Medical Center [VAMC]), between 1980 and 1987.

 

The 54 cases included all those where dementia was diagnosed clinically but for which an obvious etiology, such as neoplasm, trauma, major vascular lesions, or clinically evident infection had not been found. The brains, evaluated by the Division of Neuropathology of the University of Pittsburgh, were obtained from patients cared for in different settings at their time of death.

 

On the basis of the amount of information available in each case, we divided the patients into three groups. Group 1 included 12 subjects who had been followed for a minimum of 1 year by the Alzheimer Disease Research Center (ADRC) of the University of Pittsburgh. ADRC evaluations include several visits and neurologic and neuropsychological testing as well as repeated laboratory tests, EEG, and CT.19,20

 

Group 2 included 28 patients who had been seen in the Neurology Service of PUH, of the VAMC, or in geriatric or psychiatric facilities of the University of Pittsburgh or at Western Psychiatric Institute and Clinic. All patients were personally evaluated by a neurologist and received a work-up to elucidate the etiology of their dementia.

 

Group 3 included 14 patients seen in other institutions; in most cases, they had also been seen by a neurologist and had had laboratory studies that included CT of the head. In three of the 14 cases, however, the information could be gathered only from the clinical summary found in the autopsy records.

 

Many of these subjects were referred for autopsy to the ADRC because of a public education campaign that encourages families to seek an autopsy for their relatives with dementia.

 

Pathologic data. All brains were removed by a neuropathologist as the first procedure of the autopsy at postmortem intervals of between 4 and 12 hours. The unfixed brain was weighed and the brainstem and cerebellum were separated by intercollicular section. The cerebral hemispheres were sectioned at 1-cm intervals and placed on a glass surface cooled by ice to prevent adhesion of the tissue to the cutting surface. The brainstem and cerebellum were sectioned in the transverse plane at 6-mm intervals. Brain sections were fixed in 10% buffered formalin. Selected tissue blocks for light microscopy were obtained from sections corresponding as exactly as possible to a set of predetermined areas used for processing brains for the ADRC protocol; additional details of the neuropathologic protocol have been previously published.18,21 Following standard tissue processing and paraffin embedding, 8-um-thick sections stained with hematoxylin and eosin and with the Bielschowsky ammoniacal silver nitrate impregnation were evaluted. Additional stains were used when indicated by the survey stains, including the Bielschowsky silver technique as previously reported.21

 

Clinical data. The medical history, as well as the results of examinations and laboratory tests, were obtained from the medical records libraries of the institutions where the patient had been followed and had died. We supplemented these data, when appropriate, with a personal or telephone interview with the relatives.

 

One neurologist (O.L.L.) recorded the information to be evaluated on two forms. The first form included sex, age, handedness, age at onset, age at death, course and duration of the disease, education, family history, EEG, CT, NMR, medical history, and physical examination as well as examination of blood and CSF for factors that could affect memory and other cognitive functions. The form also listed the results of neuropsychological assessment, and the characteristics and course of psychiatric and neurologic symptoms. The form provided details on the presence, nature, and course of cognitive deficits and neurologic signs. The second form was a 26-item checklist derived from the NINCDS-ADRDA Work Group Criteria for probable Alzheimer's disease.2 The forms did not include the patient's identity, the institution where they had been evaluated, the clinical diagnosis, or the pathologic findings.

 

Each form was reviewed independently by two other neurologists (F.B. and J.M.), who were asked to provide a clinical diagnosis. In cases of probable or possible AD, the two neurologists followed the diagnostic criteria of the NINCDS/ ADRDA work group.2

 

The results were tabulated on a summary sheet filled out after the two neurologists had provided their diagnosis on each case. The sheet included the diagnosis reached by the two neurologists and the diagnosis resulting from the autopsy.

 

Table 1. Pathologic diagnosis in 54 patients with dementia

 

 N %

 

Alzheimer's disease alone 34 62.9

 

Alzheimer's disease and 2 3.7 Parkinsons's disease

 

Alzheimer's disease with 2 3.7 multi-infarct dementia

 

Alzheimer's disease with amyotrophic lateral sclerosis 39 72.2

 

Total Alzheimers disease 39 72.2

 

Multi-infarct dementia 4 7.4

 

Multi-infarct dementa 1 1.8 with Parkinson's disease

 

Parkinson's disease 2 3.7

 

Progressive subcortical gliosis 2 3.7

 

Creutzfeldt-Jakob disease 3 5.5

 

Progressive supranuclear palsy 1 1.8

 

Huntington's disease 1 1.8

 

Unclassified 1 1.8

 

Total other disease 15 27.7

 

Total all cases 54

 

Table 2. Clinical diagnosis

 

Clinical diagnosis Clinician #1 --- #2

 

Probable AD 29 21

 

Probable AD and MID 3 0

 

Probable AD and thyroid disease 1 2

 

Probable AD and PD 3 1

 

Probable AD and ALS 1 0

 

Probable AD and 0 1 olivopontocerebellar degeneration

 

Total probable AD 37 25 (68.5%) (46.2%)

 

Possible AD 3 2

 

Possible AD and MID 2 2

 

Possible AD and alcoholism 0 1

 

Possible AD and depression 1 0

 

Possible and thyroid disease 0 3

 

Possible AD and traumatic 1 2 encephalopathy

 

Possible AD and PD 3 6

 

Total Possible AD 10 16 (18.5%) (29.6%)

 

Atypical AD 0 1

 

Atuypical AD and MID 0 1

 

MID 2 4

 

MID and PD 3 0

 

Dementia syndrome of depression 0 1

 

HD 1 1

 

Wernicke-Korsakoff syndrome 1 0

 

Dementia of unknown etiology 0 5

 

Total 54 54

 

Results. The subjects included 26 women and 28 men who ranged in age from 30 to 91 years (mean, 72.2; SD, 10.7).

 

Autopsy findings. Table 1 shows that 39 (72.2%) of the 54 cases fulfilled histologic criteria for AD, with or without other histopathologic findings. The remaining 15 cases (27.7%) showed changes corresponding to other neurodegenerative disorders, cerebrovascular disease, or Creutzfeldt-Jakob disease (CJD). Seven cases met the histopathologic criteria for multi-infarct de­mentia (MID). Five cases (9.2%) showed changes associated with Parkinson's disease (PD).

 

Twenty-two of the 39 AD patients (56%) were age 65 or greater at the time of the onset of the disease. Seven of the 15 patients in the group with other diseases (47%) were age 65 or older at the time of disease onset.

 

Clinical diagnosis. There was a general adherence to the criteria specified by McKhann et al.2 However, the two clinicians in this study considered the diagnosis of probable AD when the probability of AD was strong even if a patient had another disease potentially associated with dementia that might or might not have made some contribution to the patient's clinical state (table 2).

 

Accuracy of the clinical diagnosis (table 3). Group 1 (N = 12). There were six men and six women. Ten cases (83.3%) met the histologic criteria for AD. In nine cases (75.0%), the diagnosis of both clinicians agreed with the pathologic findings; in the other case (8.3%), one clinical diagnosis agreed with the histologic findings. The remaining two cases (16.6%) had histopathologic diagnoses of CJD and progressive supranuclear palsy (PSP), respectively. Both cases were incorrectly diagnosed by both clinicians.

 

Group 2 (N = 28). There were 11 women and 17 men. Eighteen cases (64.2%) had the histopathologic features for AD with or without additional findings. Sixteen of these cases (57.1%) were correctly diagnosed by both clinicians, one case by one of them, and both incorrectly diagnosed one case. The remaining ten cases (35.7%) included two with CJD; two with subcortical gliosis (SG); two with PD, one of which was associated with MID; one case of Huntington's disease (HD); two cases with MID; and one unclassifed. Only one, the HD case (3.5%), was correctly diagnosed by both observers, and four cases (14.2%), two MID and two PD, one associated with MID, were correctly diagnosed by one clinician.

 

Group 3 (N = 14). In this group there were nine women and five men. Eleven cases (78.5%) met the histopathologic criteria for AD with or without additional findings. Eight of these cases (57.1%) were correctly diagnosed by both clinicians, two cases by one of them, while both were incorrect in one case. Of the remaining three cases (21.4%), only one was correctly diagnosed (7.1%) by one clinician. Both missed the two other cases of MID.

 

There was no statistically significant difference in diagnostic agreement across patient groups in which the amount of clinical information was different (X2 = 1.19; p > 0.05).

 

Table 3. Accuracy of the clinical diagnosis by two clinicians

 

 Both One Neither Correct Correct Correct

 

Group 1 (N = 12) 9 1 2(16.6%)

 

Group 2 (N = 28) 17 5 6(21.4%)

 

Group 3 (N = 14) 8 3 3(21.4%)

 

Table 4. Previously reported studies of clinicopathologic correlation in demented patients*

 

 Agreement %

 

 Number of cases AD

 

Retrospective studies

 

Todorov et al, 1975(7) 776 43

 

Perl et al, 1984(9) 26 81

 

Wade et al, 1987(12) 65 85

 

Alafuzoff et al, 1987(13) 55 63

 

Kokmen at al, 1987(14) 32 72

 

Joachim et al, 1987(15) 150 87

 

Prospective studies

 

Sulkava et al, 1983(8) 27 82

 

Molsa et al, 1985(10) 58 71

 

Neary et al, 1986(11) 24 75

 

Martin et al, 1987(16) 11 100

 

Morris et al, 1987(17) 25 100

 

* Certain differences in methodology need clarification. Some authors7,8,10,11,12,13,16,17 tabulated patients with AD alone, and others9,14,15 included patients with AD plus other diseases, eg, Parkinson's disease and MID. We have combined AD alone and AD plus MID and other neurodegenerative diseases.

 

Discussion. Our results indicate that in a population of patients with dementias of varied etiology, the diagnosis could be correctly inferred by at least one of two clinicians in approximately 80% of cases. For one observer, the sensitivity of clinical diagnosis for AD was 85% and the specificity was 13%, and for the other, it was 95% and 33% respectively.

 

In the cases with a discrepancy between the clinical diagnosis and the neuropathologic findings, the great majority of patients had atypical clinical courses and findings. The three cases with autopsy findings of CJD had a much longer course than is usually seen with that condition and failed to show the usual EEG abnormalities. The patient with autopsy findings of PSP did not show the disorder in the extraocular movements usually associated with that condition. An atypical course was also present for two AD cases and two MID cases that did not have any feature suggestive of vascular disease. In one MID case, the CT did not show any focal lesions, while in the other it was not available. With regard to the two patients with SG, the pathologic diagnosis is so unusual and so infrequently recorded that clear clinical correlates are not evident.18 The third category of possible error is the patient listed as unclassified, for whom no specific neuropathologic diagnosis could be reached.22

 

The small number of neuropathologic diagnoses of Parkinson's disease reflects that, for the purpose of this series, the diagnosis of PD was made only when there were both a clear-cut clinical history and the neuropathologic findings characteristic of the disease, such as Lewy bodies, neuronal loss, globose neurofibrillary tangles, astrocytosis, and extraneuronal melanin pigment in substantia nigra and locus ceruleus.

 

Are these results derived from a sample of 54 patients representative of disease patterns in the community? Generally, the diagnosis of patients reported from major medical centers tend to be biased since the more complicated cases are referred there. In this study, however, this bias may be less important. Due to the major public education campaign about dementia and AD sponsored by the ADRC, there is a widespread awareness in Pittsburgh and in the surrounding regions of Western Pennsylvania of the value of an autopsy for a definitive diagnosis. Therefore, the great majority of cases were referred to us because the family wanted to know the precise etiology of a case of dementia.

 

The significant improvement in the clinical diagnosis of AD is a recent phenomenon. Due to the publicity and the advances in communication of scientific investigations, most physicians are more likely to consider AD as the main cause of dementia. The current risk of overdiagnosing AD reminds one of what occurred during the 1960s with the diagnosis of "atherosclerotic dementia."6 The high sensitivity and low specificity for AD shown in our study may reflect that possibility.

 

Because of the varying criteria for "other dementias" in many publications, we chose to analyze the accuracy of clinical diagnosis in terms of the diagnosis of AD alone or AD plus other neuropathologic findings. Several retrospective studies have attempted to point out reliable clinical and pathologic features for diagnosing the dementias, especially AD. The study of Tomlinson et al6 is not included in table 4 because there was no attempt to validate the clinical diagnosis with pathologic findings. The reports surveyed vary considerably in size and methodology. Sample size, for example, ranges from 26 subjects9 to 776 subjects.7 Some studies base the diagnosis on limited clinical information,7'9'14'15 others use widely accepted diagnostic criteria such as those specified in DSM III,13 and one group uses a standardized clinical assessment of patients enrolled in a longitudinal study.12 The reported accuracy of the clinical diagnosis of AD ranges from 43%7 to 87%.15

 

Recent prospective studies that adhere to strict clinical criteria,10'11'17 those in DSM III8 or those proposed by McKhann et al,16 indicate improved accuracy of clinical diagnosis of the most common causes of dementia, especially AD. In sample sizes ranging from 11 subjects16 to 58 subjects,l0 the accuracy of clinical diagnosis is reported as ranging from 71%10 to 100%16'17' Only two series, both based on small samples, report a 100% accuracy. We consider it unlikely that such accuracy could be confirmed in large series because of some inevitable imprecision in clinical diagnoses and the variability of clinical pictures. Furthermore, although researchers generally agree on the application of uniform criteria in clinical diagnosis of dementia, opinions still differ about specific diagnostic criteria, as well as about the pathologic characterization of dementia. Except for those small series, the results summarized in table 4(7-15) is are remarkably consistent with ours.

 

In table 3, although there was no statistical difference (p > 0.05) in diagnostic agreement across patient groups, there is a trend toward a lower percentage of diagnostic errors for the patients who had been followed most intensely (16% in group 1 compared with 21% in groups 2 and 3). The difference is not great, and it is, in fact, surprising to find out that in the patients about whom relatively little was known (group 3) the percentage of diagnostic error was the same as among patients seen by neurologists and for whom much more data were available (group 2). These paradoxical findings probably indicate that both clinicians learned to extract essential diagnostic criteria2 in spite of the variations in the amount of information available for consideration. It may well be that clinical, radiographic, and laboratory assessment of patients with dementia is burdened with information that is excessive and unessential for purely diagnostic purposes.

 

Acknowledgments

 

We thank Dr. A. Julio Martinez and Dr. Gutti Rao from the Division of Neuropathology for autopsy data. Mrs. Margaret Forbes, Ms. Annette Grechen, and Mrs. Paula Gent helped in the preparation of the manuscript.

 

References

 

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Organic Dementia Disorders, 3rd ed. Washington DC, APA, 1983:101-161.

 

2. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Dis­ease. Neurology 1984;34:939-944.

 

3. Khachaturian Z. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105.

 

4. Cummings J, Benson F. Dementia: a clinical approach, 1st ed. Boston: Butterworths, 1983.

 

5. Rosen WG, Terry R, Fuld P, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980;7:486-488.

 

6. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11.205-242.

 

7. Todorov A, Go R, Constantinidis J, Elston R. Specificity of the clinical diagnosis of dementia. J Neurol Sci 1975;26:81-98.

 

8. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983;46:9-13.

 

9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua­tion of banked brain specimens submitted with clinical diagnosis of Alzheimer's disease. In: Wirtman R, Corkin S, Growdon J, eds. Alzheimer's disease: advances in basic research and therapies. Proceedings of the Fourth Meeting of International Study Group on the Treatment of Memory Disorders Associated with Aging. Zurich, January 1984. Cambridge, MA: CBSM, 1984:463. Molsa PK, Paljarvi L, Rinne JO, Rinne UK, Sako E. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 1985;48:1085-1090.

 

11. Neary D, Snowden JS, Bowen D, et al. Neuropsychological syn­dromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986;49:163-174.

 

12. Wade J, Mirsen T, Hachinski V, Fismm~ M, Lau C, Merskey H. The clinical diagnosis of Alzheimer disease. Arch Neurol 1987;44:24-29.

 

13. Alafuzoff I, Igbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinicalpathological correlation and classification by multivariate data analysis. Acta Neuropathol (Berl) 1987,74:209-225.

 

14. Kokmen E, Offord K, Okazaki H. A clinical and autopsy study of dementia in Olmsted County, Minnesota, 1980-1981. Neurology 1987;37:426-430.

 

15. Joachim CL, Morris JH, Selkoe D. Clinically diagnosed Alzheimer's disease: autopsy neuropathological results in 150 cases. Ann Neurol 1988;24:50-56.

 

16. Martin EM, Wilson RS, Penn RD, Fox JH, Clasen RA, Savoy SM. Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits. Neurology 1987;37:1201-1204.

 

17. Morris JC, Berg L, Fulling K, Torack RM, McKeel DW. Validation of clinical diagnostic criteria in senile dementia of the Alzheimer type. Ann Neurol 1987;22:122.

 

18. Moossy J, Martinaz J, Hanin I, Rao G, Yonas H, Boiler F. Thalamic and subcortical gliosis with dementia. Arch Neurol 1987;44:510-513.

 

19. Huff J, Becker J, Belle S, Nebes R, Holland A, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology 1987;37:1119-1124.

 

20. Huff J, Boiler F, Lucchelli F, Querriera R, Beyer J, Belle S. The neurological examination in patients with probable Alzheimer's disease. Arch Neurol 1987;44:929-932.

 

21. Moossy J, Zubenko G, Martinez AJ, Rao G. Bilateral symmetry of morphologic lesions in Alzheimer's disease. Arch Neurol 1988;45:251-254.

 

22. Heilig CW, Knopman DS, Mastri AR, Frey W II. Dementia without Alzheimer pathology. Neurology 1985;35:762-765.

 

From the Departments of Neurology (Drs. Boller, Lopez, and Moossy), Psychiatry (Dr. Boller), Pittsburgh (University Drive) Veterans Administration Medical Center (Dr. Boller), Department of Pathology (Division of Neuropathology) (Dr. Moossy), and the Pittsburgh Alzheimer Disease Research Center (Drs. Boller, Lopez, and Moossy), University of Pittsburgh Medical School, Pittsburgh, PA.

 

Supported in part by NIH Grants nos. AG05133 and AG03705, NIMH Grant no. MH30915, by funds from the Veterans Admin., and by the Pathology Education and Research Foundation (PERF) of the Department of Pathology, University of Pittsburgh.

 

Presented in part at the fortieth annual meeting of the American Academy of Neurology, Cincinnati. OH, April 1988.

 

Received April 7, 1988. Accepted for publication in final form July 20, 1988.

 

Address correspondence and reprint requests to Dr. Boller, Department of Neurology, 322 Scaife Hall, University of Pittsburgh Medical School, Pittsburgh, PA 15261.

 

January 1989 NEUROLOGY 39 79

 

TSS

 

==============

 

From: TSS (216-119-130-151.ipset10.wt.net)

 

Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

 

Date: May 8, 2001 at 6:27 pm PST

 

 Subject: Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

 

Date: Tue, 8 May 2001 21:09:43 –0700

 

From: "Terry S. Singeltary Sr."

 

Reply-To: Bovine Spongiform Encephalopathy

 

To: BSE-L@uni-karlsruhe.de

 

 ######### Bovine Spongiform Encephalopathy #########

 

Evaluation of Cerebral Biopsies for the Diagnosis of Dementia

 

Christine M. Hulette, MD; Nancy L. Earl, Md; Barbara J. Crain, MD, Phd

 

· To identify those patients most likely to benefit from a cerebral biopsy to diagnose dementia, we reviewed a series of 14 unselected biopsies performed during a 9-year period (1980 through 1989) at Duke University Medical Center, Durham, NC. Pathognomonic features allowed a definitive diagnosis in seven specimens. Nondiagnostic abnormalities but not diagnostic neuropathologic changes were seen in five additional specimens, and two specimens were normal. Creutzfeldt-Jakob disease was the most frequent diagnosis. One patient each was diagnosed as having Alzheimer's disease, diffuse Lewy body disease, adult-onset Niemann-Pick disease, and anaplastic astrocytoma. We conclude that a substantial proportion of patients presenting clinically with atypical dementia are likely to receive a definitive diagnosis from a cerebral biopsy. However, in those with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs, cerebral biopsies are less likely to be diagnostic. (Arch Neurol. 1992;49:28-31)

 

"Dementia" is a syndrome characterized by global deterioration of cognitive abilities and is the general term used to describe the symptom complex of intellectual deterioration in the adult. It is associated with multiple causes, although Alzheimer's disease (AD) alone accounts for approximately 60% of cases.1-3

 

Interest in the accuracy of the diagnosis of dementia is a relatively recent phenomenon, reflecting both an increase in physicians' awareness of multiple specific causes of dementia and a marked increase in both the incidence and prevalence of dementia associated with the increase in the elderly population.4' The clinical evaluation remains the key to the differential diagnosis, and in most cases dementia can be diagnosed accurately by clinical criteria. However, the definitive diagnoses of AD.1'5'7 Pick's disease,8'10 Creutzfeldt-Jakob disease (CJD),11-16 Binswanger's disease,17'18' and diffuse Lewy body disease19-22 still require histologic examination of the cortex to identify characteristic structural changes.

 

Brain tissue is almost invariably obtained at autopsy, and the vast majority of pathologic diagnoses are thus made post mortem. Alternatively, an antemortem histologic diagnosis can be provided to the patient and his or her family if a cerebral biopsy is performed while the patient is still alive. Because brain biopsies for dementia are not routinely performed, we sought to define the spectrum of pathologic changes seen in a retrospective unselected series of adult patients undergoing cerebral biopsy for the diagnosis of atypical dementing illnesses and to determine the patient selection criteria most likely to result in a definitive diagnosis.

 

MATERIALS AND METHODS

 

Cerebral biopsies performed solely for the diagnosis of dementia in adult patients were identified by a manual search of the patient files of the Division of Neuropathology, Duke University Medical Center Durham, NC, and by a computerized search of discharge diagnoses of patients undergoing brain biopsies. Fourteen cases were identified from the period 1980 to 1989. Patients undergoing biopsies for suspected tumor, inflammation, or demyelinating disease were excluded. A clinical history of dementia was an absolute requirement for inclusion in the study. Diagnosis was based on Dignostic and Statistical Manual of Mental Disorders, Third Edition, and on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for probable AD.23

 

The published recommendations for handling tissue from patients with suspected CJD were followed in every case.24-26 Briefly, tissue was transported in double containers clearly marked "Infectious Disease Precations." Double gloves, aprons, and goggles were used at all times. Tissue was fixed in saturated phenol in 3.7% phosphate-buffered formaldehyde for 48 hours25 and subsequently hand processed for paraffin embedding. At least 1 cm(to 3 power) of tissue was available for examination from each patient, except for patient 7, who underwent bilateral temporal lobe needle biopsies. Patient 14 underwent biopsy of both frontal and temporal lobes.

 

One paraffin block was prepared for each biopsy specimen, and sections were routinely stained with hematoxylin-eosin, luxol fast blue, Congo red, alcian blue, periodic acidSchiff, and modified King's silver stain27 in every ease, except for case 7, in which the diagnosis was made by frozen section. Portions of both gray and white matter were primarily fixed in glutaraldehyde and embedded in epoxy resin (Epon). Tissue was examined by electron microscopy if abnormalties, such as neuronal storage or other inclusions, were seen in routine paraffin sections.

 

Khachaturian's5 National Institute of Neurological and Communicative Disorderers and Stroke/ADRDA criteria for quantitation of senile plaques and the diagnosis of AD were used in all cases after 1985. At the time of our, study, these criteria were also applied retrospectively to cases accessioned before 1985. No attempt was made to grade the severity of other abnormalities (eg, gliosis and spongiform change), and the original pathologic diagnoses were not revised.

 

RESULTS

 

The clinical presentations, biopsy findings, and follow-up data, including postoperative complications, are summarized in Table 1 for all 14 patients. Their bipsy findings are summarized in Table 2.

 

The ages of this unselected group of 14 patients who underwent cerebral biopsies for dementia ranged from 32 to 78 years (mean, 51.6 years). There were seven men and seven women. Duration of symptoms ranged from 1 month to 6 years (mean, 2.3 years). No differences were noted between the group with diagnostic biopsies (cases 1 through 7) and the group with nondiagnostic biopsies (cases 8 through 14) with regard to age at the time of biopsy or duration of symptoms. However, five of seven patients in the nondiagnostic group had hemiparesis, chorea, athetosis, or lower motor neuron signs. None of these findings was present in the patients with diagnostic biopsies. Visual disturbances, abnormal eye movements, and ataxia were present in four of seven cases with diagnostic biopsies but were absent in the group with nondiagnostic biopsies.

 

In this series of 14 patients, two experienced postoperative complications, one of which was severe. Patient 2 developed an intraparenchymal parietal cortex hemorrhage and was mute after biopsy. Patient 9 developed a subdural hygroma that was treated uneventfully.

 

Eight patients died 1 month to 9 years after biopsy. An autopsy was performed in five of these eight patients. One of these patients (patient 4) had a firm diagnosis of presenile AD on biopsy, which was confirmed at autopsy. Patient 3 had a biopsy diagnosis of CJD, which was also confirmed at autopsy. Two patients with only white-matter gliosis diagnosed at biopsy had autopsy diagnoses of amyotrophic lateral sclerosis with dementia (patient 8) and CJD (patient 9). One patient in whom a biopsy specimen appeared to be normal had Huntington disease identified at autopsy (patient 14). At the time of this writing, four patients are still alive, two are in clinically stable condition 1 to 2 years after biopsy, and two are severely demented 2 to 3 years after biopsy. Two patients (one with a definite and one with a possible diagnosis of CJD) have been unavailable for follow-up.

 

COMMENT Our study of patients presenting with atypical dementia reaffirms the diagnostic utility of cerebral biopsy. In selected cases, cerebral biopsy results in a high yield of definitive diagnostic information. A wide variety of disorders may be encountered, including CJD, AD, diffuse Lewy body disease, and storage disorders, such as Niemann-Pick disease.28-30 The diagnosis of Niemann-Pick disease type C was confirmed by assay of cholesterol esterification in cultured fibroblasts31'32' with markedly abnormal results in one patient, who was described in detail elsewhere.33

 

One example of an unsuspected anaplastic astrocytoma (case 7) was also encountered. This case was unusual in light of currently used sensitive imaging techniques. This patient may have been suffering from gliomatosis cerebri.

 

Table 1.--Summary of Clinical Presentation and Course*

 

Case/Age,y/Sex

 

Duration of Symptoms, y

 

Clincial Findings

 

Biopsy

 

Follow-up ==========

 

1/60/F

 

0.1

 

Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral synchronous discharges

 

CJD

 

Unavailable ==========

 

2/57/M

 

0.4

 

Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal EEG

 

CJD

 

Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy ==========

 

3/59/M

 

2

 

Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic sharp waves

 

CJD

 

Dead at 61 y, autopsy showed CJD =========

 

4/32/M

 

1

 

Dementia, myclonus, ataxia, family history of early-onset dementia

 

AD

 

Dead at 40 y, autopsy showed AD =========

 

5/78/M

 

6

 

Dementia, paranoia, agitation, rigidity

 

Diffuse Lewy body disease

 

Dead at 78 y, no autopsy =========

 

6/37/F

 

6

 

Dementia, dysarthria, abnormal eye movements, ataxia

 

Neuronal storage disorder, adultonset N-P type II

 

Stable at 39 y =========

 

7/58/F

 

0.3

 

Dementia, amnesia, depression, partial complex seizures

 

Anaplastic astrocytoma

 

Dead at 58 y, no autopsy ==========

 

8/37/M

 

2

 

Dementia, dysarthria, upper-extremity atrophy and fasciculations

 

Gliosis

 

Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter gliosis =========

 

9/45/F

 

2

 

Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis

 

Gliosis

 

Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD =========

 

10/56/F

 

2

 

Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic sharp waves

 

Consistent with CJD

 

Unavailable ==========

 

11/60/F

 

2

 

Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic resonance image showing small vessel disease

 

Plaques, gliosis

 

stable at 61 y =========

 

12/52/F

 

2

 

Dementia, aphasia, right-sided hemiparesis

 

Gliosis

 

Bedridden, severely demented at 54 y =========

 

13/40/M

 

0.5

 

Dementia, mild bifacial weakness, concrete thinking, altered speech

 

Normal

 

Stable at 41 y =========

 

14/52/M

 

6

 

Dementia, choreoathetosis, family history of senile dementia, computed tomographic scan showing normal caudate

 

Normal

 

Dead at 61y, autopsy showed Huntington's disease, grade II/IV ========== * EEG indicates electroencephalogram; CJD, Creutzfeldt-Jakob disease; AD, Alzheimer's disease; and N-P, Niemann-Pick disease.

 

Table 2.--Pathologic Findings at Biopsy *

 

Case Site of Biopsy Type of Biopsy Tissue Examined Spongiform Change Neuritic Plaques per X 10 Field Tangles White Matter Gliosis Other

 

1 R temporal Open 1 cm3 + 0 0 0 0 =====

 

2 L temporal Open 1 cm3 + 0 0 0 0 =====

 

3 R temporal Open 1 cm3 + 0 0 0 0 =====

 

4 R frontal Open 1 cm3 0 >100 + + Amyloid angiopathy =====

 

5 R temporal Open 1 cm3 0 9 0 0 Lewy bodies =====

 

6 R temporal Open 1 cm3 0 0 0 0 Neuronal storage =====

 

7 R temporal/L temporal Needle/needle 1 X 0.3 X 0.3 cm / 1 X 0.3 X 0.1 cm 0/0 0/0 0/0 +/0 0/anaplastic astrocytoma =====

 

8 R frontal Open 1 cm3 o o o + 0 =====

 

9 L parietal Open 1 cm3 0 0 +/- + 0 =====

 

10 R temporal Open 1 cm3 +/- 0 0 0 0 =====

 

11 L temporal Open 1 cm3 0 23 0 + 0 =====

 

12 L temporal Open 1 cm3 0 0 0 + 0 =====

 

13 r frontal Open 1 cm3 0 0 0 0 0 =====

 

14 L temporal/L frontal Open/open 1 cm3/ 1 cm3 0/0 0/0 0/0 0/0 0/0 ===== * Plus sign indicates present; zero, absent; and plus/minus sign, questionably present

 

Positron emission tomography showed multiple areas of increased uptake, even though the magnetic resonance image was nondiagnostic and showed only subtle increased signal intensity on review. Bilateral temporal lobe needle biopsies yielded abnormal findings. Biopsy of the right side showed only reactive gliosis, which may have been adjacent to tumor. Biopsy of the left side, performed 3 days later, was diagnostic for anaplastic astrocytoma. Unfortunately, permission for an autopsy was refused, and complete evaluation of the underlying pathologic process thus must remain speculative.

 

The high incidence of definite and probable CJD in our series indicates that it is imperative that appropriate precautions are taken to prevent the transmission 0f disease to health care workers when biopsy tissue from patients with dementia is handled.24-26

 

At our institution, cerebral biopsy for the diagnosis of dementia is reserved for patients with an unusual clinical course or symptoms that cannot be diagnosed with sufficient certainty by other means. In most instances, cerebral biopsy is unnecessary and is clearly not a procedure to be proposed for routine diagnostic evaluation. In all cases, extensive clinical, metabolic, neuropsychological and radiologic evaluations must be performed before cerebral biopsy is considered. In addition, preoperative consultations among neurologists, neurosurgeons, neuroradiologists, and neuropathologists are necessary to ascertain the optimal biopsy site given the clinical data to ensure that maximal infornmtion is derived from the biopsy tissue.

 

An optimal biopsy specimen is one that is taken from an affected area, handled to eliminate artifact, and large enough to include both gray and white matter.34 Open biopsy is generally preferred because it is performed under direct visualization and does not distort the architecture of the cerebral cortex. This method also provides sufficient tissue (approximately 1 cm3) to perform the required histologic procedures.

 

Some physicians question the utility of diagnostic cerebral biopsies in dementia, stating that the procedure is unlikely to help the patient. While it is frequently true that the diagnoses made are untreatable with currently available therapeutic modalities, this is by no means universally true. Kaufman and Catalano35 noted that cerebral biopsy has revealed specific treatable illnesses, such as meningoencephalitis and multiple sclerosis. Our patient with anaplastic astrocytoma (patient 7) underwent radiation therapy, although she quickly died of her disease. Furthermore, when a definitive diagnosis can be made, even of incurable illnesses, such as CJD and AD, it is often possible to give an informed prognosis to the family and to help them plan for the future.

 

The formulation of indications, for diagnostic cerebral biopsy raises difficult and complex issues. In 1986, Blemond36 addressed the clinical indications and the legal and moral aspects of cerebral biopsy, and his recommendations remain valid today: (1)The patient has a chronic progressixe cerehral disorder with documented dementia. (2) All other possible diagnostic methods have already been tried and have failed to provide sufficient diagnostic certainty. (3) The general condition of the patient permits cerebral biopsy. (4) Several specialists are in agreement regarding the indication. (5) Informed consent is obtained from relatives. (6) Modern diagnostic tools, such as immunocytochemistry and electron microscopy, are used to the fullest capacity in the examination of the material obtained.

 

As with any intracranial surgical procedure involving the cerebral cortex, the risks of cerebral biopsy include anesthetic complications, hemorrhage, infections, and seizures. Guthkelch37 stated that the mortality associated with brain biopsy is not greater than that associated with general anesthesia. Cerebral biopsy, however can result in substantial morbidity. In our series, two of 14 patients suffered operative complications, intraparenchymal hemorrhage in one patient (patient 2) resulted in aphasia, while another patient (patient 10) developed a subdural hygroma, which was successfully treated, and recovered her baseline status.

 

The current diagnostic accuracy of cerebral biopsy in the evaluation of dementia is unknown. Most of the larger general series 34'38-41 were reported before computed tomography was available and included many pediatric cases presenting with genetic neurodegenerative disorders that are now more readily diagnosed by other means. For adults with dementia, less information is available. Katzman et al4 recently reviewed the literature concerning the diagnostic accuracy of cerebral biopsy for dementia and concluded that 75% of these procedures result in diagnostic material. Patient selection is very important, and the literature is heavily weighted toward patients with a clinical diagnosis of AD.35'42-44 Our study thus provides documentation of the diagnostic accuracy of cerebral biopsies in unselected patients with atypical dementia.

 

Autopsy follow-up is imperative in any dementia program,2 as a definitive diagnosis will not be made in a substantial proportion of patients. In our series, three patients died without a diagnosis, and autopsy was performed in all three. The diagnostic features were not present in the cortical area in which the biopsy was performed. In case 8, examination of the spinal cord revealed amyotrophic lateral sclerosis. Diffuse gliosis of the white matter was noted, which was the pathologic basis of the patient's dementia. In case 9. the spongiform change of CJD was focal, according to the pathologist's report; unfortunately, the tissue was not available for our review. In case 14, the diagnosis of Huntington's disease grade II/IV was made after close examination of the caudate nucleus. As one might predict, fewer autopsies were performed in the group with diagnostic biopsies; only two of five deaths in this category were followed by postmortem examinations. The diagnosis of AD was confirmed in case 4. In ease 3, the biopsy diagnosis of CJD was confirmed.

 

In summary, a series of 14 unselected cerebral biopsies performed for the diagnosis of atypical dementia was reviewed to define the spectrum of pathologic changes seen and to estimate the likelihood of obtaining diagnostic tissue. Histologic diagnoses of CJD, AD, diffuse Lewy body disease, Niemann-Pick disease type C, or anaplastic astrocytoma were made in seven patients. The high incidence of CJD in this population (four of 14 cases) emphasizes the need to use appropriate precautions when tissue from patients with unusual dementing illnesses is handled. Consultation among neurologist, neurosurgeons, neuroradiologists, and neuropathologists is essential to select appropriate patients and to choose the proper biopsy site. Demented patients with coexisting hemiparesis, chorea, athetosis, or lower motor neuron signs are unlikely to benefit from cortical biopsy.

 

This investigation was supported by Clinical Investigator Award PHS AG-00446 from the National Institute on Aging (Dr. Hulette) and by grant PHS SP50AG05128-03 from the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (Drs Earl and Crain). Dr Hulette is a College of American Pathologists Foundation Scholar, Northfield, Ill.

 

The Authors thank Ms Bonnie Lynch and Ian Sutherland, PhD, for thier assistance.

 

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2. Jellinger K, Danielczyk W, Fischer P, Gabriel E. Clinicopathological analysis of dementia disorder's in the elderly, J Neurol Sci. 1990:95:239-258.

 

3. Katzman R. Alzheimer's disease. N Engl J Med. 1986;314:964-973.

 

4. Katzman R, Lasker B, Bernstein N. Advances in the diagnosis of dementia: accuracy of diagnosis and consequences of misdiagnosis of disorders causing dementia. In: Terry RD ed. Aging and the Brain. New York, NY: Raven Press; 1988: 17-62.

 

5. Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol. 1985;42;1097-1105.

 

6. Koranyi E. The cortical dementias. Can J Psychiatry 1988;33;838-845.

 

7. Wilcock GK, Hope RA, Brooks DN, et al. Recommended minimum data to be collected in research studies on Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1989;52;693-700

 

8. Esiri MM, Oppenheimer DR. Diagnostic neuropathology. Boston, Mass: Blackwell Scientific publications Inc; 1989;236-239.

 

9. Sim M, Bale RN. Familial pre-senile dementia: the relevance of a histological diagnosis of Pick's disease. Br J Psychiatry. 1973;122;671-673.

 

10. Tomlinson BE, Corsellis JAN. Aging and the dementias, In Adams JH, Cosellis JAN, Duchen LW, eds. Greensfield's Neuropathology. New York, NY: John Wiley & Sons Inc; 1984:951-1025

 

11. F;endheim PE. The hunmn spongitbrm ence-phahq,athies. Ncl~rol Clim 19¥,1:2:281-29¥.

 

12. Brown P, Rodgers-Johnson P, Cathala L, Gibbs CJ, Gajdusek DC. Creutzfeldt-Jakob disease of long duration; clinicopathologic characteristics, Transmissibility and differential diagnosis. Ann Neurol. 1984;16:295-304.

 

13. Davanipour Z, Alter M, Sobel E. Creutzfeldt-Jakob disease. Neurol Clin. 1986:4:415-425.

 

14. Masters CL, Richardson EP: Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease): the nature and progression of spongiform changes. Brain 1978;101:333-344.

 

15. Neatherlin JS. Creutzfeldt-Jakob disease. J Neurosci Nurs. 1988;20:309-313.

 

16. Nochlin D, Sumi SM, Bird TD, et al. Familial dementia with Prp-positive amyloid plaques: a variant of Gerstmann-Straussler syndrome. Neurology. 1989;39;910-918

 

17. Fisher CM. Binswanger's encephalopathy: a review. J Neurol 1989;236;65-79

 

18. Roman GC. Senile dementia of the Bins­wanger type. JAMA. 1987125811782-1788.

 

19. Burkhardt CR, Tilley CM, Kleinschmidt-DeMasters BK, de la Monte S, Norenberg MD, Sehneck SR. Diffuse Lewy hody disease and progressive dementia. Neurology. 1988;38:1520-1528.

 

20. Dickson DW, Davies P, Mayeux R, et al. Diffuse Lewy body disease: neuropathological and biochemical studies of six patients. Acta Neuropathol (Berl). 1987;75:8-15.

 

21. Gibb WRG. Neuropathelogy in movement disorders. J Neurol Neurosurg Psychiatry. 1989:supl:55-67.

 

22. Gibb WRG, Luthert PJ, Janota A. Lantos PL. Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry. 1989;52;185-192.

 

23. MeKhann G. Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimers disease: report of the NINCDS-ADRDA work group. Neurology. 1984;34:939-944.

 

24. Brown P, Gibbs CJ Jr, Gajdusek DC, Cathala F, LaBauge R. Chemical disinfection of Creutzfeldt-Jakob disease virus. N Engl J Med. 1982;306;1279-1282.

 

25. Brumbach RA. Routine use of phenolipid formalin in fixation of autopsy brain tissue reduce risk of inadvertent transmission of Creutzfeldt-Jakob disease. N Engl J Med. 1988;319;654.

 

26. Rosenberg RN, White CL, Brown P, et al. Precautions in handling tissues, fluids and other contaminated materials from patients with documented or suspected Creutzfeldt-Jakob disease. Ann Neurol. 1986;12:75-77.

 

27. Lloyd B, Brinn N, Burger PC. Silver-staining of senile plaques and neurofibrillary change in paraffin-embedded tissues, J Histotech. 1985;8: 155-156.

 

28. Brady RO. Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The Metabolic Basis of Inherited Disease. 5th ed. New York, NY: McGraw-Hill International Book Co; 1983:831-841.

 

29. Cogan DG, Chu FC, Reingold D, Barranger J. Ocular motor signs in some metabolic diseases. Arch Ophthalmol. 1981:99:1802-1808.

 

30. Lake BD. Lysosomal enzyme deficiencies. In: Adams JH, Corsellis JAN, Duchen LW. eds. Greenfield's Neuropathology. 4th ed. New York, NY:John Wiley & Sons Inc; 1984;491-572.

 

31. Pentchev PC. Comly ME, Kruth HS, et al. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82;8247-8251.

 

32. Vanier MT, Wenger DA, Comly ME, Rousson R. Brady RO, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. Clin Genet. 1988;33;331-348.

 

33. Hulette CM, Earl NL, Anthony DC, Crain BJ. Adult onset Niemann-Pick disease type C: a case presenting with dementia and absent organomegaly. Clin Neuropathol. In press.

 

31. Pentchev PC, Comly ME, Kruth HS, et al. A defect in cholesterol esterfication in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82;8247-8251

 

32. Vanier MT, Wenger Da, Comly ME, Rousson R, Brady Ro, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. Clin Genet. 1988;33;331-348

 

33. Hulette CM, Earl NL, Anthony DC, Crain Bj. Adult onset Niemann-Pick disease type C; a case presenting with dementia and absen organomegaly. Cliln Neuropathol. In Press.

 

34. Groves R, Moller J. The value of the cerebral cortical biopsy. Acta Neurol Scand. 1966;42;477-482

 

35. Kaufman HH. Catalano LW. DiaGnostic brain biopsy: a series of 50 cases and a review. NeUROSURGERY. 1979:4:129-136.

 

36. Blemond A. Indications, legal and moral aspects of cerebral biopsies, In: Proceedings of Fifth International Congress of Neuropathology, Zurich, 1965, Princeton, NJ: Excerpta Medica; 1966:372-375.

 

37. Guthkelch AN. Brain biopsy in infancy and childhood. Dev Med Child Neurol, 1968;10;107-109.

 

38. Blackwood W, Cumings JN. The combined histological and chemical aspects of cerebral biopsies. In: Proceeedings of Fifth International Congress of Neuropathology, Zurich, 1965. Princeton, NJ: Excerpta Medica; 1966:364-371.

 

39. Green MA, Stevenson LD, Fonseca JE, Wortis SB. Cerebral biopsy in patients with presenile dementia. Dis Nerv Syst. 1952;13:303-307.

 

40. Sim M, Turner E, Smith WT. Cerebral biopsy in the investigation of presenile dementia, I: clinical aspects, Br J Psychiatry. 1966;112:119-125.

 

41. Turner E, Sim M. Cerebral biopsy in the investigation of presenile dementia, II: pathological aspects, Br J Phychiatry. 1966;112:127-133.

 

42. Bowen DM, Benton JS, Spillane JA. Smith CCT, Allen SJ. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci. 1982;57:191-202.

 

43. Neary D, Snowden JS, Bowen DM, et al. Cerebral biopsy in the investigation of presenile dementia due to cerebral atrophy. J Neurol Neurosury Psychiatry. 1986;49:157-162.

 

44. Neary D, Snowden JS, Mann DMA, et al. Alzheimer's disease: a corelative study. J Neurol Neurosurg Psychiatry. 1986;49:229-237.

 

Cerebral Biopsies in Dementia-- Hulette et al 31

 

Accepted for publication July 11, 1991. >From the Department of Pathology, Division of Neuropathology (Drs Hulette and Crain), the Department of Medicine, Division of Neurology (Dr Earl), and the Department of Neurobiology (Dr. Crain), Duke University Medical Center, Durham, NC.

 

Arch Neurol--Vol 49, January 1992

 

TSS/5/7/01

 

############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############

 

Clinico-Pathological Correlation in Dementias

 

F. TeixeiraI, E. Alonso2, V. Romerol, A. Ortiz', C. Martinez3, E. Otero4 'Departnents of Experimental Neuropathology and 2Genetics, and the 3Division of Psychology and 4Neurology, National Institute of Neurology and Neurosurgery, Mexico City, Mexico

 

Submitted: February 22, 1994

 

Accepted: February 9, 1995

 

The object of this study is to investigate whether or not there are clinical signs and symptoms in patients with dementia that, by themselves or jointly, can be associated with the pathological diagnosis of Alzheimer's disease. Twelve patients with dementia were studied, in whom the clinical diagnosis of Alzheimer's disease was made according to established criteria. A sample of leptomeninges, cortex and subcortical white matter was obtained from each patient and was processed for light and electron microscopy. In the cases in whom neuritic plaques and neurofibrilary tangles were present, pathological changes were quantified. The diagnosis of Alzheimer's disease was confirmed in 5 cases, whereas in 3 patients spongiform encephalopathy was present. In the remaining patients, the number of neuritic plaques was within normal limits for the age of the subjects. Comparison of the data in Alzheimer (n = 5) and non-Alzheimer (n = 7) groups showed an increased, statistically significant incidence of acalculia, abnormalities of judgment, impairment of abstraction and primitive reflexes in the former. Although good fitting models were obtained, none achieved perfect discrimination. The model that included alterations ofjudgment and acalculia gave the best fit.

 

Key Words: Alzheimer's disease, dementia

 

INTRODUCTION

 

Several signs and symptoms have been described extensively in the various diseases that lead to dementia. These symptoms include lack of attention, defective memory, apathy, emotional lability, judgment changes and delirium (Karp and Mirra 1986). Many of these characteristics, as well as electrophysiological changes, are said to be shared by different forms of dementia (McKhann et al 1984). It is the object of this paper to investigate whether or not, in Alzheimer's disease, there is a constellation ofclinical data that will allow the clinician to reach the diagnosis without the aid of a brain biopsy. Address reprint requests to: Dr F Teixeira, Instituto Nacional de Neurologfa y Neurocirugia, Insurgentes Sur, 3877, Mexico 14269, DF, Mexico.

 

METHODS

 

Twelve patients were studied. Because of degeneration of the patient's brain functions, a detailed medical history was obtained from family members. A complete clinical examination was performed, including cranial nerves, tone, reflexes, coordination, gait and proprioception. None ofthese patients had a history or clinical findings suggestive of other causes of dementia such as cerebral infarction, trauma to the head, intracranial neoplasia, substance abuse or systemic or neurological diseases associated with dementia. Neuropsychological examination was designed by the Division of Psychology of the National Institute of Neurology and Neurosurgery so that the exploration could be adapted to the sociocultural level and schooling of the patients. Basic neuropsychological exploration investigated

 

JPsychiatry Neurosci, VoL 20, No. 4, 1995 276

 

Dementia

 

Table 1 Degree of psychological deterioration expressed as percentages Degree of deficit Marked (%) Moderate/slight (%) 77 82 84 100 60 66 100 23 18 16 0 20 28 0 Nil (%) 0% 0% 0% 0 20 6 0

 

Gnosias 66 22 12 R & D): repetition and denomination; I & I: ideomotor and ideatory; VI, P & C: visuomotor integration, perception and coordination. attention, concentration, memory (immediate, recent, remote and learning), language (flow, repetition denomination and comprehension), praxis (ideomotor, ideatory and visuoconstructive) and all modalities of gnosias. Degrees of impairment in each patient were qualified as follows, per different area: 0 = nil, 1 = slight to moderate, and 2 = severe. In 7 patients, a scale was used to assess 5 different aspects of the ability to perform everyday activities: personal hygiene, work, interpersonal relation, motor system (abnormal movements, gait) and memory and visuospacial Qrganization. The scale consists of 100 tests, each one graded as follows: 0 = normal; I = slight deficit; 2 = moderate deficit, and 3= severe deficit. Normal subjects score 20 points or less. The patients underwent an extensive battery of laboratory and neuroimaging studies to evaluate the degree and topography of cerebral atrophy, to exclude vascular impairment and causes of partially or completely reversible dementias. This detailed work-up included a complete blood count, erythrocyte sedimentation rate, Chem 20, thyroid tests, levels of B12, syphilis serology, HIV testing, chest X-ray, electrocardiogram, examination of cerebrospinal fluid, computerized tomographic scanning, and magnetic resonance imaging. Baseline electroencephalographic measures were used to follow the course of the disease. The latency and amplitude of P 300 cognitive-evoked potential were correlated with neuropsychological deterioration.

 

After the studies were completed, the relatives were briefed on the risks of a brain biopsy and on its nature, i.e., that the biopsies are not curative, but part of research protocol to study changes in blood-brain barrier in Alzheimer's disease that is still in process. This protocol was approved by the Committee for Ethics in Biomedical Research from the National Institute of Neurology and Neurosurgery. After permission for the biopsy was granted in writing, a sample of the superior frontal gyrus was taken, as this adds the least operative time and risk. In addition, quantitative studies by de la Monte (1989) showed that, in Alzheimer brains, the regional distribution ofplaques and tangles usually correlates with the distribution of cerebral atrophy. In all of this study's patients, neuroimaging studies revealed that the frontal gyri were severely affected.

 

The s4mple, which included the leptomeninges, cerebral cortex and subcortical white matter, was divided into 2 parts. The first part of the specimen was fixed in buffered formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin; luxol fast blue-cresyl violet was used for myelin and nerve cells; Bielschowsky and Von Braunmuhl methods were used for neurofibrillary tangles and neuritic plaques; and Congo Red was used for amyloid. Immunoperoxidase techniques, using monoclonal mouse antibodies to human beta amyloid and to amyloyd A4 component (Dako A/S, Denmark), were also applied. Senile plaques and neurofibrillary tangles were counted at 100 x power and 400 x power, respectively, on the whole surface of the cortex contained in sections stained with silver methods or immunoperoxidase techniques. Their numbers were expressed per square millimeter unit. The second part of the specimen was finely sectioned and fixed in 2.5% glutaraldehyde in 0.1 M cacodylate buffer, pH 7.4, post-fixed in 1% osmium tetroxide in the same buffer, dehydrated in acetone and embedded in Epon. Semithin sections were stained with toluidine blue and examined under a light microscope. Ultrathin sections, in the silver/grey area of the spectrum of interference colors, were stained with uranyl acetate and lead citrate and observed under a Zeiss EMIO transmission electron microscopy.

 

Attention Concentration Memory Language Fluidity R&D Praxias I&I VI, P & C .-I.. IL I-I 277 July 1995 Journal ofPsychiatry & Neuroscience The following packages were used for statistical analysis of the results: BMDP 1990 version on a VAX 11n750, and GLIM 3.77 version on an AT microcomputer with coprocessor. Pearson's Chi-Square Test and Fisher's Exact Test were used to compare clinical features.

 

RESULTS

 

The results of clinical and laboratory examinations did not rule out Alzheimer's disease in any of the patients, according to established criteria (McKhann et al 1984). There were no instances of hypothyroidism, or cardiac, renal or hepatic malfunction. Cerebrospinal fluid examination was normal in all patients. Computerized tomographic scanning and magnetic resonance imaging showed, in all individuals, global cerebral atrophy with marked reduction in overall crosssectional areas of the brain, an increase of the volume of the ventricular system and of the subarachnoid space. No areas of cerebral infarction were seen in any of the images. Results of the basic neuropsychological exploration are expressed in Table 1. Eighty-eight percent of the patients showed a marked deterioration of judgment and a similar deficit in the performance of abstract tasks and calculation. The mean score of the 7 subjects tested for everyday activity scales was 49, which reflects marked deterioration, and indicates a requirement for permanent assistance and care. In summary, there was a severe degeneration of superior cerebral functions involving cortical and subcortical areas. At this advanced stage of dementia, it is not possible to detect significant differences of involvement among several areas. Five patients (numbers 8 to 12) were diagnosed as having Alzheimer's disease with base on morphologic criteria determined by Khachaturian et al (1985) and Crystal et al (1988). They had numerous neuritic plaques and a variable density of neurofibrillary tangles. Three patients (5 to 7) showed numerous small (1 to 12 micrometer in diameter) vacuoles, many of them confluent, which markedly distorted the neuropil of the cortex. There was severe astrocytic gliosis. No plaques or tangles were seen in these biopsies, and no congophilic or A4 positive material was present. Electron microscopy showed that these vacuoles were located in the cytoplasm of astrocytes and neurons, and contained cytoplasmic and membranous debris. These cases were diagnosed as having Jakob-Creutzfeldt disease. Patients 1 to 3 had few neuritic plaques; their biopsy was reported as being normal for their age. In patient 4, many neurons were atrophic, with dense nuclei and abundant cytoplasmic lipofuscin. These neurons were located far from the surgical margins of the specimen and belonged to all cortical layers. In none of the biopsies were there cytoplasmic or nuclear abnormal bodies, inflammation, neoplasia or demyelination.

 

On the basis of the result of the brain biopsy, the patients were divided into two groups: A (Alzheimer group: patients 8 to 12) and NA (non-Alzheimer group, patients 1 to 7). Individuals from either group were similar in regard to age and sex distribution (see Table 2). In many patients, the number of cortical argyrophilic plaques exceeded by far the minimum established by Khachaturian et al (1985) for each age. Differences between mean numbers ofplaques and neurofibrillary tangles in A and NA subjects were highly significant. Time of evolution tended to be shorter in NA cases, but the difference with the A group was not significant because of the presence of patient 1, who had an unusually long course.

 

Clinico-pathological correlation

 

Family history

 

Two patients had one or more first-degree relatives with dementia. Patient 1 was 83 years old at the time of the biopsy, and his intellectual deterioration had been progressing for 10 years. His sister, aged 71, had a similar clinical picture with 15 years' evolution. This patient had few argyrophilic plaques and no neurofibrillary tangles; this pattern was considered within normal limits for his age. Patient 9, a 52-yearold woman whose diagnosis of Alzheimer's disease was confirmed by brain biopsy, belonged to an extraordinary family in that her mother, her maternal grandmother, a brother, a sister and a maternal aunt had all died after presenting a clinical picture similar to hers. Two other sisters were demented and still alive. The pattern of inheritance for this family corresponds to an autosomal dominant. Pearson's Chi-Square Test showed no statistically significant difference for this variable between the A group and the NA group.

 

Seizures

 

This variable was observed in 3 patients. Patient 8 of the A group, who had a 36-month history of behavioral changes, presented 3 episodes of generalized seizures in the last 4 months before being admitted. Patients 5 and 7, with spongiform encephalopathy, also had convulsive episodes in the last 5 months before being admitted. The difference of incidence between the two groups was not significant.

 

Speech abnormalities

 

Three out of five patients with Alzheimer's disease presented with speech abnormalities, characterized by reduced fluidity and problems for expression and comprehension. Verbal expression was, in the most severely affected patients, reduced to stereotypes, with no residual ability to communicate ideas. Patient 6 of the NA group had marked problems communicating verbally, and was limited to mumbling one of the last words said by the interviewer. The statistical significance for this variable was moderate (p < 0. 1). 278 VoL 20., No. 4,1995 July 1995

 

Table 2

 

Clinical and pathological data Case Diagnosis Age Sex Evolution (months) NFI NP 1 Non-Alzheimer 83 M 120 0 8 2 Non-Alzheimer 68 F 66 3 5 3 Non-Alzheimer 43 M 9 0 1 4 Non-Alzheimer 57 F 15 1 0 S Non-Alzheimer 56 M 16 0 0 6 Non-Alzheimer 68 F 5 0 0 7 Non-Alzheimer 61 F II 0 0 Mean 62.29 34.57 0.57 2.0 sd 12.49 M =43% 43.01 1.13 3.21 8 Alzheimer 77 M 60 2 23 9 Alzheimer 52 F 72 8 16 10 Alzheimer 65 F 36 5 14 11 Alzheimer 69 M 19 3 35 12 Alzheimer 59 F 84 6 21 Mean 64.40 54.20 4.8 21.80 sd 9.53 M = 40% 26.50 2.39 8.23 F= 0.10 0.45 17.1 34.36 p n.s. n.s. n.s. p <0 .01="" 0.01="" age="" div="" expressed="" in="" is="" millimeter="" n.s.="not" neuritic="" neurofibrillary="" nft="numbers" np="numbers" of="" p="" per="" plaques="" significant.="" square="" tangles="" years="">

 

Cerebellar changes

 

All patients with Alzheimer's disease performed adequately at the tests for coordination, albeit slowly. Among the NA patients, only one woman (number 6) showed generalized incoordination, with dysmetria and truncal ataxia. There was no significant difference between the A group and the NA group regarding this variable.

 

Delirium

 

Relatives of most patients from both groups attested to delirious episodes, with restlessness, visual and auditory hallucination and disorientation. There was no significant difference between the groups.

 

Abnormal movements

 

These movements manifested as intentional tremor of hands. Again, the difference was not significant. None of the cases diagnosed histologically as Jakob-Creutzfeldt disease had myoclonic jerks.

 

Pyramidal abnormalities

 

Three subjects for each group showed mild generalized spasticity, gastrocnemial clonus and bilateral Babinski sign. The difference was not significant.

 

Primitive reflexes

 

Suction, searching, palmar and plantar grasping reflexes were present in all patients with Alzheimer's disease and 3 out of 7 NA individuals. The level of significance was p <0 .04.="" div="">

 

Impairment of memory

 

Impairment involves both short-term and long-term memory consolidation and retrieval. All patients with Alzheimer's disease were severely affected, as were 5 out of 7 from the NA group. The remaining 2 NA subjects showed a moderate to slight impairment. There was no statistically significant difference between the A group and the NA group. Impairment of abstraction, Judgment alterations and acalculia The first 2 features were characteristic of Alzheimer cases and were present in all patients. Acalculia was observed in all patients with Alzheimer's disease but one, in contrast to 1 out of 7 NA cases. In some A individuals, acalculia presented early in the course of the disease. Regarding all 3 features, there was a significant difference (p < 0.05) between the A group and the NA group.

 

Dementia 279

 

Journal of Psychiatry & Neuroscience

 

Table 3

 

Summary of clinical variables in Alzheimer (A) and non-Alzheimer (NA) patients (see text)

 

A Group NA Group

 

n=5 Family history Seizures Speech changes Cerebellar abnormalities Delirium Abnornal movements Pyramidal abnormalities Primitive reflexes Impaired memory Impaired abstraction Judgment alterations Acalculia Dysarthria Apraxia Agnosia T-s 1 2 3 0 4 2 3 5 S S 5 4 2 2 2 Incontinence I Disorientation 3 Abnormal EEG 5 n.s.: difference statistically not significant; +: 0.05 < p < 0.10; ++: p < 0.05. n=7 1 1 5 3 3 3 5 2 1 4 3 4 1 3 Significance n.s. n.s. n.s. n.s. n.s. n.s. n.s. ++ n.s. ++ ++ ++ n.s. n.s. n.s. n.s. n.s.

 

Dysarthria, apraxia and agnosia

 

There was no significant difference in any ofthese features between the A group and the NA group.

 

Incontinence

 

Although this symptom was more common in the NA group, the difference was, once more, not significant. Disorientation

 

Three out of five patients with Alzheimer's disease were disoriented in time and space, compared with 1 out of 7 NA patients. The difference was not significant.

 

Abnormal EEG

 

Electroencephalographic changes, characterized by deficient organization and a generalized slow activity was found in all A patients, and in 3 out of 7 NA patients. The significance of the difference was moderate (p < 0.07).

 

None of the patients presented headache, fever, vertigo or cranial nerve changes. The above discussed variables are shown in Table 3.

 

Logistic discriminant functions

 

The joint effects of the variables were selected in stages because of the small sample size. Although good fitting models were obtained, none achieved a perfect discrimination. Among the models with two variables, alterations in judgment and acalculia gave the best fit (deviance 4.50 with 9 d]) and only I patient with Alzheimer's disease was misclassified (see Table 4).

 

DISCUSSION

 

The rates of accuracy of the clinical diagnosis of Alzheimer's disease in several clinico-pathological studies range from 43% to 87% (Joachim et al 1988; Mosla et al 1985; Muller and Schwartz 1978; Nott and Fleminger 1975; Sulkava et al 1983; Todorov et al 1975; Wade et al 1987). It should be interesting, therefore, if selected clinical data could help to reach this diagnosis without the aid of a brain biopsy. The results of this study show a very significant association of Alzheimer's disease with the following variables: primitive reflexes, impairment of abstraction, changes in judgment and acalculia. In studying the joint effect of 280 VoL 20, No. 4,1995

 

July 1995 Dementia 281

 

Table 4 Fitting model including alteradons ofjudgment and acalculia Case Diagnosis Fitted I NA 0.250 2 NA 0.000 3 NA 0.250 4 NA 0.250 5 NA 0.000 6 NA 0.000 7 NA 0.000 8 A 1.000 9 A 1.000 10 A 1.000 11 A 0.250+ 12 A 1.000 NA = non-Alzheimer; A = Alzheimer; + = misclassified Alzheimer patient variables, it was seen that alterations of judgment and acalculia produced the best fit.

 

The sample in this study may be considered small for the purpose of selecting a set of signs and symptoms that can characterize Alzheimer's disease clinically. However, it is not an easy task to obtain the permission to perform a brain biopsy which is of no benefit for the patient when the relative is informed of the risks involved.

 

The definite diagnosis of Alzheimer's disease depends on the microscopical examination of brain tissue, either by autopsy or biopsy. In the USA, the Alzheimer Disease Research Center of the University of Pittsburgh has launched a public campaign to encourage relatives of demented patients to request a postmortem examination of the brain (Boller et al 1989). However, in Mexico, a similar campaign has enjoyed little success so far for several reasons. The patient who suffers from Alzheimer's disease usually dies at home. The relatives, who are already exhausted by the demands of caretaking, obtain a death certificate from the family physician, and proceed quickly to the funeral rites. The few families who do request an autopsy are almost invariably denied admission to the hospital where the patient had been admitted because cadavers without a death certificate must be sent to the police department for autopsy. Many patients die in small towns or villages where there are no pathologists, let alone neuropathologists. Therefore, brain biopsy remains the only possibility for confirming the clinical diagnosis. It is true that there is no benefit derived by the patient from this procedure and that he or she faces surgical and anesthetic risks. In contrast, brain biopsy allows: 1. the development of new diagnostic procedures that might, in the future, replace it; 2. adequate genetic counselling in cases with an autosomal dominant pattern of inheritance, so that family members can take part in studies at the molecular biology level; and 3. the performance of therapeutic trials and of epidemiological surveys in Mexico.

 

Familiar aggregation has been demonstrated in 40% of cases of Alzheimer's disease. In 15% of these cases, the pattern of inheritance was autosomal dominant (Heston et al 1981). Patient number nine's family is an example of the latter, and showed an early age of onset.

 

Vacuolar change, similar to that present in Jakob- Creutzfeldt disease, has been described in brains of patients with Alzheimer's disease, especially at the medial temporal isocortex, where it has a high, statistically significant association with the presence of large numbers of neurofibrillary tangles and argyrophilic plaques (Smith et al 1987). This study considered the possibility that cases 5 to 7, diagnosed as Jakob-Creutzfeldt disease, could be, in fact, Alzheimer cases with this peculiar vacuolar change. A good method for separating the two entities would be the use of antibodies against prion (Pr-P) proteins (Tateishi et al 1988), which were, unfortunately, not available to the authors. However, none of these cases showed positivity for A4 protein, neither had one single argyrophilic plaque or tangle. Moreover, the biopsies were taken from the frontal regions, which are reported to be free of involvement in instances of Alzheimer's disease with vacuolar changes (Smith et al 1987).

 

Although the diagnosis of probable Alzheimer's disease was made in all of the patients in this study, according to the criteria established by McKhann et al (1984), this diagnosis was confirmed in only 47.1% of them. This low rate might be the result of several factors. The National Institute of Neurology and Neurosurgery in Mexico City is an institution that concentrates especially on difficult or unusual cases that are referred from all over the country. Therefore, it received a biased sample that included as many as 3 cases of spongiform encephalopathy. In addition, it is important to remember that a small, 1 cubic centimeter sample of cortex and white matter may not be representative of the extent of the damage in other areas of the brain, and so, correlates poorly with the clinical picture. This illustration is particularly true of cases 1 to 4, which did not fit into any of the pathological entities that manifest clinically as dementia. To understand more clearly the relation between damage and clinical impairment, further prospective studies using autopsy material are needed.

 

REFERENCES

 

American Psychiatric Association. 1987. Diagnostic and statistical manual of mental disorders. 3rd ed., revised. Washington DC: American Psychiatric Association. 282 Journal ofPsychiaty & Neuroscience VoL 20, No. 4,1995 Boller F, Lopez OL, Moossy J. 1989. Diagnosis of dementia: clinicopathologic correlations. Neurology 39:76-79. Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L. 1988. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology 38: 1682-1687. De la Monte SM. 1989. Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease. Ann Neurol 25:450-459. Heston LL, Mastri AR, Andersen E, White V. 1981. Dementia of the Alzheimer type. Arch Gen Psychiat 38:1085- 1090. Joachim CL, Morris JH, Selkoe DJ. 1988. Clinically diagnosed Alzheimer's disease: autopsy results in 150 cases. Ann Neurol 24:50-56. Karp HR, Mirra SS. 1986. Dementia in adults. In: Joynt RJ, editor. Clinical neurology. Philadelphia PA: Lippincott. pp 1-74. Khachaturian ZS. 1985. Diagnosis of Alzheimer's disease. Arch Neurol 42:1097-1104. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 1984. Clinical diagnosis of Alzheimer's disease. Neurology 34:939-944. Mosla PK, Paijarvi L, Rinne JO, Rinne UK, Sako E. 1985. Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J Neurol Neurosurg Psychiatry 48:1085-1090. Muller HF, Schwartz G. 1978. Electroencephalograms and autopsy findings in geropsychiatry. J Geront 4:504-513. Nott PN, Fleminger JJ. 1975. Presenile dementia: the difficulties of early diagnosis. Acta Psychiatr Scand 51: 210- 217. Smith TW, Anwer U, DeGirolami U, Drachman DA. 1987. Vacuolar change in Alzheimer's disease. Arch Neurol 44:1225-1228. Sulkava R, Haltia M, Paetau A, Wikstrom JU, Palo J. 1983. Accuracy of clinical diagnosis in primary degenerative dementia: correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 46:9-13. Tateishi J, Tetsuyuki K, Mashigu Chi M, Shii M. 1988. Gerstmann Straussler-Scheinker disease: immunohistological and experimental studies. Ann Neurol 24:35-40. Todorov A, Go R, Constantinidis J, Eiston R. 1975. Specificity of the clinical diagnosis of dementia. J Neurol Sci 26:81-98. Wade JPH, Mirsen TR, Hachinski VC, Fisman M, Lau C, Merskey H. 1987. The clinical diagnosis of Alzheimer's disease. Arch Neurol 44:24-29...END...NO URL...tss

 

=============================== END...TSS==============================

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

 

Terry S. Singeltary, Sr Bacliff, Tex

 

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT

 

http://jama.jamanetwork.com/article.aspx?articleid=1031186

 

Views & Reviews

 

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

 

Ermias D. Belay, MD, Ryan A. Maddox, MPH, Pierluigi Gambetti, MD and Lawrence B. Schonberger, MD

 

+ Author Affiliations

 

From the Division of Viral and Rickettsial Diseases (Drs. Belay and Schonberger and R.A. Maddox), National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA; and National Prion Disease Pathology Surveillance Center (Dr. Gambetti), Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH.

 

Address correspondence and reprint requests to Dr. Ermias D. Belay, 1600 Clifton Road, Mailstop A-39, Atlanta, GA 30333.

 

http://www.neurology.org/content/60/2/176

 

26 March 2003

 

Terry S. Singeltary, retired (medically) CJD WATCH

 

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

 

http://www.neurology.org/content/60/2/176/reply#neurology_el_535

 

The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003 doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI

 

Tracking spongiform encephalopathies in North America

 

Original

 

Xavier Bosch

 

“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.” 49-year—old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt—Jakob ...

 

http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/%20fulltext

 

http://www.thelancet.com/journals/laninf/issue/vol3no8/PIIS1473-3099(00)X0025-4

 

2 January 2000

 

British Medical Journal

 

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

 

http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well

 

15 November 1999

 

British Medical Journal

 

vCJD in the USA * BSE in U.S.

 

http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Background

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.

 

Methods

 

Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

 

Results

 

I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.

 

Conclusions

 

There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.

 

end...tss

 

SEE FULL TEXT AND SOURCE REFERENCES ;

 

Wednesday, May 16, 2012

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Proposal ID: 29403

 

http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html

 

From:

 

 Sent: Saturday, April 07, 2012 8:20 PM

 

 To: Terry S. Singeltary Sr.

 

 Subject: RE: re-submission

 

 Dear Terry,

 

 Yes, your proposal was accepted as a poster presentation. Please decline the invitation if appropriate.

 

 Best Regards,

 

 ______________________________________

 

 Alzheimer’s Association – National Office

 

225 North Michigan Avenue – Floor 17

 

Chicago, Illinois 60601

 

 =============snip...end...source reference...# 29403==========

 

 Final Abstract Number: ISE.114

 

Session: International Scientific Exchange

 

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

 

T. Singeltary Bacliff, TX, USA

 

Background: An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and feed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

 

Methods: 12 years independent research of available data

 

Results: I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

 

Conclusion: I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

 

http://www.isid.org/events/archives/14th_icid/Downloads/14th_ICID_ISE_Abstracts.pdf

 

 Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

 

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF

 

Singeltary comment reply to above ‘’Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease’’

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Posted by flounder on 05 Nov 2014 at 21:27 GMT

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Background

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.

 

Methods

 

Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

 

Results

 

I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.

 

Conclusions

 

There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.

 

end...tss

 

Ann N Y Acad Sci. 1982;396:131-43.

 

Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).

 

Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.

 

Abstract

 

Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract

 

CJD1/9 0185 Ref: 1M51A

 

IN STRICT CONFIDENCE

 

Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:

 

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;

 

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

 

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1

 

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

 

BSE101/1 0136

 

IN CONFIDENCE

 

5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

 

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?

 

3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

 

92/11.4/1-1 BSE101/1 0137

 

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

 

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2

 

http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

 

BSE101/1 0136

 

IN CONFIDENCE

 

CMO

 

From: Dr J S Metters DCMO

 

4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 

http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

 

CJD1/9 0185

 

Ref: 1M51A

 

IN STRICT CONFIDENCE

 

From: Dr. A Wight Date: 5 January 1993

 

Copies:

 

Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

 

Tuesday, November 26, 2013

 

Transmission of multiple system atrophy prions to transgenic mice

 

‘’Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions.’’

 

http://www.pnas.org/content/110/48/19555.abstract.html?etoc

 

Transmission of a neurodegenerative disorder from humans to mice

 

The findings suggest that the α-synuclein deposits that form in the brains of patients with MSA behave like prions and are transmissible under certain circumstances, according to the authors. — N.Z.

 

α-Synuclein deposits in the brainstems of inoculated mice.

 

http://www.pnas.org/content/110/48/19175.full.pdf+html

 

kind regards, terry

 

No competing interests declared.

 

*** Singeltary comment ***

 

http://www.plosone.org/annotation/listThread.action?root=82860

 

Terry S. Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis

 

http://www.youtube.com/watch?v=zf3lfz9NrT4

 

http://www.youtube.com/watch?v=c0tWkNvhO4g

 

http://www.youtube.com/watch?v=zf3lfz9NrT4&feature=results_main&playnext=1&list=PL780BE2AF0B62A944

 

full text with source references ;

 

http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/terry-singeltary-sr-on-creutzfeldt.html

 

re-Human Prion Diseases in the United States Posted by flounder on 01 Jan 2010 at 18:11 GMT

 

I kindly disagree with your synopsis for the following reasons ;

 

http://www.plosone.org/annotation/listThread.action?root=363

 

*** Singeltary reply ;

 

ruminant feed ban for cervids in the United States ?

 

31 Jan 2015 at 20:14 GMT

 

http://www.plosone.org/annotation/listThread.action?root=85351

 

*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply ;

 

http://www.plosone.org/annotation/listThread.action;jsessionid=635CE9094E0EA15D5362B7D7B809448C?root=7143

 

Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.

 

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.

 

Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

 

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.

 

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract

 

now what about all those folks that are consuming CWD TSE prion, and then going to have a medical procedure, dental, donating blood, tissue, or what about those medical instruments, either on humans, and or, what about medical and surgical instruments that are used on animals ???

 

Monday, August 17, 2015

 

FDA Says Endoscope Makers Failed to Report Superbug Problems OLYMPUS

 

*** I told Olympus 15 years ago about these risk factors from endoscopy equipment, disinfection, even spoke with the Doctor at Olympus, this was back in 1999. I tried to tell them that they were exposing patients to dangerous pathogens such as the CJD TSE prion, because they could not properly clean them. even presented my concern to a peer review journal GUT, that was going to publish, but then it was pulled by Professor Michael Farthing et al... see ;

 

http://transmissiblespongiformencephalopathy.blogspot.com/2015/08/fda-says-endoscope-makers-failed-to.html

 

*** iatrogenic, what if ??? ***

 

It is currently unknown whether α-synuclein prions can attach to surgical instruments and to what extent they may persist following sterilization. Although attempts to transmit PD to monkeys by intracerebral inoculation were unsuccessful (37), our transmission data suggest that caution should be exercised when reusing neurosurgical instruments that have been previously used on suspected cases of MSA or PD to minimize any risk for iatrogenic transmission of the disease. Although deep brain stimulation is not commonly used to treat MSA patients, its increasingly wide use to control dyskinesias often found in many patients with advanced PD requires surgical implantation (38) and, as such, may represent a potential risk for human-to-human transmission of α-synuclein prions. ...SEE;

 

Tuesday, September 1, 2015

 

*** Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism ***

 

http://transmissiblespongiformencephalopathy.blogspot.com/2015/09/multiple-system-atrophy-msa.html

 

Thursday, July 30, 2015

 

Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

 

http://betaamyloidcjd.blogspot.com/2015/07/prion-disease-induces-alzheimer-disease.html

 

Tuesday, June 30, 2015

 

visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant Creutzfeldt Jakob Disease hvCJD

 

http://betaamyloidcjd.blogspot.com/2015/06/visual-variant-of-alzheimers-disease.html

 

PRION2015 Alzheimer’s disease

 

*** P.34: Preliminary study of Alzheimer’s disease transmission to bank vole

 

Guido Di Donato1, Geraldina Riccardi1, Claudia D’Agostino1, Flavio Torriani1, Maurizio Pocchiari2, Romolo Nonno1, Umberto Agrimi1, and Michele Angelo Di Bari1

 

1Department of Food Safety and Veterinary Public Health Istituto Superiore di Sanit a, Rome, Italy; 2Department of Cellular Biology and Neuroscience; Istituto Superiore di Sanit a, Rome, Italy

 

Extensive experimental findings indicate that prion-like mechanisms underly the pathogenesis of Alzheimer disease (AD). Transgenic mice have been pivotal for investigating prionlike mechanisms in AD, still these models have not been able so far to recapitulate the complex clinical-pathological features of AD. Here we aimed at investigating the potential of bank vole, a wild-type rodent highly susceptible to prions, in reproducing AD pathology upon experimental inoculation.

 

Voles were intracerebrally inoculated with brain homogenate from a familial AD patient. Animals were examined for the appearance of neurological signs until the end of experiment (800 d post-inoculation, d.p.i.). Brains were studied by immunohistochemistry for pTau Prion 2015 Poster Abstracts S29 (with AT180 and PHF-1 antibodies) and b-amyloid (4G8).

 

Voles didn’t show an overt clinical signs, still most of them (11/16) were found pTau positive when culled for intercurrent disease or at the end of experiment. Interestingly, voles culled as early as 125 d.p.i. already showed pTau aggregates. Deposition of pTau was similar in all voles and was characterized by neuropil threads and coiled bodies in the alveus, and by rare neurofibrillary tangles in gray matter. Conversely, b-amyloid deposition was rather rare (2/16). Nonetheless, a single vole showed the contemporaneous presence of pTau in the alveus and a few Ab plaque-like deposits in the subiculum. Uninfected age-matched voles were negative for pTau and Ab.

 

*** These findings corroborate and extend previous evidences on the transmissibility of pTau and Ab aggregation. Furthermore, the observation of a vole with contemporaneous propagation of pTau and Ab is intriguing and deserves further studies.

 

=================

 

P.155: Quantitative real-time analysis of disease specific tau amyloid seeding activity

 

Davin Henderson and Edward Hoover Prion Research Center; College of Veterinary Medicine and Biomedical Sciences; Colorado State University; Fort Collins, CO USA

 

A leading hypothesis for the cause of neurodegenerative diseases is the templated misfolding of cellular proteins to an amyloid state. Spongiform encephalopathies were the first diseases discovered to be caused by a misfolded amyloid-rich protein. It is now recognized that the major human neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE), also are associated with amyloid formation. Moreover, AD and PD amyloids have been shown competent to transmit disease in experimental animal models, suggesting shared mechanisms with traditional prion diseases. Sensitive detection of prion disease has been advanced by in vitro amplification of low levels of disease specific amyloid seeds, e.g. serial protein misfolding amplification (sPMCA), amyloid seeding (ASA) and real-time quaking induced conversion (RT-QuIC), thereby replicating the disease process in vitro. In addition, measurement of the amyloid formation rate can estimate the level of disease-associated seed by using methods analogous to quantitative polymerase chain reaction (qPCR). In the present work, we apply these principles to show that seeding activity of in vitro generated amyloid tau and AD brain amyloid tau can be readily detected and quantitated.

 

=============

 

P.83: Gerstmann-Str€aussler-Scheinker disease with F198S mutation: Selective propagation of PrPSc and pTau upon inoculation in bank vole

 

Michele Angelo Di Bari1, Romolo Nonno1, Laura Pirisinu1, Claudia D’Agostino1, Geraldina Riccardi1, Guido Di Donato1, Paolo Frassanito1, Bernardino Ghetti2, Pierluigi Gambetti3, and Umberto Agrimi1

 

1Department of Veterinary Public Health and Food Safety; Istituto Superiore di Sanit a; Rome, Italy;

 

2Indiana University-Purdue University Indianapolis; Department of Pathology and Laboratory Medicine; Indianapolis, IN USA; 3Case Western Reserve University; Cleveland, OH USA

 

Gerstmann-Str€aussler-Scheinker disease with F198S mutation (GSS-F198S) is characterized by the presence of PrP amyloid plaques as well as neurofibrillary tangles with abnormally-phosphorylated tau protein (pTau) in the brain. The relationship between tau protein and PrP in the pathogenesis of GSS-F198S is unknown. In a previous study, we inoculated intracerebrally 2 GSS-F198S cases in 2 lines of voles carrying either methionine (Bv109M) or isoleucine (Bv109I) at codon 109 of PrP. GSS-F198S transmitted rather efficiently to Bv109I, but not to Bv109M.

 

Here we investigated the presence of pTau, as assessed by immunohistochemistry with anti-pTau antibodies AT180 and PHF-1, in the same voles previously inoculated with GSSF198S. Among these voles, most Bv109I showed clinical signs after short survival times (»150 d.p.i.) and were positive for PrPSc. The remaining Bv109I and all Bv109M survived for longer times without showing prion-related pathology or detectable PrPSc. All Bv109I which were previously found PrPSc-positive,

 

S54 Prion 2015 Poster Abstracts

 

were immunonegative for pTau deposition. In contrast, pTau deposition was detected in 16/20 voles culled without clinical signs after long survival times (225–804 d.p.i.). pTau deposition was characterized by neuropil threads and coiled bodies in the alveus, and was similar in all voles analyzed.

 

These findings highlight that pTau from GSS-F198S can propagate in voles. Importantly, pTau propagation was independent from PrPSc, as pTau was only found in PrPSc-negative voles surviving longer than 225 d.p.i. Thus, selective transmission of PrPSc and pTau proteinopathies from GSS-F198S can be accomplished by experimental transmission in voles.

 

=========

 

=========

 

I3 Aβ Strains and Alzheimer’s Disease

 

Lary Walker Emory University, Atlanta, GA, USA

 

An essential early event in the development of Alzheimer’s disease is the misfolding and aggregation of Aβ. Enigmatically, despite the extensive deposition of human-sequence Aβ in the aging brain, nonhuman primates do not develop the full pathologic or cognitive phenotype of Alzheimer’s disease, which appears to be unique to humans. In addition, some humans with marked Aβ accumulation in the brain retain their cognitive abilities, raising the question of whether the pathogenicity of Aβ is linked to the molecular features of the misfolded protein. I will present evidence for strain-like molecular differences in aggregated Aβ between humans and nonhuman primates, and among end-stage Alzheimer patients. I will also discuss a case of Alzheimer’s disease with atypical Aβ deposition to illustrate heterogeneity in the molecular architecture of Aβ assemblies, and how this variability might influence the nature of the disease. As in the case of prion diseases, strain-like variations in the molecular architecture of Aβ could help to explain the phenotypic variability in Alzheimer’s disease, as well as the distinctively human susceptibility to the disorder.

 

This research was conducted in collaboration with Harry LeVine, Rebecca Rosen, Amarallys Cintron, David Lynn, Yury Chernoff, Anil Mehta and Mathias Jucker and colleagues. Supported by AG040589, RR165/OD11132, AG005119, NS077049, the CART Foundation and MetLife.

 

==========

 

I5 Pathogenic properties of synthetically generated prions

 

Jiyan Ma Van Andel Research Institute, Grand Rapids, Michigan, USA

 

Synthetically generating prions with bacterially expressed recombinant prion protein (recPrP) strongly supports the prion hypothesis. Yet, it remains unclear whether the pathogenic properties of synthetically generated prions (rec-Prion) fully recapitulate those of naturally occurring prions. A series of analyses including intracerebral and intraperitoneal transmissions of rec-Prion in wild-type mice were performed to determine the characteristics of rec-Prion induced diseases. Results from these analyses demonstrated that the rec-Prion exhibits the same pathogenic properties with naturally occurring prions, including a titratable infectivity that can be determined by endpoint titration assays, capability of transmitting prion disease via routes other than the direct intra-cerebral inoculation, causing ultra-structural lesions that are specific to prion disease, and sharing a similar manner of visceral dissemination and neuroinvasion with naturally occurring scrapie and chronic wasting disease. These findings confirmed that the disease caused by rec-Prion in wild-type mice is bona fide prion disease or transmissible spongiform encephalopathiges, and the rec-Prion contains similar pathogenic properties as naturally occurring prions.

 

I6 Transmissible protein toxins in neurodegenerative disease

 

Jacob Ayers, David Borchelt University of Florida, Gainesville, FL, USA

 

Amyotrophic lateral sclerosis (ALS) is an obvious example of neurodegenerative disease that seems to spread along anatomical pathways. The spread of symptoms from the site of onset (e.g. limb) to the respiratory musculature drives the rate of disease progression. In cognitive disorders, such as Alzheimer’s disease, one can find similarly find evidence of spreading dysfunction and pathology. One mechanism to account for this spread of disease from one neural structure to another is by evoking prion-like propagation of a toxic misfolded protein from cell to cell. Recent studies in animals that model aspects of Alzheimer’s Disease, Parkinson’s Disease, and Tauopathy, have bolstered the arguments in favor of prion-like, although in most of these models the mice do not develop overt “clinical” symptoms. Recently, Jacob Ayers demonstrated that the symptoms of ALS can be transmitted from a strain of mice that expresses mutant SOD1-G93A at high levels to a second transgenic strain that expresses mutant SOD1 at low, nontoxic, levels. This model showed many prion-like features including evidence of host-adaptation (earlier and more penetrant disease upon second passage). Interestingly, homogenates from paralyzed mice expressing the G37R variant of SOD1 transmitted poorly, a finding suggestive that different SOD1 variants may exhibit strain-like properties. These “ i n d u c i b l e ” m o d e l s o f h u m a n neurodegenerative disease enable the generation of models that do not require extraordinary levels of transgene expression and provide a more precise means of initiating the disease process, advances that may translate into more predictive pre-clinical models.

 

=======

 

P188 Transmission of amyloid pathology by peripheral administration of misfolded Aβ

 

Javiera Bravo-Alegria1 ,2, Rodrigo Morales2, Claudia Duran-Aniotz3, Claudio Soto2 1University of Los Andes, Santiago, Chile, 2Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School, Houston, Texas, USA, 3University of Chile, Santiago, Chile

 

Misfolding and aggregation of Amyloid-β (Aβ) is one of the primary events involved in the pathogenesis of Alzheimer's disease (AD). Recently, it has been proposed that Aβ aggregates can transmit and spread the pathology following a prion-like mechanism. Prions can be exogenously transmitted by many different routes of administration. In the case of Aβ, previous studies showed that intraperitoneal (i.p.) injection of seeds can accelerate cerebral amyloidosis in mouse models. However, other potential routes have not yet been studied. The goal of this work was to assess whether Aβ amyloidosis can be seeded in the brain of a transgenic mouse model of AD by peripheral administration of misfolded particles.

 

Young tg2576 animals (50 days old) were inoculated with a pool of brain extract coming from old Tg2576 animals (10%w/v) by different routes: i.p. (100μL), eye drops (5μL each eye, 3 times), intramuscular (i.m., 50μL), and per os (p.o., 1000μL). Animals were sacrificed at 300 days old, and brain samples were analyzed for amyloid pathology by IHC and ELISA.

 

The i.p., i.m., and eye drops administration of Aβ seeds significantly accelerated pathological features in tg2576. Regardless of the higher volume administered, p.o. treated animals did not show any pathological changes when compared to untreated controls. Differences in the proportion of diffuse, core and vascular deposition was observed within experimental groups. Our data show that peripheral administration of Aβ seeds could accelerate pathological changes in the brain and suggest that an orchestrated cross-talk between the brain and peripheral tissues occurs in AD.

 

==========

 

 https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

 

Tuesday, June 30, 2015

 

PRION2015 Alzheimer’s disease

 

http://betaamyloidcjd.blogspot.com/2015/06/prion2015-alzheimers-disease.html

 

Tuesday, March 19, 2013

 

Alzheimer's Association 2013 Alzheimer's Disease Facts and Figures

 

Today, an American develops Alzheimer's disease every 68 seconds. In 2050, an American will develop the disease every 33 seconds.

 

http://betaamyloidcjd.blogspot.com/2013/03/alzheimers-association-2013-alzheimers.html

 

 Sunday, February 10, 2013

 

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

 

http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html

 

SCENARIO 3: ‘THE THIN STEMMED GLASS’

 

... a TSE is found that is linked to Alzheimer’s disease.

 

http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html

 

Wednesday, September 21, 2011

 

PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)

 

http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html

 

Friday, September 3, 2010

 

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

 

http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html

 

PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS

 

*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***

 

O18

 

Zoonotic Potential of CWD Prions

 

Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1, Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy, 3Encore Health Resources, Houston, Texas, USA

 

Chronic wasting disease (CWD) is a widespread and expanding prion disease in free-ranging and captive cervid species in North America. The zoonotic potential of CWD prions is a serious public health concern. Current literature generated with in vitro methods and in vivo animal models (transgenic mice, macaques and squirrel monkeys) reports conflicting results. The susceptibility of human CNS and peripheral organs to CWD prions remains largely unresolved. In our earlier bioassay experiments using several humanized transgenic mouse lines, we detected protease-resistant PrPSc in the spleen of two out of 140 mice that were intracerebrally inoculated with natural CWD isolates, but PrPSc was not detected in the brain of the same mice. Secondary passages with such PrPSc-positive CWD-inoculated humanized mouse spleen tissues led to efficient prion transmission with clear clinical and pathological signs in both humanized and cervidized transgenic mice. Furthermore, a recent bioassay with natural CWD isolates in a new humanized transgenic mouse line led to clinical prion infection in 2 out of 20 mice. These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.

 

==================

 

***These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.***

 

==================

 

P.105: RT-QuIC models trans-species prion transmission

 

Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover Prion Research Center; Colorado State University; Fort Collins, CO USA

 

The propensity for trans-species prion transmission is related to the structural characteristics of the enciphering and heterologous PrP, but the exact mechanism remains mostly mysterious. Studies of the effects of primary or tertiary prion protein structures on trans-species prion transmission have relied primarily upon animal bioassays, making the influence of prion protein structure vs. host co-factors (e.g. cellular constituents, trafficking, and innate immune interactions) difficult to dissect. As an alternative strategy, we used real-time quakinginduced conversion (RT-QuIC) to investigate trans-species prion conversion.

 

To assess trans-species conversion in the RT-QuIC system, we compared chronic wasting disease (CWD) and bovine spongiform encephalopathy (BSE) prions, as well as feline CWD (fCWD) and feline spongiform encephalopathy (FSE). Each prion was seeded into each host recombinant PrP (full-length rPrP of white-tailed deer, bovine or feline). We demonstrated that fCWD is a more efficient seed for feline rPrP than for white-tailed deer rPrP, which suggests adaptation to the new host.

 

Conversely, FSE maintained sufficient BSE characteristics to more efficiently convert bovine rPrP than feline rPrP. Additionally, human rPrP was competent for conversion by CWD and fCWD. ***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.

 

================

 

***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.***

 

================

 

https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

 

From: Terry S. Singeltary Sr.

 

Sent: Saturday, November 15, 2014 9:29 PM

 

To: Terry S. Singeltary Sr.

 

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

 

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE

 

R. G. WILL

 

1984

 

*** The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;

 

snip...

 

http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf

 

 Thursday, July 23, 2015

 

Chronic Wasting Disease (CWD) 101 Drs. Walter Cook & Donald S. Davis

 

http://chronic-wasting-disease.blogspot.com/2015/07/chronic-wasting-disease-cwd-101-drs.html http://chronic-wasting-disease.blogspot.com/

 

Monday, August 31, 2015

 

Illinois Loosing Ground to Chronic Wasting Disease CWD cases mounting with 71 confirmed in 2015 and 538 confirmed cases to date

 

http://chronic-wasting-disease.blogspot.com/2015/08/illinois-loosing-ground-to-chronic.html

 

Monday, August 24, 2015

 

Ohio wildlife officials ramp up fight against fatal deer brain disease after 17 more positive tests CWD

 

http://chronic-wasting-disease.blogspot.com/2015/08/ohio-wildlife-officials-ramp-up-fight.html

 

Sunday, August 23, 2015

 

*** TAHC Chronic Wasting Disease CWD TSE Prion and how to put lipstick on a pig and take her to the dance in Texas ***

 

TAHC TPWD CWD CAPTIVE MEDINA TRACE OUT INDEX UPDATE THE SILENCE IS DEAFENING $$$

 

http://chronic-wasting-disease.blogspot.com/2015/08/tahc-chronic-wasting-disease-cwd-tse.html

 

Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle

 

Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

 

snip...

 

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/mb/m09/tab05.pdf

 

In Confidence - Perceptions of unconventional slow virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells

 

3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. ...

 

http://web.archive.org/web/20060307063531/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf

 

human cwd will NOT look like nvCJD. in fact, see ;

 

*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).***

 

https://www.landesbioscience.com/journals/prion/article/28124/?nocache=112223249

 

Tuesday, August 4, 2015

 

*** FDA U.S. Measures to Protect Against BSE ***

 

http://bseusa.blogspot.com/2015/08/fda-us-measures-to-protect-against-bse.html

 

http://creutzfeldt-jakob-disease.blogspot.com/

 

http://transmissiblespongiformencephalopathy.blogspot.com/

 

http://vcjd.blogspot.com/

 

http://kuru-tse.blogspot.com/

 

http://sporadicffi.blogspot.com/

 

http://vpspr.blogspot.com/

 

http://betaamyloidcjd.blogspot.com/

 

http://prionoid.blogspot.com/

 

http://prionopathy.blogspot.com/

 

http://proteinopathies.blogspot.com/

 

http://earlyonsetdementia.blogspot.com/

 

http://bovineprp.blogspot.com/

 

http://bseusa.blogspot.com/

 

http://madcowusda.blogspot.com/

 

http://bse-atypical.blogspot.com/

 

http://scrapie-usa.blogspot.com/

 

http://nor-98.blogspot.com/

 

http://felinespongiformencephalopathyfse.blogspot.com/

 

http://caninespongiformencephalopathy.blogspot.com/

 

http://madporcinedisease.blogspot.com/

 

http://creutzfeldt-jakob-disease.blogspot.com/

 

 

 

 

layperson, no scholar, no PhDs

 

just made a promise to mom, never forget, and never let them forget...

 

MOM DOD 12/14/97 confirmed hvCJD...just saying.

 

Terry S. Singeltary Sr.

Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

Journal of Neuropathology & Experimental Neurology:

 

Post Author Corrections: July 29, 2015

 

doi: 10.1097/NEN.0000000000000228

 

Original Article: PDF Only

 

Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes.

 

Tousseyn, Thomas MD, PhD; Bajsarowicz, Krystyna MS; Sánchez, Henry MD; Gheyara, Ania MD, PhD; Oehler, Abby BS; Geschwind, Michael MD, PhD; DeArmond, Bernadette MD, MPH; DeArmond, Stephen J. MD, PhD

 

Abstract

 

We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many [beta]-amyloid (A[beta]; A[beta]42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified A[beta]42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many A[beta]42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrPSc, low A[beta]42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (H[tau]) and H[tau]-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain A[beta]42 deposits; however, there were rare H[tau]-positive threads in 5 controls, and 2 controls had few H[tau]-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrPSc, A[beta]42, APOE-4, and abnormal tau.

 

(C) 2015 by American Association of Neuropathologists, Inc.

 

http://journals.lww.com/jneuropath/Abstract/publishahead/Prion_Disease_Induces_Alzheimer_Disease_Like.99273.aspx

 

Int. J. Exp. Path. (1993) 74, 441-454

 

Evidence for the experimental transmission of cerebral f-amyloidosis to primates

 

H.F. BAKER*, R.M. RIDLEY*, L.W. DUCHENt, T.J. CROW* AND C.J. BRUTON*t

 

*Division of Psychiatry, Clinical Research Centre, Harrow; tDepartment of Neuropathology, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG;

 

4MRC Department of Neuropathology, Runwell Hospital, Wickford, Essex SS1 17QE, UK

 

Received for publication 8 March 1993

 

Accepted for publication 21 May 1993

 

Summary. The brains of three marmosets (Callithrix jacchus) injected intracerebrally 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease were found to contain moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy but no neurofibrillary tangles. The plaques and vascular amyloid stained positively with antibodies to fl(A4)-protein. The brains of three age-matched control marmosets from the same colony did not show these neuropathological features. The brain of one of two marmosets injected with brain tissue from a patient with prion disease with concomitant fl-amyloid plaques and cerebral amyloid angiopathy also showed fl-amyloid plaques and angiopathy but no spongiform encephalopathy. An occasional plaque was found in the brains of two of four marmosets injected with brain tissue from three elderly patients with age-related pathology, two of whom had an additional diagnosis of possible prion disease. Neither plaques nor cerebral amyloid angiopathy were found in six other marmosets who were older than the injected animals, in 12 further marmosets who were slightly younger but who had been injected several years previously with brain tissue which did not contain ,B-amyloid, or in 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that cerebral ,B-amyloidosis may be induced by the introduction of exogenous amyloid fl-protein.

 

SNIP...

 

Despite some alarmist claims, the occurrence of prion disease with none of the hallmarks of prion disease and all of the hallmarks of another neurodegenerative disease is 'imagined' (Brown et a/. 1993). There are no differential clinical or neuropathological features to suggest that case 1 had a prion disease rather than AD and the lack of a characteristic EEG, myoclonus, SE or PrP-staining plaques argue against a diagnosis of prion disease. Although ,B-amyloid plaques have been found in prion disease, the majority of these occur in elderly patients (Roberts et a/. 1988). Occasional concomitant ,B-amyloidosis has been found in prion disease (as in case 2; Watanabe & Duchen 1993) but in these cases the degree of ,B-amyloidosis is not as extensive as that seen in case 1 which was extremely severe. Neurofibrillary tangles are an unusual feature in prion disease and, when they do occur, tend to be localized to the hippocampus. However, in the Indiana kindred, which does have a large number of NFT and plaques and a PrP198 mutation (Dlouhy et al. 1992), the plaques stain with anti-PrP as well as anti-,B-amyloid antibodies (Bugiani et a/. 1993).

 

Thus the pathology of case 1 was typical of AD and we conclude that the amyloidosis of that and the other brains wi.th ,B-amyloid has been transmitted to marmosets by intracerebral injection.

 

Keywords: fJ(A4)-amyloid, senile plaques, primates, Alzheimer's disease

 

https://www.researchgate.net/profile/Timothy_Crow/publication/14981061_Evidence_for_the_experimental_transmission_of_cerebral_beta-amyloidosis_to_primates/links/00b49522763cce765d000000.pdf

 

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

 

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF

 

*** Singeltary comment ***

 

http://www.plosone.org/annotation/listThread.action?root=82860

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Background

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.

 

Methods

 

Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

 

Results

 

I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.

 

Conclusions

 

There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.

 

end...tss

 

SEE FULL TEXT AND SOURCE REFERENCES ;

 

Wednesday, May 16, 2012

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Proposal ID: 29403

 

http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html

 

Ann N Y Acad Sci. 1982;396:131-43.

 

Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).

 

Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.

 

Abstract

 

Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract

 

 

IN STRICT CONFIDENCE

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1992/10/23001001.pdf

 

CJD1/9 0185 Ref: 1M51A

 

IN STRICT CONFIDENCE

 

Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:

 

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;

 

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

 

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1

 

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

 

BSE101/1 0136

 

IN CONFIDENCE

 

5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

 

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?

 

3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

 

92/11.4/1-1 BSE101/1 0137

 

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

 

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2

 

http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

 

BSE101/1 0136

 

IN CONFIDENCE

 

CMO

 

From: Dr J S Metters DCMO

 

4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 

http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

 

CJD1/9 0185

 

Ref: 1M51A

 

IN STRICT CONFIDENCE

 

From: Dr. A Wight Date: 5 January 1993

 

Copies:

 

Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf

 

***PRION2015 Ft. Collins***

 

Alzheimer’s disease

 

*** P.34: Preliminary study of Alzheimer’s disease transmission to bank vole ***

 

Guido Di Donato1, Geraldina Riccardi1, Claudia D’Agostino1, Flavio Torriani1, Maurizio Pocchiari2, Romolo Nonno1, Umberto Agrimi1, and Michele Angelo Di Bari1

 

1Department of Food Safety and Veterinary Public Health Istituto Superiore di Sanit a, Rome, Italy; 2Department of Cellular Biology and Neuroscience; Istituto Superiore di Sanit a, Rome, Italy

 

Extensive experimental findings indicate that prion-like mechanisms underly the pathogenesis of Alzheimer disease (AD). Transgenic mice have been pivotal for investigating prionlike mechanisms in AD, still these models have not been able so far to recapitulate the complex clinical-pathological features of AD. Here we aimed at investigating the potential of bank vole, a wild-type rodent highly susceptible to prions, in reproducing AD pathology upon experimental inoculation.

 

Voles were intracerebrally inoculated with brain homogenate from a familial AD patient. Animals were examined for the appearance of neurological signs until the end of experiment (800 d post-inoculation, d.p.i.). Brains were studied by immunohistochemistry for pTau Prion 2015 Poster Abstracts S29 (with AT180 and PHF-1 antibodies) and b-amyloid (4G8).

 

Voles didn’t show an overt clinical signs, still most of them (11/16) were found pTau positive when culled for intercurrent disease or at the end of experiment. Interestingly, voles culled as early as 125 d.p.i. already showed pTau aggregates. Deposition of pTau was similar in all voles and was characterized by neuropil threads and coiled bodies in the alveus, and by rare neurofibrillary tangles in gray matter. Conversely, b-amyloid deposition was rather rare (2/16). Nonetheless, a single vole showed the contemporaneous presence of pTau in the alveus and a few Ab plaque-like deposits in the subiculum. Uninfected age-matched voles were negative for pTau and Ab.

 

*** These findings corroborate and extend previous evidences on the transmissibility of pTau and Ab aggregation. Furthermore, the observation of a vole with contemporaneous propagation of pTau and Ab is intriguing and deserves further studies.

 

=================

 

P.155: Quantitative real-time analysis of disease specific tau amyloid seeding activity

 

Davin Henderson and Edward Hoover Prion Research Center; College of Veterinary Medicine and Biomedical Sciences; Colorado State University; Fort Collins, CO USA

 

A leading hypothesis for the cause of neurodegenerative diseases is the templated misfolding of cellular proteins to an amyloid state. Spongiform encephalopathies were the first diseases discovered to be caused by a misfolded amyloid-rich protein. It is now recognized that the major human neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE), also are associated with amyloid formation. Moreover, AD and PD amyloids have been shown competent to transmit disease in experimental animal models, suggesting shared mechanisms with traditional prion diseases. Sensitive detection of prion disease has been advanced by in vitro amplification of low levels of disease specific amyloid seeds, e.g. serial protein misfolding amplification (sPMCA), amyloid seeding (ASA) and real-time quaking induced conversion (RT-QuIC), thereby replicating the disease process in vitro. In addition, measurement of the amyloid formation rate can estimate the level of disease-associated seed by using methods analogous to quantitative polymerase chain reaction (qPCR). In the present work, we apply these principles to show that seeding activity of in vitro generated amyloid tau and AD brain amyloid tau can be readily detected and quantitated.

 

=============

 

P.83: Gerstmann-Str€aussler-Scheinker disease with F198S mutation: Selective propagation of PrPSc and pTau upon inoculation in bank vole

 

Michele Angelo Di Bari1, Romolo Nonno1, Laura Pirisinu1, Claudia D’Agostino1, Geraldina Riccardi1, Guido Di Donato1, Paolo Frassanito1, Bernardino Ghetti2, Pierluigi Gambetti3, and Umberto Agrimi1

 

1Department of Veterinary Public Health and Food Safety; Istituto Superiore di Sanit a; Rome, Italy;

 

2Indiana University-Purdue University Indianapolis; Department of Pathology and Laboratory Medicine; Indianapolis, IN USA; 3Case Western Reserve University; Cleveland, OH USA

 

Gerstmann-Str€aussler-Scheinker disease with F198S mutation (GSS-F198S) is characterized by the presence of PrP amyloid plaques as well as neurofibrillary tangles with abnormally-phosphorylated tau protein (pTau) in the brain. The relationship between tau protein and PrP in the pathogenesis of GSS-F198S is unknown. In a previous study, we inoculated intracerebrally 2 GSS-F198S cases in 2 lines of voles carrying either methionine (Bv109M) or isoleucine (Bv109I) at codon 109 of PrP. GSS-F198S transmitted rather efficiently to Bv109I, but not to Bv109M.

 

Here we investigated the presence of pTau, as assessed by immunohistochemistry with anti-pTau antibodies AT180 and PHF-1, in the same voles previously inoculated with GSSF198S. Among these voles, most Bv109I showed clinical signs after short survival times (»150 d.p.i.) and were positive for PrPSc. The remaining Bv109I and all Bv109M survived for longer times without showing prion-related pathology or detectable PrPSc. All Bv109I which were previously found PrPSc-positive,

 

S54 Prion 2015 Poster Abstracts

 

were immunonegative for pTau deposition. In contrast, pTau deposition was detected in 16/20 voles culled without clinical signs after long survival times (225–804 d.p.i.). pTau deposition was characterized by neuropil threads and coiled bodies in the alveus, and was similar in all voles analyzed.

 

These findings highlight that pTau from GSS-F198S can propagate in voles. Importantly, pTau propagation was independent from PrPSc, as pTau was only found in PrPSc-negative voles surviving longer than 225 d.p.i. Thus, selective transmission of PrPSc and pTau proteinopathies from GSS-F198S can be accomplished by experimental transmission in voles.

 

=========

 

I3 Aβ Strains and Alzheimer’s Disease

 

Lary Walker Emory University, Atlanta, GA, USA

 

An essential early event in the development of Alzheimer’s disease is the misfolding and aggregation of Aβ. Enigmatically, despite the extensive deposition of human-sequence Aβ in the aging brain, nonhuman primates do not develop the full pathologic or cognitive phenotype of Alzheimer’s disease, which appears to be unique to humans. In addition, some humans with marked Aβ accumulation in the brain retain their cognitive abilities, raising the question of whether the pathogenicity of Aβ is linked to the molecular features of the misfolded protein. I will present evidence for strain-like molecular differences in aggregated Aβ between humans and nonhuman primates, and among end-stage Alzheimer patients. I will also discuss a case of Alzheimer’s disease with atypical Aβ deposition to illustrate heterogeneity in the molecular architecture of Aβ assemblies, and how this variability might influence the nature of the disease. As in the case of prion diseases, strain-like variations in the molecular architecture of Aβ could help to explain the phenotypic variability in Alzheimer’s disease, as well as the distinctively human susceptibility to the disorder.

 

This research was conducted in collaboration with Harry LeVine, Rebecca Rosen, Amarallys Cintron, David Lynn, Yury Chernoff, Anil Mehta and Mathias Jucker and colleagues. Supported by AG040589, RR165/OD11132, AG005119, NS077049, the CART Foundation and MetLife.

 

==========

 

I5 Pathogenic properties of synthetically generated prions

 

Jiyan Ma Van Andel Research Institute, Grand Rapids, Michigan, USA

 

Synthetically generating prions with bacterially expressed recombinant prion protein (recPrP) strongly supports the prion hypothesis. Yet, it remains unclear whether the pathogenic properties of synthetically generated prions (rec-Prion) fully recapitulate those of naturally occurring prions. A series of analyses including intracerebral and intraperitoneal transmissions of rec-Prion in wild-type mice were performed to determine the characteristics of rec-Prion induced diseases. Results from these analyses demonstrated that the rec-Prion exhibits the same pathogenic properties with naturally occurring prions, including a titratable infectivity that can be determined by endpoint titration assays, capability of transmitting prion disease via routes other than the direct intra-cerebral inoculation, causing ultra-structural lesions that are specific to prion disease, and sharing a similar manner of visceral dissemination and neuroinvasion with naturally occurring scrapie and chronic wasting disease. These findings confirmed that the disease caused by rec-Prion in wild-type mice is bona fide prion disease or transmissible spongiform encephalopathiges, and the rec-Prion contains similar pathogenic properties as naturally occurring prions.

 

I6 Transmissible protein toxins in neurodegenerative disease

 

Jacob Ayers, David Borchelt University of Florida, Gainesville, FL, USA

 

Amyotrophic lateral sclerosis (ALS) is an obvious example of neurodegenerative disease that seems to spread along anatomical pathways. The spread of symptoms from the site of onset (e.g. limb) to the respiratory musculature drives the rate of disease progression. In cognitive disorders, such as Alzheimer’s disease, one can find similarly find evidence of spreading dysfunction and pathology. One mechanism to account for this spread of disease from one neural structure to another is by evoking prion-like propagation of a toxic misfolded protein from cell to cell. Recent studies in animals that model aspects of Alzheimer’s Disease, Parkinson’s Disease, and Tauopathy, have bolstered the arguments in favor of prion-like, although in most of these models the mice do not develop overt “clinical” symptoms. Recently, Jacob Ayers demonstrated that the symptoms of ALS can be transmitted from a strain of mice that expresses mutant SOD1-G93A at high levels to a second transgenic strain that expresses mutant SOD1 at low, nontoxic, levels. This model showed many prion-like features including evidence of host-adaptation (earlier and more penetrant disease upon second passage). Interestingly, homogenates from paralyzed mice expressing the G37R variant of SOD1 transmitted poorly, a finding suggestive that different SOD1 variants may exhibit strain-like properties. These “ i n d u c i b l e ” m o d e l s o f h u m a n neurodegenerative disease enable the generation of models that do not require extraordinary levels of transgene expression and provide a more precise means of initiating the disease process, advances that may translate into more predictive pre-clinical models.

 

=======

 

P188 Transmission of amyloid pathology by peripheral administration of misfolded Aβ

 

Javiera Bravo-Alegria1 ,2, Rodrigo Morales2, Claudia Duran-Aniotz3, Claudio Soto2 1University of Los Andes, Santiago, Chile, 2Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School, Houston, Texas, USA, 3University of Chile, Santiago, Chile

 

Misfolding and aggregation of Amyloid-β (Aβ) is one of the primary events involved in the pathogenesis of Alzheimer's disease (AD). Recently, it has been proposed that Aβ aggregates can transmit and spread the pathology following a prion-like mechanism. Prions can be exogenously transmitted by many different routes of administration. In the case of Aβ, previous studies showed that intraperitoneal (i.p.) injection of seeds can accelerate cerebral amyloidosis in mouse models. However, other potential routes have not yet been studied. The goal of this work was to assess whether Aβ amyloidosis can be seeded in the brain of a transgenic mouse model of AD by peripheral administration of misfolded particles.

 

Young tg2576 animals (50 days old) were inoculated with a pool of brain extract coming from old Tg2576 animals (10%w/v) by different routes: i.p. (100μL), eye drops (5μL each eye, 3 times), intramuscular (i.m., 50μL), and per os (p.o., 1000μL). Animals were sacrificed at 300 days old, and brain samples were analyzed for amyloid pathology by IHC and ELISA.

 

The i.p., i.m., and eye drops administration of Aβ seeds significantly accelerated pathological features in tg2576. Regardless of the higher volume administered, p.o. treated animals did not show any pathological changes when compared to untreated controls. Differences in the proportion of diffuse, core and vascular deposition was observed within experimental groups. Our data show that peripheral administration of Aβ seeds could accelerate pathological changes in the brain and suggest that an orchestrated cross-talk between the brain and peripheral tissues occurs in AD.

 

==========

 

 https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

 

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

 

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF

 

*** Singeltary comment ;

 

http://www.plosone.org/annotation/listThread.action?root=82860

 

Tuesday, June 30, 2015

 

PRION2015 Alzheimer’s disease

 

http://betaamyloidcjd.blogspot.com/2015/06/prion2015-alzheimers-disease.html

 

Tuesday, June 30, 2015

 

visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant Creutzfeldt Jakob Disease hvCJD

 

http://betaamyloidcjd.blogspot.com/2015/06/visual-variant-of-alzheimers-disease.html

 

2015 PRION CONFERENCE

 

*** RE-P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study

 

***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. ***

 

ran across an old paper from 1984 ;

 

***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent. ***

 

http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html

 

***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD...see;

 

P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study

 

Paul Brown1, Diane Ritchie2, James Ironside2, Christian Abee3, Thomas Kreil4, and Susan Gibson5 1NIH (retired); Bethesda, MD USA; 2University of Edinburgh; Edinburgh, UK; 3University of Texas; Bastrop, TX USA; 4Baxter Bioscience; Vienna, Austria; 5University of South Alabama; Mobile, AL USA

 

Five vCJD disease transmissions and an estimated 1 in 2000 ‘silent’ infections in UK residents emphasize the continued need for information about disease risk in humans. A large study of blood component infectivity in a non-human primate model has now been completed and analyzed. Among 1 GSS, 4 sCJD, and 3 vCJD cases, only GSS leukocytes transmitted disease within a 5–6 year surveillance period. A transmission study in recipients of multiple whole blood transfusions during the incubation and clinical stages of sCJD and vCJD in ic-infected donor animals was uniformly negative. These results, together with other laboratory studies in rodents and nonhuman primates and epidemiological observations in humans, ***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. The issue of decades-long incubation periods in ‘silent’ vCJD carriers remains open.

 

=============

 

***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD...see;

 

Wednesday, December 11, 2013

 

*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***

 

http://creutzfeldt-jakob-disease.blogspot.com/2013/12/detection-of-infectivity-in-blood-of.html

 

THE BAXTER STUDY...SEE MORE HERE ;

 

http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html

 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

 

From: Terry S. Singeltary Sr.

 

Sent: Saturday, November 15, 2014 9:29 PM

 

To: Terry S. Singeltary Sr.

 

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

 

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE

 

R. G. WILL

 

1984

 

snip...

 

http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf

 

THE BAXTER STUDY...SEE MORE HERE ;

 

http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html

 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

 

Friday, January 10, 2014

 

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ??? Greetings Friends, Neighbors, and Colleagues,

 

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???

 

Confucius is confused again.

 

I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.

 

what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???

 

it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.

 

sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.

 

I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.

 

I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.

 

by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?

 

this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.

 

the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).

 

http://www.ncbi.nlm.nih.gov/pubmed/?term=sporadic

 

the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.

 

http://www.ncbi.nlm.nih.gov/pubmed/?term=familial

 

again, sporadic and familial is a red herring, in my opinion.

 

also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.

 

*UPDATE* NOVEMBER 16, 2014 vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ??? Friday, January 10, 2014

 

Greetings again Friends, Neighbors, and Colleagues,

 

snip...see ;

 

http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html

 

Wednesday, January 28, 2015

 

Another new prion disease: relationship with central and peripheral amyloidoses

 

http://betaamyloidcjd.blogspot.com/2015/01/another-new-prion-disease-relationship.html

 

Sunday, February 10, 2013

 

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

 

http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html

 

Wednesday, September 21, 2011

 

PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)

 

http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html

 

Wednesday, January 5, 2011

 

ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions

 

David W. Colby1,* and Stanley B. Prusiner1,2

 

http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html

 

http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html

 

Tuesday, October 4, 2011

 

Molecular Psychiatry

 

advance online publication 4 October 2011; doi: 10.1038/mp.2011.120

 

De novo induction of amyloid-ß deposition in vivo

 

Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention. Keywords: amyloid; prion; protein misfolding; disease transmission

 

http://www.nature.com/mp/journal/vaop/ncurrent/abs/mp2011120a.html

 

see more here ;

 

http://betaamyloidcjd.blogspot.com/2011/10/de-novo-induction-of-amyloid-deposition.html

 

http://transmissiblespongiformencephalopathy.blogspot.com/2011/10/alzheimers-disease-is-transmissible.html

 

Friday, September 3, 2010

 

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

 

http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html

 

http://betaamyloidcjd.blogspot.com/

 

SCENARIO 3: ‘THE THIN STEMMED GLASS’

 

... a TSE is found that is linked to Alzheimer’s disease.

 

http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html

 

Wednesday, July 15, 2015

 

*** Additional BSE TSE prion testing detects pathologic lesion in unusual brain location and PrPsc by PMCA only, how many cases have we missed? ***

 

http://transmissiblespongiformencephalopathy.blogspot.com/2015/07/additional-bse-tse-prion-testing.html

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

 

Terry S. Singeltary, Sr Bacliff, Tex

 

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

 

http://jama.jamanetwork.com/article.aspx?articleid=1031186

 

http://transmissiblespongiformencephalopathy.blogspot.com/2014/12/terry-s-singeltary-sr-publications-tse.html

 

http://transmissiblespongiformencephalopathy.blogspot.com/

 

http://creutzfeldt-jakob-disease.blogspot.com/

 

http://vcjd.blogspot.com/

 

http://kuru-tse.blogspot.com/

 

http://sporadicffi.blogspot.com/

 

http://vpspr.blogspot.com/

 

http://betaamyloidcjd.blogspot.com/

 

http://prionoid.blogspot.com/

 

http://prionopathy.blogspot.com/

 

http://proteinopathies.blogspot.com/

 

http://earlyonsetdementia.blogspot.com/

 

http://bovineprp.blogspot.com/

 

http://bseusa.blogspot.com/

 

http://madcowusda.blogspot.com/

 

http://bse-atypical.blogspot.com/

 

http://scrapie-usa.blogspot.com/

 

http://nor-98.blogspot.com/

 

http://felinespongiformencephalopathyfse.blogspot.com/

 

http://caninespongiformencephalopathy.blogspot.com/

 

http://creutzfeldt-jakob-disease.blogspot.com/

 

 

iatrogenic, what if ???

 

Terry S. Singeltary Sr.

PRION2015 Alzheimer’s disease

PRION2015 Alzheimer’s disease

 

*** P.34: Preliminary study of Alzheimer’s disease transmission to bank vole

 

Guido Di Donato1, Geraldina Riccardi1, Claudia D’Agostino1, Flavio Torriani1, Maurizio Pocchiari2, Romolo Nonno1, Umberto Agrimi1, and Michele Angelo Di Bari1

 

1Department of Food Safety and Veterinary Public Health Istituto Superiore di Sanit a, Rome, Italy; 2Department of Cellular Biology and Neuroscience; Istituto Superiore di Sanit a, Rome, Italy

 

Extensive experimental findings indicate that prion-like mechanisms underly the pathogenesis of Alzheimer disease (AD). Transgenic mice have been pivotal for investigating prionlike mechanisms in AD, still these models have not been able so far to recapitulate the complex clinical-pathological features of AD. Here we aimed at investigating the potential of bank vole, a wild-type rodent highly susceptible to prions, in reproducing AD pathology upon experimental inoculation.

 

Voles were intracerebrally inoculated with brain homogenate from a familial AD patient. Animals were examined for the appearance of neurological signs until the end of experiment (800 d post-inoculation, d.p.i.). Brains were studied by immunohistochemistry for pTau Prion 2015 Poster Abstracts S29 (with AT180 and PHF-1 antibodies) and b-amyloid (4G8).

 

Voles didn’t show an overt clinical signs, still most of them (11/16) were found pTau positive when culled for intercurrent disease or at the end of experiment. Interestingly, voles culled as early as 125 d.p.i. already showed pTau aggregates. Deposition of pTau was similar in all voles and was characterized by neuropil threads and coiled bodies in the alveus, and by rare neurofibrillary tangles in gray matter. Conversely, b-amyloid deposition was rather rare (2/16). Nonetheless, a single vole showed the contemporaneous presence of pTau in the alveus and a few Ab plaque-like deposits in the subiculum. Uninfected age-matched voles were negative for pTau and Ab.

 

*** These findings corroborate and extend previous evidences on the transmissibility of pTau and Ab aggregation. Furthermore, the observation of a vole with contemporaneous propagation of pTau and Ab is intriguing and deserves further studies.

 

=================

 

P.155: Quantitative real-time analysis of disease specific tau amyloid seeding activity

 

Davin Henderson and Edward Hoover Prion Research Center; College of Veterinary Medicine and Biomedical Sciences; Colorado State University; Fort Collins, CO USA

 

A leading hypothesis for the cause of neurodegenerative diseases is the templated misfolding of cellular proteins to an amyloid state. Spongiform encephalopathies were the first diseases discovered to be caused by a misfolded amyloid-rich protein. It is now recognized that the major human neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE), also are associated with amyloid formation. Moreover, AD and PD amyloids have been shown competent to transmit disease in experimental animal models, suggesting shared mechanisms with traditional prion diseases. Sensitive detection of prion disease has been advanced by in vitro amplification of low levels of disease specific amyloid seeds, e.g. serial protein misfolding amplification (sPMCA), amyloid seeding (ASA) and real-time quaking induced conversion (RT-QuIC), thereby replicating the disease process in vitro. In addition, measurement of the amyloid formation rate can estimate the level of disease-associated seed by using methods analogous to quantitative polymerase chain reaction (qPCR). In the present work, we apply these principles to show that seeding activity of in vitro generated amyloid tau and AD brain amyloid tau can be readily detected and quantitated.

 

=============

 

P.83: Gerstmann-Str€aussler-Scheinker disease with F198S mutation: Selective propagation of PrPSc and pTau upon inoculation in bank vole

 

Michele Angelo Di Bari1, Romolo Nonno1, Laura Pirisinu1, Claudia D’Agostino1, Geraldina Riccardi1, Guido Di Donato1, Paolo Frassanito1, Bernardino Ghetti2, Pierluigi Gambetti3, and Umberto Agrimi1

 

1Department of Veterinary Public Health and Food Safety; Istituto Superiore di Sanit a; Rome, Italy;

 

2Indiana University-Purdue University Indianapolis; Department of Pathology and Laboratory Medicine; Indianapolis, IN USA; 3Case Western Reserve University; Cleveland, OH USA

 

Gerstmann-Str€aussler-Scheinker disease with F198S mutation (GSS-F198S) is characterized by the presence of PrP amyloid plaques as well as neurofibrillary tangles with abnormally-phosphorylated tau protein (pTau) in the brain. The relationship between tau protein and PrP in the pathogenesis of GSS-F198S is unknown. In a previous study, we inoculated intracerebrally 2 GSS-F198S cases in 2 lines of voles carrying either methionine (Bv109M) or isoleucine (Bv109I) at codon 109 of PrP. GSS-F198S transmitted rather efficiently to Bv109I, but not to Bv109M.

 

Here we investigated the presence of pTau, as assessed by immunohistochemistry with anti-pTau antibodies AT180 and PHF-1, in the same voles previously inoculated with GSSF198S. Among these voles, most Bv109I showed clinical signs after short survival times (»150 d.p.i.) and were positive for PrPSc. The remaining Bv109I and all Bv109M survived for longer times without showing prion-related pathology or detectable PrPSc. All Bv109I which were previously found PrPSc-positive,

 

S54 Prion 2015 Poster Abstracts

 

were immunonegative for pTau deposition. In contrast, pTau deposition was detected in 16/20 voles culled without clinical signs after long survival times (225–804 d.p.i.). pTau deposition was characterized by neuropil threads and coiled bodies in the alveus, and was similar in all voles analyzed.

 

These findings highlight that pTau from GSS-F198S can propagate in voles. Importantly, pTau propagation was independent from PrPSc, as pTau was only found in PrPSc-negative voles surviving longer than 225 d.p.i. Thus, selective transmission of PrPSc and pTau proteinopathies from GSS-F198S can be accomplished by experimental transmission in voles.

 

=========

 

=========

 

I3 Aβ Strains and Alzheimer’s Disease

 

Lary Walker Emory University, Atlanta, GA, USA

 

An essential early event in the development of Alzheimer’s disease is the misfolding and aggregation of Aβ. Enigmatically, despite the extensive deposition of human-sequence Aβ in the aging brain, nonhuman primates do not develop the full pathologic or cognitive phenotype of Alzheimer’s disease, which appears to be unique to humans. In addition, some humans with marked Aβ accumulation in the brain retain their cognitive abilities, raising the question of whether the pathogenicity of Aβ is linked to the molecular features of the misfolded protein. I will present evidence for strain-like molecular differences in aggregated Aβ between humans and nonhuman primates, and among end-stage Alzheimer patients. I will also discuss a case of Alzheimer’s disease with atypical Aβ deposition to illustrate heterogeneity in the molecular architecture of Aβ assemblies, and how this variability might influence the nature of the disease. As in the case of prion diseases, strain-like variations in the molecular architecture of Aβ could help to explain the phenotypic variability in Alzheimer’s disease, as well as the distinctively human susceptibility to the disorder.

 

This research was conducted in collaboration with Harry LeVine, Rebecca Rosen, Amarallys Cintron, David Lynn, Yury Chernoff, Anil Mehta and Mathias Jucker and colleagues. Supported by AG040589, RR165/OD11132, AG005119, NS077049, the CART Foundation and MetLife.

 

==========

 

I5 Pathogenic properties of synthetically generated prions

 

Jiyan Ma Van Andel Research Institute, Grand Rapids, Michigan, USA

 

Synthetically generating prions with bacterially expressed recombinant prion protein (recPrP) strongly supports the prion hypothesis. Yet, it remains unclear whether the pathogenic properties of synthetically generated prions (rec-Prion) fully recapitulate those of naturally occurring prions. A series of analyses including intracerebral and intraperitoneal transmissions of rec-Prion in wild-type mice were performed to determine the characteristics of rec-Prion induced diseases. Results from these analyses demonstrated that the rec-Prion exhibits the same pathogenic properties with naturally occurring prions, including a titratable infectivity that can be determined by endpoint titration assays, capability of transmitting prion disease via routes other than the direct intra-cerebral inoculation, causing ultra-structural lesions that are specific to prion disease, and sharing a similar manner of visceral dissemination and neuroinvasion with naturally occurring scrapie and chronic wasting disease. These findings confirmed that the disease caused by rec-Prion in wild-type mice is bona fide prion disease or transmissible spongiform encephalopathiges, and the rec-Prion contains similar pathogenic properties as naturally occurring prions.

 

I6 Transmissible protein toxins in neurodegenerative disease

 

Jacob Ayers, David Borchelt University of Florida, Gainesville, FL, USA

 

Amyotrophic lateral sclerosis (ALS) is an obvious example of neurodegenerative disease that seems to spread along anatomical pathways. The spread of symptoms from the site of onset (e.g. limb) to the respiratory musculature drives the rate of disease progression. In cognitive disorders, such as Alzheimer’s disease, one can find similarly find evidence of spreading dysfunction and pathology. One mechanism to account for this spread of disease from one neural structure to another is by evoking prion-like propagation of a toxic misfolded protein from cell to cell. Recent studies in animals that model aspects of Alzheimer’s Disease, Parkinson’s Disease, and Tauopathy, have bolstered the arguments in favor of prion-like, although in most of these models the mice do not develop overt “clinical” symptoms. Recently, Jacob Ayers demonstrated that the symptoms of ALS can be transmitted from a strain of mice that expresses mutant SOD1-G93A at high levels to a second transgenic strain that expresses mutant SOD1 at low, nontoxic, levels. This model showed many prion-like features including evidence of host-adaptation (earlier and more penetrant disease upon second passage). Interestingly, homogenates from paralyzed mice expressing the G37R variant of SOD1 transmitted poorly, a finding suggestive that different SOD1 variants may exhibit strain-like properties. These “ i n d u c i b l e ” m o d e l s o f h u m a n neurodegenerative disease enable the generation of models that do not require extraordinary levels of transgene expression and provide a more precise means of initiating the disease process, advances that may translate into more predictive pre-clinical models.

 

=======

 

P188 Transmission of amyloid pathology by peripheral administration of misfolded Aβ

 

Javiera Bravo-Alegria1 ,2, Rodrigo Morales2, Claudia Duran-Aniotz3, Claudio Soto2 1University of Los Andes, Santiago, Chile, 2Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School, Houston, Texas, USA, 3University of Chile, Santiago, Chile

 

Misfolding and aggregation of Amyloid-β (Aβ) is one of the primary events involved in the pathogenesis of Alzheimer's disease (AD). Recently, it has been proposed that Aβ aggregates can transmit and spread the pathology following a prion-like mechanism. Prions can be exogenously transmitted by many different routes of administration. In the case of Aβ, previous studies showed that intraperitoneal (i.p.) injection of seeds can accelerate cerebral amyloidosis in mouse models. However, other potential routes have not yet been studied. The goal of this work was to assess whether Aβ amyloidosis can be seeded in the brain of a transgenic mouse model of AD by peripheral administration of misfolded particles.

 

Young tg2576 animals (50 days old) were inoculated with a pool of brain extract coming from old Tg2576 animals (10%w/v) by different routes: i.p. (100μL), eye drops (5μL each eye, 3 times), intramuscular (i.m., 50μL), and per os (p.o., 1000μL). Animals were sacrificed at 300 days old, and brain samples were analyzed for amyloid pathology by IHC and ELISA.

 

The i.p., i.m., and eye drops administration of Aβ seeds significantly accelerated pathological features in tg2576. Regardless of the higher volume administered, p.o. treated animals did not show any pathological changes when compared to untreated controls. Differences in the proportion of diffuse, core and vascular deposition was observed within experimental groups. Our data show that peripheral administration of Aβ seeds could accelerate pathological changes in the brain and suggest that an orchestrated cross-talk between the brain and peripheral tissues occurs in AD.

 

==========

 

 https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

 

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

 

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

 

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF

 

*** Singeltary comment ;

 

http://www.plosone.org/annotation/listThread.action?root=82860

 

TSS

visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant Creutzfeldt Jakob Disease hvCJD

Subject: visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant Creutzfeldt Jakob Disease hvCJD

 

Research article

 

Visual signs and symptoms in patients with the visual variant of Alzheimer disease

 

Pierre-François Kaeser1, Joseph Ghika2 and François-Xavier Borruat1*

 

* Corresponding author: François-Xavier Borruat francois.borruat@fa2.ch

 

Author Affiliations

 

1 Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Avenue de France 15, Lausanne, CH-1004, Switzerland

 

2 Department of Neurology, University of Lausanne, CHUV, Lausanne, Switzerland

 

For all author emails, please log on.

 

BMC Ophthalmology 2015, 15:65 doi:10.1186/s12886-015-0060-9

 

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2415/15/65

 

Received: 11 July 2014 Accepted: 19 June 2015 Published: 30 June 2015

 

© 2015 Kaeser et al.

 

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

 

Abstract Background

 

Prominent visual symptoms can present in the visual variant of Alzheimer’s disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD.

 

Methods

 

We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro-ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients.

 

Results

 

The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, “visual blur” in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients

 

Conclusions

 

Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties.

 

Keywords: Alzheimer; Reading difficulty; Homonymous hemianopsia; Simultanagnosia

 

http://www.biomedcentral.com/1471-2415/15/65

 

Journal of Neuro-Ophthalmology: March 2014 - Volume 34 - Issue 1 - p 4–9 doi: 10.1097/WNO.0b013e3182916155

 

Original Contribution

 

The Heidenhain Variant of Creutzfeldt-Jakob Disease—A Case Series

 

Parker, Sarah E. MD; Gujrati, Meena MD; Pula, John H. MD; Zallek, Sarah N. MD; Kattah, Jorge C. MD

 

Supplemental Author Material Collapse Box Abstract Background: To study the neuro-ophthalmologic characteristics of patients with the visual variant of Creuztfeldt-Jakob disease (CJD) predominantly affecting the occipital and parietal lobes, known as the Heidenhain variant (HvCJD). The initial symptoms and findings may overlap with other posterior cerebral degenerative disorders. We reviewed our experience with HvCJD including clinical course and results of neuroimaging, electroencephalography (EEG), and cerebrospinal fluid (CSF) studies. Neuropathological postmortem findings were reviewed when available to confirm the clinical impression.

 

Methods: Retrospective study of HvCJD patients examined in the past 15 years at a single tertiary referral university hospital. Rapid rate of visual and neurological deterioration and abnormal diffusion-weighted imaging (DWI) were characteristic for HvCJD.

 

Results: Three patients displayed abnormalities in DWI, EEG, and CSF and had rapid clinical progression, leading to a clinical diagnosis of HvCJD. None underwent diagnostic cerebral biopsy. In 2 patients, the diagnosis of sporadic CJD was confirmed by postmortem neuropathologic, immunohistochemical, and genetic studies.

 

Conclusions: The gold standard for establishing the diagnosis of HvCJD is based on the characteristic histopathologic findings and molecular confirmation. Concern with potential iatrogenic CJD, related to surgical instrumentation or operating room prion contamination, has limited the availability of confirmatory brain biopsy. Our case series illustrates how the combination of clinical neuroimaging and EEG studies and 14:3:3 protein and other neuronal protein marker levels can lead to the diagnosis of HvCJD. Immunohistochemical analysis and genetic testing at a specialized prion research center will assist in identifying the sporadic variant and genetic forms of CJD.

 

© 2014 by North American Neuro-Ophthalmology Society

 

SNIP...

 

DISCUSSION

 

In 1998, Benson et al (11) described PCD as an unusual neurodegenerative disorder involving the posterior parietal and occipital lobes. Neuropathologic findings in PCD include senile plaques and neurofibrillary tangles, typical for Alzheimer disease in the majority of cases (7–9). Less frequently, subcortical gliosis as a variant of Pick disease and spongiform changes, neuronal loss and gliosis due to prion infection were reported (9). However, epidemiologic data are lacking. Clinical findings in PCD and HvCJD include combinations of visual field defects, cortical blindness, dyschromatopsia, visual agnosia, alexia, prosopagnosia, palinopsia, optical anosognosia, Balint and Gertsmann syndrome (12–16). Between 1998 and 2012, we evaluated 10 patients with PCD; 3 had sporadic HvCJD who were followed until their death. We are uncertain about the etiology in the remaining 7 patients who developed either a slowly progressive dementia (evolving over several years) and are still alive or were lost to follow-up. The largest published series of the HvCJD included 34 pathologically confirmed cases over a 51-month period (6). This study from the University of Göttingen in Germany is the geographic base of the “German National Creutzfeldt-Jakob Disease Surveillance Study.” Clinical findings were available in 25 cases and consisted of a combination of visual loss and higher visual deficits as found in previous studies. The rate of neurological deterioration was faster in the HvCJD group compared with other CJD variants and did not correlate with location or extent of neuropathologic findings. Homozygosis for methionine in codon 129, identified in 2 of our patients, was noted as a possible genetic indicator of an aggressive clinical course. We evaluated our patients by applying the diagnostic criteria used by Kropp et al (6) and endorsed by the World Health Organization (Table 1). Neuroimaging findings showed subtle increased intensity in the parieto-occipital region on T2 and FLAIR images only in case 2. Yet all 3 patients had striking visual deficits on examination. Therefore, HvCJD should be considered in any patient with visual field loss and a normal MRI or when imaging abnormalities fail to explain the clinical findings (15). Our imaging protocol included diffusion-weighted imaging (DWI) sequences (12,16). Restricted diffusion involving the gyri of the parieto-occipital cortex was observed in 2 of our cases (Fig. 3). The third patient (Case 2) was evaluated before the incorporation of DWI sequences in the MRI protocol at our institution. DWI was the most helpful ancillary test supporting the diagnosis of HvCJD, and to our knowledge, other PCD variants usually are not associated with DWI changes. Graphic Table 1

 

Initial EEG results showed nonspecific focal or generalized slowing, but follow-up EEG showed periodic sharp waves (Fig. 2) characteristic of CJD in later stages, correlating with the presence of myoclonus. SPECT scanning confirmed occipital hypoperfusion in one of our cases and should be part of PCD evaluation. SPECT largely has been replaced by PET that demonstrates focal cerebral hypometabolism in PCD (13,17). An important characteristic observation suggesting HvCJD in our patients was rapid clinical deterioration. The initial HvCJD diagnosis in Case 1 was supported by progressive neurological deterioration over 10 weeks after the onset of visual symptoms. Our other 2 patients were evaluated at an earlier stage of disease and were scheduled for additional testing over several days. Both patients failed to keep their 2-week follow-up appointments, and contact with their families revealed that they experienced rapid neurological deterioration with inability to perform activities of daily living. This prompted us to perform house calls to complete neurological evaluation and discussion with the family. Markers of massive neuronal loss (14:3:3 protein and neuronal-specific enolase) were elevated in 2 of our cases. These markers are deemed highly specific and sensitive (1). Their value must be interpreted with caution in individual cases, as increased neuronal protein levels (false positives) may be found in other rapidly progressive dementias and potential PCD mimics including autoimmune and paraneoplastic encephalitis, nonconvulsive status epilepticus, intravascular lymphoma, and vasculitis (2,5). Although characteristic histopathology of CJD remains the gold standard in establishing the diagnosis, the risk of instrument or surgical suite prion contamination during brain biopsy has limited the availability of brain biopsy (10). Until a specific serum or CSF prion marker is available, the premortem diagnosis of HvCJD in a patient with PCD continues to rely on close clinical monitoring, neuroimaging testing, serial EEG, and elevated CSF markers (18,19). We strongly recommend that specimens be sent to the National Prion Research Center at Case Western Reserve University in Cleveland, OH, and similar prion research centers for confirmatory, cerebral histopathology, immunohistochemical staining of abnormal protease-resistant prion protein, and genetic testing. This testing protocol establishes the diagnosis of sporadic, variant, and genetic forms of CJD and hopefully will prevent delay in establishing the correct diagnosis (20). In vitro, anti-prion agents have been found effective in controlling prion growth and progression. Unfortunately, these agents have failed to cure or slow CJD infection in humans (21–23).

 

http://journals.lww.com/jneuro-ophthalmology/pages/articleviewer.aspx?year=2014&issue=03000&article=00003&type=abstract

 

P07 Behavioral Neurology: Aging and Dementia MRI More Useful Than PET for Diagnosis of Heidenhain Variant Creutzfeldt-Jacob Disease (P07.163)

 

Jonathan Beary1 and Edward Manno2 1 General Neurology, Neurological Institute Cleveland Clinic Cleveland OH 2 Cerebrovascular Neurology, Neurological Institute Cleveland Clinic Cleveland OH

 

OBJECTIVE: To demonstrate that MRI detection of subtle focal cortical abnormalities can prove more useful than positron emission tomography (PET) in the diagnosis of Heidenhain variant Creutzfeldt-Jakob Disease (hvCJD).

 

BACKGROUND: hvCJD is a rare neurodegenerative, spongiform encephalopathy with an aggressive clinical course. PET brain imaging has been reported to detect focal cortical abnormalities in hvCJD with greater sensitivity than MRI. However, because PET is both more costly and less accessable than MRI, early diagnosis of this disease and subsequent prognostication may be unnecessarily delayed. The reliability of MRI over PET in detecting isolated occipital cortical changes suggestive of hvCJD has not been well studied.

 

DESIGN/METHODS: This is a case report with relevent neuroimaging review.

 

RESULTS: A 70 year-old right-handed male experienced visual hallucinations and visuospatial disorientation with worsening ataxia followed by progressive anterograde amnesia and cortical blindness. Six weeks later he was comatose with startle myoclonus. A sharply-contoured periodic pattern was evident posteriorly on continuous EEG monitoring with brain MRI revealing subtle bilateral occipital cortical diffusion restriction. PET brain imaging showed diffuse non-focal cortical hypometabolism. Both cerebrospinal fluid (CSF) 14-3-3 and tau protein studies were positive. EEG progressed to refractory status epilepticus and the patient died four days later. ***The presence of abnormal brain protease-resistant prion protein and MM1 genotype at autopsy supported the diagnosis of hvCJD.

 

CONCLUSIONS: hvCJD should be considered in patients with rapid-onset idiopathic visual disturbance and dementia. When combined with EEG and CSF analysis, isolated MRI visual cortex diffusion restriction is suggestive of this ultra-aggressive prion variant. MRI is able to efficiently facilitate valuable prognostication early in hvCJD and can be more useful than costly PET imaging.

 

Disclosure: Dr. Beary has nothing to disclose. Dr. Manno has nothing to disclose.

 

http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P07.163

 

Resident and Fellow Section

 

Mystery Case:

 

Heidenhain variant of Creutzfeldt-Jakob disease

 

Matthew Kalp, MD, PhD and Christopher H. Gottschalk, MD

 

A 75-year-old woman complained of a “scrambled brain” for 1 month. She endorsed poor depth perception and an inability to construct “mental maps” of her home and the grocery store. Examination revealed impaired delayed recall, ocular apraxia, optic ataxia, and simultanagnosia (Bálint syndrome). Diffusion-weighted MRI demonstrated cortical hyperintensities in the occipital lobes extending into the right parietal lobe, suggesting spongiform encephalopathy (figure). The 14-3-3 protein and elevated neuron-specific enolase were detected in the CSF. The patient was diagnosed with the Heidenhain variant of Creutzfeldt-Jakob disease.1 Early in the disease, this subgroup of patients with prion disease have isolated visual, not cognitive, symptoms and may be referred to an ophthalmologist.2

 

© 2014 American Academy of Neurology

 

http://www.neurology.org/content/83/22/e187.extract?etoc

 

Heidenhain Variant Creutzfeldt Jakob Disease autopsy case report 'MOM'

 

DIVISION OF NEUROPATHOLOGY University of Texas Medical Branch 114 McCullough Bldg. Galveston, Texas 77555-0785

 

FAX COVER SHEET

 

DATE: 4-23-98

 

TO: Mr. Terry Singeltary @ -------

 

FROM: Gerald Campbell

 

FAX: (409) 772-5315 PHONE: (409) 772-2881

 

Number of Pages (including cover sheet):

 

Message:

 

*CONFIDENTIALITY NOTICE*

 

http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzfeldt-jakob.html

Saturday, June 27, 2015

 

A Naturally Occurring Bovine Tauopathy Is Geographically Widespread in the UK

 

Research Article

 

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129499

 

Singeltary Comment;

 

IBNC Tauopathy or TSE Prion disease, it appears, no one is sure

 

Posted by flounder on 27 Jun 2015 at 16:29 GMT

 

http://www.plosone.org/annotation/listThread.action?root=86554

 

http://bovineprp.blogspot.com/2015/06/a-naturally-occurring-bovine-tauopathy.html

 

Thursday, January 2, 2014

 

CWD TSE Prion in cervids to hTGmice, Heidenhain Variant Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ???

 

http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/cwd-tse-prion-in-cervids-to-htgmice.html

 

 

 

kind regards, terry