[Opinion] Diagnosing Dementia in the Dark: Who Really Tests Koreans for CJD and Alzheimer’s?
By Mark D. Whitaker
Who really tests Koreans for neurological diseases like prion diseases of CJD and Alzheimer’s? No one. Given the U.S. mad cow beef scare in Korea, it is important to keep updated demographic information on changing dementia patterns in any population. This helps to determine if any particular beef consumption may be tied to ‘human mad cow,’ otherwise known as Creutzfeldt-Jakob Disease, the human form of prion disease. However, at present it is possible to give correct diagnoses of many neurological diseases like CJD only via autopsy after death. The U.S. lacks required autopsies for neurological diseases to verify if any doctors’ diagnoses of dementia were correct. It is truly a diagnosis of dementia in the dark.
In the U.S. real autopsy tests of neurological disease deaths are undertaken voluntarily, if at all. In the U.S., at one time autopsies were performed on about half of all corpses. However, by 2003 that percentage dropped to 15% or less. In 1995, the U.S. National Center for Health Statistics even stopped collecting autopsy data at all.
In Korea, it is the same. There are no laws requiring verification of any diagnoses of neurological diseases to see if what doctors claim people are dying of is true.
Why is this important? It is important because classification error and incorrect diagnoses can hide a lot of CJD this way. In fact, there is evidence that such misdiagnosis of neurological disease is widespread in the USA. A total of three different peer-reviewed studies find a lot of ’human mad cow‘ (CJD) in the USA when autopsies actually are done and the false diagnoses of “Alzheimer’s” are revealed. It is scandalous to keep ignoring it.
Three studies have found classification error hiding CJD in the USA. First, as long ago as 1989, a Yale team finally did systematic autopsies on those in the U.S. diagnosed as Alzheimer’s-and found 13% really had CJD. www.vegsource.com/articles/bse_editorial.htm. In a second smaller investigation, the result was similar: 3 of 12 diagnosed with Alzheimer’s really had a TSE disease.
www.organicconsumers.org/madcow/andrew1804.cfm. Third, a much larger University of Pittsburgh study “found the [U.S. prion disease] misdiagnosis rate of 5%,...estimated at 200,000 CJD in the U.S. per year.”
www.organicconsumers.org/madcow/andrew1804.cfm. Third, a much larger University of Pittsburgh study “found the [U.S. prion disease] misdiagnosis rate of 5%,...estimated at 200,000 CJD in the U.S. per year.”
To elaborate one study, Laura Manuelidis, chief of surgery of the Neuropathology Department of Yale University in 1989 study found 13% U.S. Alzheimer‘s patients really had CJD. Several studies including hers found autopsies show 3% to 14% of patients falsely diagnosed with Alzheimer’s or dementia really suffered from CJD. Those numbers might sound low, but there are 5.4 million Alzheimer‘s cases, hundreds of thousands of dementia cases in the U.S. by 2011, and up to 200,000 early onset Alzheimer’s in the USA by 2011. They argued that a small percentage of these can be up to 120,000 or more CJD cases undetected, not included in official statistics.
Thus the fact is that probably a lot of Americans--and many others worldwide--have died due to American beef infected with prions, leading to human Creutzfeldt-Jakob disease (CJD). There is evidence connecting prion-tainted food intakes to even CJD, particularly Dr. Jean-Philippe Deslys work at the French Atomic Energy Commission‘s medical research laboratory, or Prof. Richard Marsh’s work (his grant proposals to test more U.S. cattle for what he found were routinely turned down). So there is evidence that ‘human forms’ of CJD are indeed linked to under-researched forms of animal BSE. There is related evidence that neurological diseases in the USA continue to be falsely classified as Alzheimer‘s disease (that is exploding in the United States) instead of classified by actual tests to show how much of it is really CJD.
Dementia is rising in Korea as well, and not all of it can be attributed to an aging population.
I anticipate that the Korean “Alzheimer’s” rate will soon go up in a politically convenient fashion unless something is done to set up medical tests to discriminate accurately between the scale of actual Alzheimer‘s and actual CJD in Korea.
Three facts are important here. First, the import of US beef was banned in South Korea and elsewhere in the world after a case of BSE was discovered in a U.S. cow in 2003. At the time, South Korea was one of the world’s biggest consumers of U.S. beef with an estimated market value of $815 million.
Second, “Alzheimer‘s” has indeed been going up in Korea since 2005. You might say that an aging population causes this, and it is bound to happen. However, these Korean Alzheimer’s diagnoses are growing among those whom you least expect it--young adults in their 30s. As reported in the Korea Times recently (30-Somethings Vulnerable to Dementia? [5-07-2012]), The National Health Insurance Corporation notes that since 2005 “patients with pre-senile diseases have been steadily rising particularly among those in their 30s.”
Those in their 30s account for “about 9 percent of patients suffering from illnesses such as early onset Alzheimer’s.” They report that dementia among the elderly additionally shot up bizarrely high since 2005 as well. “From 2005 to 2010, those in the 75 to 84 age group who acquired the dementia causing diseases rose more than twofold, reaching 309,000.” An age-adjusted dementia rate more than doubled in this elderly group in just five years. From 2005 they measured a similar onset of dementia in among people in their 30s as well. There’s something special about that year. What happened from 2005? Is it only better testing or is this actually dementia, Alzheimer’s, or CJD after short-term incubation in human brains? The only way to tell is via brain autopsy after death. Any other diagnosis of living dementia patients by doctors is without this data, and doctors are merely guessing with a “diagnosis in the dark.”
As reported by the International Journal of Geriatric Psychiatry in 2006, South Korea is already one of the places where by 2002 there was a growing cost in elderly “dementia” patients. How many of these might be CJD? Does the money that Korea saves by importing cheaper beef actually cost the government and public far more in health care later on?
For my suggestions on Korean policy improvement, we can update science and public policy to test every Korean neurological patient via autopsy when they die (to catch misdiagnoses of Alzheimer’s and other neurological problems--that may be CJD/mad cow in humans). Soon there may be an alternative test, a better way to test for CJD called the Surround Optical Fiber Immunoassay (SOFIA) first tested in New York in 2010. With this technique, doctors could test for CJD in the living instead of having to wait for autopsy to verify which diagnoses of human dementia are correct. However autopsy is currently still the only accurate test for verifying dementia diagnoses. My other suggestion is to test every cow for BSE (U.S. and Korean cows), and my suggestion is to use the “Western Blotting” test.
Japan (from 2001-2005) and the European Union test all cows. US and Canada test less than 1%. Moreover the so-called “Gold Standard” test (real name) that the USA has chosen for its mad cow test is an immunohistochemical screening test. This choice of test (intentionally?) doesn‘t get its results back for several weeks. So by that time, is any tested beef already processed and likely in a consumer stomach or in another industrial food product?
The Japanese call the mad cow test the “Western Blotting” test. It is a protein-based test for prions. Japan’s choice of Western Blotting is a much cheaper and quicker test. It takes only hours to test a cow’s brains so the Japanese can remove all BSE-tainted meat easily while it is still in the factory. Noted from a scandal in 2001, the Japanese Western Blotting test seems to be a better gold standard since it is more sensitive to cases of BSE that the U.S.’s chosen so-called “Gold Standard” test that misses them. So despite this already low international standard of regulation and prion testing across North America for beef, the USDA testing for mad cow has been reduced even lower--by 90% since 2005.
Which regulation system do you think produces the better product as a result, and which one has less systemic health problems you have to worry about?
The best solution is to encourage a more sound local food supply that can at least be regulated by the Korean government with potential checks and balances of national politics--unlike the “Melamine Roulette” game from China, or the “Mad Cow Roulette” from the USA and Canada.
Take the high road: regulate your own industry at home better, and the whole world will want and trust Korean safer products. South Korea could develop a reputation for producing the world’s safest food. If the low road is taken, no one wins except the prions.
Mark D. Whitaker has taught environmental sociology at Ewha Womans University and Kookmin University. He is also the author of Toward a Bioregional State (2005), the first book on green constitutional engineering, and Ecological Revolution (2009).
The views presented in this column are the writer’s own, and do not necessarily reflect those of The Hankyoreh.
Please direct questions or comments to [email@example.com]
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what concerns me here, is the potential for the iatrogenic transmission of Alzheimer's disease. if proven, and there is other science showing the likelihood of this being true, but this would explain a great deal, and would explain the high increase of Alzheimers disease over the last decade. the medical, surgical, dental, blood, tissue, would all be a canidate for potential transmission. we must fund all these TSE prion disease research, and pursuit the cause and cure of these neurological mad cow type TSE prion disease...
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Mar 20, 2007 – Alzheimer's Disease Prevalence Rates Rise to More than Five Million in the .... actually had CJD. trying to find reference... thank you,
> Terry S. Singeltary Sr. ... vCJD and alzeheimer's in that alzheimers may be misdiagnosed.
Re: CJDs/TSEs VS Alzheimer's ??? (YALE STUDY 13% CJD ...
Nov 11, 2002 – (YALE STUDY 13% CJD MISDIAGNOSED) ...
In Reply to: CJDs/TSEs VS Alzheimer's ??? posted by TSS on ... To: "Terry S. Singeltary Sr." ...
CJD or Alzheimer's, THE PA STUDY...full text
change to ;
Evaluation of Cerebral Biopsies for the Diagnosis of Dementia
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.
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 examinationas 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
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 de-mentia (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*
Number of cases AD
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
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.
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.
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9. Perl D, Pendlebury W, Bird E. Detailed neuropathologic evalua-tion 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 syn-dromes 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.
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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
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
#### 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 accountsfor 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 abnormalities, 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 severityof other abnormalities (eg, gliosis and spongiform change), and the original pathologic diagnoses were not revised.
The clinical presentations, biopsy findings, and follow-up data, including postoperative complications, are summarized in Table 1 for all 14 patients. Their biopsy 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*
Duration of Symptoms, y
Dementia, left-sided homonymous hemianopia, myoclonus, EEG showing bilateral synchronous discharges
Dementia, aphasia, myoclonus; visual disturbance; facial asymmetry, abnormal EEG
Postoperative intraparenchymal hemorrhage, mute dead at 58 y, no autopsy ==========
Dementia, apraxia, visual disturbance, bradykinesia, EEG showing periodic sharp waves
Dead at 61 y, autopsy showed CJD =========
Dementia, myclonus, ataxia, family history of early-onset dementia
Dead at 40 y, autopsy showed AD =========
Dementia, paranoia, agitation, rigidity
Diffuse Lewy body disease
Dead at 78 y, no autopsy =========
Dementia, dysarthria, abnormal eye movements, ataxia
Neuronal storage disorder, adultonset N-P type II
Stable at 39 y =========
Dementia, amnesia, depression, partial complex seizures
Dead at 58 y, no autopsy ==========
Dementia, dysarthria, upper-extremity atrophy and fasciculations
Dead at 38 y, auotpsy showed amyotrophic lateral sclerosis with white-matter gliosis =========
Dementia, aphasia, right-sided hemiparesis, rigidity, athetosis
Postoperative subdural hygroma, dead at 50 y, autopsy showed focal CJD =========
Dementia, myoclonus, cerebellar dysaarthria, EEG showing biphasic periodic sharp waves
Consistent with CJD
Dementia, dysarthria, right-sided hemiparesis, hypertension, magnetic resonance image showing small vessel disease
stable at 61 y =========
Dementia, aphasia, right-sided hemiparesis
Bedridden, severely demented at 54 y =========
Dementia, mild bifacial weakness, concrete thinking, altered speech
Stable at 41 y =========
Dementia, choreoathetosis, family history of senile dementia, computed tomographic scan showing normal caudate
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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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
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
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.
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
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.
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.
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.
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.
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
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 p < 0.01 Age is expressed in years; NFT = numbers of neurofibrillary tangles per square millimeter; NP = numbers of neuritic plaques per square millimeter; n.s. = not significant.
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.
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.
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.
Three subjects for each group showed mild generalized spasticity, gastrocnemial clonus and bilateral Babinski sign. The difference was not significant.
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.
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.
Journal of Psychiatry & Neuroscience
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.
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.
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).
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.
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.tss
Subject: Re: Hello Dr. Manuelidis
Date: Fri, 22 Dec 2000 17:47:09 –0500
From: laura manuelidis firstname.lastname@example.org
Reply-To: email@example.com Organization: Yale Medical School
To: "Terry S. Singeltary Sr."
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.
Occasional PrP plaques are seen in cases of Alzheimer's Disease
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
Regarding Alzheimer's disease
(note the substantial increase on a yearly basis)
The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...
And NONE of this is relevant to BSE?
There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.
These are not relevant to any possible human hazard from BSE nor to the much more common dementia, Alzheimers.
4.5 MILLION DEMENTED ALZHEIMER'S PATIENTS, HOW MANY ARE CJD/TSEs ???
HOW CAN ONE-IN-A-MILLION BE ACCURATE WHEN CJD IS NOT REPORTABLE,
AND WHEN THE ELDERLY DO NOT GET AUTOPSIED??????