RESEARCH ARTICLE
Prevalence of Alzheimer's disease dementia in the 50 US states and 3142 counties: A population estimate using the 2020 bridged-race postcensal from the National Center for Health Statistics
Klodian Dhana, Todd Beck, Pankaja Desai, Robert S. Wilson, Denis A. Evans, Kumar B. Rajan
First published: 17 July 2023
https://doi.org/10.1002/alz.13081
Abstract
INTRODUCTION
This study estimates the prevalence and number of people living with Alzheimer's disease (AD) dementia in 50 US states and 3142 counties.
METHODS
We used cognitive data from the Chicago Health and Aging Project, a population-based study, and combined it with the National Center for Health Statistics 2020 bridged-race population estimates to determine the prevalence of AD in adults ≥65 years.
RESULTS
A higher prevalence of AD was estimated in the east and southeastern regions of the United States, with the highest in Maryland (12.9%), New York (12.7%), and Mississippi (12.5%). US states with the highest number of people with AD were California, Florida, and Texas. Among larger counties, those with the highest prevalence of AD were Miami-Dade County in Florida, Baltimore city in Maryland, and Bronx County in New York.
DISCUSSION
The state- and county-specific estimates could help public health officials develop region-specific strategies for caring for people with AD.
A 19-Year-Old Adolescent with Probable Alzheimer’s Disease1 Article type: Short Communication
Authors: Jia, Jianpinga; b; c; d; e; * | Zhang, Yuea | Shi, Yuqinga | Yin, Xupinga | Wang, Shiyuana | Li, Yana | Zhao, Tana | Liu, Wenyinga | Zhou, Aihonga | Jia, Longfeia
Affiliations: [a] Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, P.R. China | [b] Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China | [c] Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, P.R. China | [d] Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, P.R. China | [e] Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, P.R. China
Correspondence: [*] Correspondence to: Jianping Jia, MD, PhD, Professor of Neurology, Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Changchun Street 45, Xicheng District, Beijing 100053, China. Tel.: +86 10 83199449; E-mail: jjp@ccmu.edu.cn.
Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-239001, available at http://doi.org/10.3233/JAD-239001.
Abstract: Alzheimer’s disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient’s cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD.
Keywords: Case report, early-onset Alzheimer’s disease, gene mutation, hippocampal atrophy, memory impairment
DOI: 10.3233/JAD-221065
Ex vivo Detection of Amyloid-β in Naturally Formed Oral Biofilm
Article type: Research Article
Authors: Kanagasingam, Shalinia | von Ruhland, Christopherb | Welbury, Richarda | Singhrao, Sim K.a; *
Affiliations: [a] Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK | [b] Electron and Light Microscopy Facility, College of Biomedical and Life Sciences, Cardiff University, Wales, UK
Correspondence: [*] Correspondence to: Sim K. Singhrao, University of Central Lancashire, Preston, PR1 2HE, UK. E-mail: SKSinghrao@uclan.ac.uk.
Keywords: Amyloid-β fibrils, biofilm, extracellular polymeric substance, periodontal bacteria, root canal
DOI: 10.3233/ADR-220076
Journal: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 757-773, 2022
Received 21 September 2022 | Accepted 18 November 2022 | Published: 16 December 2022
Oral infection has been implicated in the possible etiology of Alzheimer’s disease.
Objective:
To detect amyloid-β (Aβ) within microbial biofilms.
Methods:
Freshly extracted teeth (N = 87) with periodontal disease were separated into Group A (N = 11), with primary root canal infection and Group B (N = 21) with failed endodontic treatment identified by the presence of, gutta percha root filling. Biofilm characteristics were observed by scanning electron microscopy (SEM). Demineralized paraffin wax embedded tooth sections and mineralized calculus biofilm were immunostained with the anti-Aβ antibody. The gutta perchas were processed either for on-section acrylic resin tissue immunocolloidal gold silver staining (IGSS) using the anti-Aβ antibody or in Araldite resin for ultrastructure.
Results:
SEM demonstrated calculus and gutta percha in situ harboring a polymicrobial biofilm featuring extracellular polymeric substance (EPS) and water channels. Immunohistochemistry on rehydrated paraffin wax tooth sections from Group A, demonstrated Aβ staining on external (calculus and plaque) and all intracanal infected regions. In Group B, the gutta percha biofilm IGSS gave an inconclusive result for Aβ. Transmission electron microscopy of selected teeth with infected intra-canals (Group A) and 20% of gutta percha biofilm (Group B) EPS contained electron dense fibrils of variable sizes, some of which were typical of human Aβ fibrils.
Conclusion:
This study detected both soluble and insoluble Aβ fibrils within the EPS of periodontal and endodontic natural biofilm, strongly suggesting its role as an antimicrobial peptide in combatting local infection, with potential risk for cross-seeding into the brain for AD development.
snip...
Conclusions
The present study has been valuable as a pilot study to understand the microbial biofilm Aβ from naturally formed oral heterogenous consortium of bacterial communities. The major strength being that they were naturally formed in the human host, which include the host-related parameters including age, local environmental factors, similar immune status, and lifestyle, such as diet and oral health condition.
The host appears to have responded to the infection by releasing Aβ as an innate response in group A tooth biofilms and to the gutta percha associated biofilm. Overall, this study detected insoluble Aβ within the periodontal and endodontic natural biofilm formation parameters. Clinical significance of the present study is that endodontic teeth can harbor multi-Kingdom species of microbes including viruses, and bacteria. These microbes can give rise to insoluble Aβ experimentally, not dissimilar to the mechanism with which prions deposit insoluble fibrils in Aβ plaques. Like prions, insoluble Aβ will remain a risk for being cross seeded to the brain and for the plausible development of AD later in life. Further research is required to clarify the extent of such a risk and the mechanism by which Aβ could translocate from the mouth to the brain.
Limitations and strengths of the study
Limitations of this study are a small N number. Absence of at least a pan antibody to microbial functional amyloids such as curli protein. Each extracted tooth could not be traced back to the donor, for example, if it came from a patient who suffered from type II diabetes or otherwise a healthy individual.
The strengths of this study are that the biofilms investigated were from human donors formed in a relatively senior age group from both males and females under patient based environmental/behavioral conditions for the true evaluation of insoluble Aβ.
Future studies
Future studies should include additional investigations such as DNA sequencing to identify the predominant bacteria, specifically from the Enterococci genus which typically harbor bacterial amyloid precursors curli, pili, and fimbriae that are said to form the elements of microbial Aβ under appropriate pathophysiological conditions. Alternatively test for at least one microbial functional amyloid such as curli protein. Specific immunocolloidal Aβ labeling of the fine filaments (assumed Aβ) should be performed at the ultrastructure level to confirm their identity for host Aβ and/or for microbial curli protein contribution. Investigations should include larger sample size and assess potential correlations with patients’ comorbidities.
Alzheimer's 'seeds' found in seven CJD victims' brains Thursday 10 September 2015
The results of a study that reported finding markers for Alzheimer's disease in the brains of some people who died of Creutzfeldt-Jakob disease (CJD) has led to many inaccurate headlines in the press.
The Daily Mirror claims "You can catch Alzheimer's", while the Mail Online claims that an "explosive new study suggests the disease is spread like CJD and could be passed on through blood transfusions, operations and dental work".
Neither claim adds up to much scrutiny, as the "explosive" study itself concludes: "There is no suggestion that Alzheimer's disease is a contagious disease and no supportive evidence … that Alzheimer's disease is transmissible, notably by blood transfusion".
The eight people involved in the study were infected with brain-damaging proteins called prions, which cause CJD, through injections of human growth hormone taken from the brains of people who had died. All the infections happened before 1985, when this type of treatment was stopped.
None of the eight people studied actually had Alzheimer's – they all died of CJD. During their autopsies, researchers were surprised to find evidence of amyloid beta protein deposits (abnormal clumps of protein), which can be a precursor of Alzheimer's, in seven people's brains.
These people were aged 36 to 51 years – too young for most people to develop Alzheimer's. The researchers suggest they may have been infected with amyloid proteins – dubbed Alzheimer's "seeds" – in the same way they had been infected with prions: through human growth hormone treatment.
But nobody should worry that they have "caught" Alzheimer's from routine medical treatment using the information this study has gathered.
snip...see full paper;
Alzheimer's disease, iatrogenic transmission, what if?
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
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.
In one transmission study documented in 1982, primates were inoculated with brain tissue from patients with confirmed Alzheimer’s disease. The animals developed a spongiform encephalopathy that was indistinguishable from CJD. However, other attempts to transmit AD have been unsuccessful.91
IN CONFIDENCE
5 NOVEMBER 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication.
There are also results to be made available shortly
(1) concerning a farmer with CJD who had BSE animals,
(2) on the possible transmissibility of Alzheimer’s and
(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
IN CONFIDENCE
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 recognised 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 emphasises 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
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.
J S METTERS
Room 509
Richmond House
Pager No: 081-884 3344 Callsign: DOH 832
92/11.4/1.2
Trouble has been brewing for some time...Dr. Collinge is lobbying hard, and is threatening to go to the media...
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
Singeltary Comment at very bottom of this Nature publishing;
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.
That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ?
who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.
Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer's and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
Singeltary Comment at very bottom of this Nature publishing;
Saturday, March 18, 2023
Autoclave treatment fails to completely inactivate DLB alpha-synuclein seeding activity
Prusiner et al, then and now!
Saturday, February 18, 2023
TAUOPATHIES, PICKS, AND PRIONS
Aβ and tau prions feature in the neuropathogenesis of Down syndrome
Carlo Condello carlo.condello@ucsf.edu, Alison M. Maxwell, Erika Castillo https://orcid.org/0000-0003-2492-901X, +9, and Stanley B. Prusiner
https://orcid.org/0000-0003-1955-5498 stanley.prusiner@ucsf.eduAuthors Info & Affiliations
Contributed by Stanley Prusiner; received August 1, 2022; accepted September 27, 2022; reviewed by Robert Brown Jr. and Neil Cashman.
November 7, 2022
119 (46) e2212954119
Significance
Approximately 5.4 million people worldwide have Down syndrome (DS), which is caused by trisomy of chromosome 21 (Chr21). The APP gene is one of approximately 250 protein-coding genes located on Chr21, and its duplication is associated with elevated Aβ production and increased incidence of Alzheimer’s disease (AD) neuropathology in most aged individuals with DS. Since AD brains have plaques composed of Aβ prions and neurofibrillary tangles composed of tau prions, we asked if DS brains have both Aβ and tau prions. We found that the age-dependent kinetics of Aβ and tau prions are distinct in DS and could even be detected in a 19-y-old individual. Whether DS is an ideal model for assessing efficacy of putative AD therapeutics remains unknown.
Abstract
Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer’s disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.
snip...
Discussion
Our findings demonstrate that the brains of people with DS feature both Aβ and tau prions, which appear to be indistinguishable from the two prions that accumulate in both the sporadic and familial forms of AD. Importantly, DS is neither sporadic nor inherited, but it is a genetic disease caused by complete or partial triplication of Chr21. In trisomic individuals who bear an extra copy of the APP gene, the overexpression of wild-type (WT) APP results in increased levels of Aβ prions. Conversely, partial trisomy lacking triplication of APP does not lead to the neuropathologic changes of AD (50, 51). While we have previously reported that Aβ prions in the absence of tau prions result in cerebral amyloid angiopathy (26), this is not the case for DS. We found both Aβ and tau prions in nearly all of the brains of our DS cohort. In agreement with others, we propose that research in people with DS may help clarify sAD pathogenesis, given that both neuropathology and prion infectivity closely resemble that found in sAD, the predominant form of AD.
Notably, some individuals with DS exhibit many co-occurring conditions, including heart defects, obesity, diabetes, and progeria. How these conditions in people with DS modify the central nervous system dysfunction in the aging DS brain is unclear. There is evidence from mouse models that triplication of some Chr21 homologs increases Aβ deposition independently of an extra APP copy (52); conversely, APP duplication alone is sufficient to cause AD (53). APP duplications in DS provide an interesting comparison to Tg(APP) mice, which also overexpress human APP and Aβ. However, we note that plaques only form in Tg mice bearing familial mutations in APP and not WT APP; efforts to knock-in the WT human APP allele or humanize the Aβ peptide sequence within rodent App do not lead to plaque formation in the lifespan of a mouse (54, 55). Moreover, while the first generation of DS mouse models, segmental trisomy of mouse Chr16 (e.g., Ts65Dn) (56, 57), do replicate many neurodevelopmental phenotypes and present age-related neurodegeneration, they do not produce robust Aβ pathology in aged mice (58). One caveat of the Ts65Dn model is that it duplicates genes not present on human Chr21. To avoid this, new models employing transchromosomic (Tc) techniques in mice and rats have been developed in which the long arm of human Chr21 is cloned into the rodent genome. Despite this advancement, there is still a lack of Aβ plaque formation during the Tc(Chr21) rodent lifespan (59, 60). Whether or not Aβ prions could be measured in Tc(Chr21) rodents using cellular bioassays remains to be determined. Nevertheless, these findings suggest that the formation of Aβ and tau prions as well as AD neuropathology resulting from overexpression of WT human APP is a uniquely human condition. These findings make it critical to use human brain samples wherever possible to investigate the molecular pathogenesis of DS.
Effects of Aβ concentration on the formation of Aβ prion strains may be amenable to study in both rodents and humans. In prior work, we demonstrated that the brain concentrations of APP, Aβ40, and Aβ42 proteins in long-lived people with AD trended significantly lower (P < 0.005) compared with people who died much younger (26). This matches the lower Aβ prion infectivity observed with cell bioassays in those same people (26). If such a trend was present from a young age, it might indicate that low APP expression over the lifespan contributes to an Aβ prion strain that is less pathogenic or slower to accumulate and contributes to longevity. Interestingly, using amyloid strain-sensitive dyes and spectral imaging methods in fixed tissues (61), we found that the conformation of Aβ plaques in aged individuals with DS and advanced neuropathology showed a distinct conformational strain phenotype, compared with sAD (62). While the relationship between amyloid plaque conformation and Aβ prion infectivity remains to be determined, there is growing evidence that supports the notion that pathogenic Aβ and tau species in DS may differ from fAD and sAD in ways not appreciated with traditional histological and biochemical measurements.
Our prion bioassays allow for measurement of both Aβ and tau prions in DS rather than inert protein deposits. The finding that Aβ and tau prions are positively correlated in DS and AD agrees well with genetic and experimental studies arguing that Aβ prions arise early in AD pathogenesis and that these prions initiate subsequent tau prion formation (63–65). Consistent with this notion, we found that samples from two of the youngest individuals with DS in our study (19 and 25 y old) exhibited robust levels of Aβ prions but insignificant levels of tau prions; in adjacent formalin-fixed sections, we found that these donors had low levels of plaques and tangles (SI Appendix, Fig. S2). In contrast, we have not found any brains with DS or AD that have readily detectable levels of tau prions accompanied by marginal levels of Aβ prions. Indeed, our studies of primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration have failed to show any detectable Aβ prions (26). To our knowledge, individuals with DS do not present with only NFTs in the absence of amyloid plaques (15). This finding is consistent with our view that Aβ prions initiate formation of tau NFTs in the vast majority of people with AD as well as DS.
Indeed, the cellular bioassays provide a functional readout of self-replicative proteins but do not provide the biophysical or structural characteristics of a given prion. It will be important for future mechanistic and drug discovery research to more precisely understand the molecular features of Aβ and tau prions in DS and AD. For example, Aβ peptides assemble into aggregates, which are called oligomers when the aggregate size is less than ∼50 peptides (66). A multitude of studies on human brain samples have reported the existence of soluble Aβ oligomers ranging in size, including dimers, trimers, and tetramers (67). Oligomer size has also been found to correlate inversely with cellular toxicity (68, 69). Moreover, the abundance of Aβ oligomers correlates well with the progression of cognitive deficits (70–72) and can differentiate patients with AD from nondemented people with comparable amyloid plaque burden (73). Extensive studies of Aβ oligomers in DS are lacking, but a few reports indicate an early (preplaque accumulation) and persistent increase of Aβ oligomers in aging DS people (74, 75). This is consistent with our data showing abundant Aβ prions in young people with DS with little to no amyloid plaque pathology. To our knowledge, there are no reports describing the characterization of tau oligomers in the brains of DS donors. Whether Aβ or tau multimer size correlates with prion infectivity and pathological deposition remains to be determined. By quantifying the oligomeric distribution and concentration, it should be possible to establish a relationship between the number of proteins in an oligomer and its prion infectivity (i.e., the particle to infectivity ratio [P/I]). For example, the P/I is ∼5,000 for the scrapie PrP isoform (76).
DS reveals a new vista of prion biology where trisomy of Chr21 results in increased Aβ production from an early age and leads to the formation of Aβ prions (77–80). It will be important to determine if this phenomenon occurs in all people with DS or a subset and to establish the earliest ages of prion detection. Despite the extraordinary contrast in etiologies between two genetic forms of Aβ prion diseases, one of which is nonheritable (DS) and the other heritable (fAD), both DS and fAD lead to a convergent neuropathogenic phenotype. Notably, by including sAD with fAD and DS, these three double-prion diseases are the most frequent neurodegenerative conditions worldwide, in which Aβ prions stimulate tau prions to cause neurodegeneration. Moreover, DS joins the expanding spectrum of NDs known to be caused by pathogenic prions (Table 1). Indeed, PrP prions cause Creutzfeldt-Jakob disease and kuru and can manifest in sporadic, heritable, and communicable disorders. While the other NDs can be sporadic or heritable, there is little evidence that Aβ, tau, or α-synuclein prions are communicable or spread by iatrogenic transmission (102–105). However, Aβ, tau, or α-synuclein prions extracted from donor brains of each disease can be transmitted to experimental animals or cultured human cells. These transmission models have enabled investigations of prion disease mechanisms and preclinical testing of novel therapeutic candidates.
Ridley et al. (34) provided the first clues of Aβ prions in the brains of people with DS, but the incubation times in marmosets are much too long for experimental investigations. In contrast, using our rapid cell bioassays, we discovered that the brains of people with DS contain both Aβ and tau prions indistinguishable from those found in AD. Our findings offer an approach to comparative clinical studies of AD and DS. As we learn more about Aβ and tau prions in DS, it may be feasible to develop smaller, shorter, and more informative clinical trials of potential AD treatments (106, 107). Whether advances in human positron emission tomography imaging for both Aβ plaques and NFTs will prove useful in assessing the levels of Aβ and tau prions in the brains of adults with DS who receive putative anti–AD prion therapeutics remains to be established. Last, because the brains of long-lived people with DS exhibit increased prion infectivity, we posit that more molecular studies for people with DS are needed to better understand how age-dependent pathogenic mechanisms in DS cause a divergent prion phenotype from sAD. The outcome of such work may have important implications for developing drugs that are more aptly tailored to improve quality of life for people with DS.
snip...see full text;
SATURDAY, NOVEMBER 19, 2022
Aβ and tau prions feature in the neuropathogenesis of Down syndrome
Cerebrovascular disease
Review
Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon
Gargi Banerjee1, Kiran Samra2, Matthew E Adams3, Zane Jaunmuktane4,5, Adrian Robert Parry-Jones6,7, Joan Grieve8, Ahmed K Toma8, Simon F Farmer9, Richard Sylvester9, Henry Houlden5, Peter Rudge1, Simon Mead1, Sebastian Brandner1,2,4, Jonathan M Schott2, John Collinge1, David J Werring10
Correspondence to Dr Gargi Banerjee, MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London W1W 7FF, UK; g.banerjee@ucl.ac.uk
Abstract
In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.
snip...
Questions remain about potential exposures and strategies to prevent further cases. The use of cadaveric human materials is restricted in most countries given the risk of iatrogenic CJD; it is difficult to know exactly how many people have been exposed due to variations in central record keeping. Prions can be transmitted via contaminated neurosurgical instruments and blood transfusions, and iatrogenic cases of CJD have been reported in association with both of these exposures.29 Our review identified 12 cases of iatrogenic CAA following neurosurgical procedures without exposure to cadaveric material, although proper ascertainment of this via historical records can be challenging. There is evidence from transgenic mice that Aβ can be transmitted via steel wires, and that transmission can be prevented by plasma sterilisation, but not boiling.14 There are no reported cases of iatrogenic CAA associated with blood transfusions in humans and epidemiological data to date do not support this,29 but there are experimental data suggesting that Aβ transmission can occur via this route.30 Large epidemiological studies are needed to fully evaluate the risk of Aβ transmission via contaminated instruments (MS1);29 this will inform future decision making regarding appropriate instrument sterilisation that prevents Aβ transmission, methods which also require further investigation.
Alternative explanations for the presence of early onset CAA in these and similar patients have been proposed, most notably the potential impact of traumatic brain injury (TBI).31–33 Aβ rapidly accumulates in the acute phase following TBI,34 35 perhaps due to disruption of the blood-brain barrier,36 37 and then usually clears over a period of days.38 39 Disentangling the role of TBI is challenging, as the injuries sustained in reported cases might have warranted neurosurgical intervention (either with or without cadaveric material); certainly the interval between brain injury and clinical presentation with symptomatic CAA would be in keeping with the latency expected for iatrogenic transmission of Aβ. These reports do not mention whether neurosurgical procedures were needed, and it is not clear whether this is because historical information regarding this is lacking, or whether they truly did not take place. Moreover, not all patients with evidence of early onset CAA have a preceding history of TBI, including those exposed to cadaveric dura mater via embolisation procedures (included two of the cases in this report, in addition to two others7 8) or cardiac procedures,40 and those who received cadaveric human growth hormone as children;6 these cadaveric materials are all well recognised as vehicles for prion protein transmission in the context of CJD.41–43 In view of these points, and the robust experimental evidence for Aβ transmission, it is our opinion that mechanism for early onset CAA in TBI is likely iatrogenic protein transmission, as in our cases, and that further retrospective interrogation of historical medical records may help to further clarify this.
Clinical details for the three cases reported here further expand the spectrum of presenting features for iatrogenic CAA. Cases have now been recognised worldwide, and it is likely that as more are described and published, our understanding of this unusual form of CAA will continue to expand. Confirming the means by which Aβ transmission can occur will have important public health implications for preventing future cases. We advise clinicians to remain vigilant for an iatrogenic cause when seeing patients with an early onset form of CAA, by specifically enquiring about previous medical procedures where Aβ transmission could have taken place.
snip...see full text;
1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8
***> 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.
PMID: 8006664 [PubMed - indexed for MEDLINE]
Prion 2022 Conference abstracts: pushing the boundaries
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 evaluated. 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
Atypical 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 unclassified. 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 Dis-ease. 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 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.
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: mailto: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 Diagnostic 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 Precautions." 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 Disorders 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 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*
Case/Age,y/Sex
Duration of Symptoms, y
Clincal 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, adult onset 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, autopsy 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 information 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 progressive cerebral 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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=============================
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 of judgment and acalculia gave the best fit.
Key Words: Alzheimer's disease, dementia
INTRODUCTION
snip...
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 of Psychiaty & 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
ONE IN A MILLION, OR EVERY 72 SECONDS $$$
Subject: Every 72 seconds someone in America develops Alzheimer’s Date: March 20, 2007 at 5:35 pm PST
Alzheimer’s Disease Prevalence Rates Rise to More than Five Million in the United States Someone develops Alzheimer’s every 72 seconds, according to new Alzheimer’s Association report
The Alzheimer’s Association today reports that in 2007 there are now more than 5 million people in the United States living with Alzheimer’s disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer’s disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.
The greatest risk factor for Alzheimer’s is increasing age, and with 78 million baby boomers beginning to turn 60 last year, it is estimated that someone in America develops Alzheimer’s every 72 seconds; by mid-century someone will develop Alzheimer’s every 33 seconds.
These new estimates, as well as other data concerning the disease and its effects, are issued today as hundreds of advocates from across the country gather in the nation’s capitol for the Alzheimer’s Association’s annual Public Policy Forum. The report titled, 2007 Alzheimer’s Disease Facts and Figures, is being released at a hearing today chaired by Senator Barbara Mikulski. Senators Barbara Mikulski and Christopher Bond and Representatives Edward Markey and Christopher Smith have introduced bipartisan legislation to address problems identified in the Association’s report. The Association’s report details the escalation of Alzheimer’s disease which now is the seventh leading cause of death in the country and the fifth leading cause of death for those over age 65. It also offers numerous statistics that convey the burden that Alzheimer’s imposes on individuals, families, state and federal governments, businesses, and the nation’s health care system. For example:
Without a cure or effective treatments to delay the onset or progression of the Alzheimer’s, the prevalence could soar to 7.7 million people with the disease by 2030, which is more than the population of 140 of the 236 United Nations countries. By mid-century, the number of people with Alzheimer’s is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined. As the prevalence impact of Alzheimer’s grows, so does the cost to the nation. The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart. “Alzheimer’s Disease Facts and Figures clearly shows the tremendous impact this disease is having on the nation; and with the projected growth of the disease, the collective impact on individuals, families, Medicare, Medicaid, and businesses will be even greater,” says Harry Johns, President and CEO of the Alzheimer’s Association. “However there is hope. There are currently nine drugs in Phase III clinical trials for Alzheimer’s several of which show great promise to slow or stop the progression of the disease. This, combined with advancements in diagnostic tools, has the potential to change the landscape of Alzheimer’s.”
According to the latest statistics from the Centers for Disease Control and Prevention, from 2000-2004 death rates have declined for most major diseases -- heart disease (-8 percent), breast cancer (-2.6 percent), prostate cancer (-6.3 percent) and stroke (-10.4 percent), while Alzheimer’s disease deaths continue to trend upward, increasing 33 percent during that period.
“We must make the fight against Alzheimer’s a national priority before it’s too late. The absence of effective disease modifying drugs, coupled with an aging population, makes Alzheimer’s the health care crisis of the 21st century,” Johns said.
Medicare currently spends nearly three times as much for people with Alzheimer’s and other dementias than for the average Medicare beneficiary. Medicare costs are projected to double from $91 billion in 2005 to more than $189 billion by 2015, more than the current gross national product of 86 percent of the world’s countries. In 2005, state and federal Medicaid spending for nursing home and home care for people with Alzheimer’s and other dementias was estimated at $21 billion; that number is projected to increase to $27 billion by 2015.
The new report also highlights the impact that Alzheimer’s has on states with more than 6 in 10 (62%) having double digit growth in prevalence by the end of the decade. In addition, Alaska (+47%), Colorado (+47%), Utah (+45%), Wyoming (+43%), Nevada (+38%), Idaho (+37%), Oregon (+33%), and Washington (+33%) will experience increases ranging from one-third to one-half. The states with the largest numbers of deaths due to Alzheimer’s disease in 2003 were (1) California, (2) Florida, (3) Texas, (4) Pennsylvania, and (5) Ohio.
The Alzheimer’s Association is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer’s. For more than 25 years, the Association has provided reliable information and care consultation; created services for families; increased funding for dementia research; and influenced public policy changes.
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Download Report: 2007 Alzheimer’s Disease Facts and Figures (28 pages)
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Every 72 seconds someone in America develops Alzheimer’s.
Alzheimer-type neuropathology 28 year old patient with idCJD
Sun Feb 19, 2006 11:14
71.248.144.164
SHORT REPORT
Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting
M Preusser1, T Ströbel1, E Gelpi1,2, M Eiler3, G Broessner4, E Schmutzhard4 and H Budka1,2 1 Institute of Neurology, Medical University Vienna, Austria 2 Austrian Reference Centre for Human Prion Diseases (OERPE), General Hospital Vienna, Austria 3 Department of Neurology, LKH Rankweil, Austria 4 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Correspondence to: Dr H Budka Institute of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 4J, 1097 Vienna, Austria; mailto:herbert.budka@kin.at
ABSTRACT
We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrPsc) in a synaptic pattern, and western blot analysis identified PrPsc of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer’s disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.
First published online August 27, 2015
Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database
Ryan A. Maddox, PhD rmaddox@cdc.gov, J. L. Blase, MPH, […], and E. D. Belay, MD+4View all authors and affiliations
https://doi.org/10.1177/1533317515602218
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.
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.
Terry S. Singeltary Sr.
