Neocortical Neurofibrillary Tangles Research Articles

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure

Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET.

The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Subtypes of dementia with Lewy bodies are associated with α-synuclein and tau distribution.

To determine whether Lewy body disease subgroups have different clinical profiles. Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder. In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles. The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.

BRAINSTEM NEURONAL LOSS OCCURRING INDEPENDENTLY FROM NEOCORTICAL ALZHEIMER, LEWY BODY, OR FOCAL ISCHEMIC LESIONS IS COMMON AND SIGNIFICANTLY ASSOCIATED WITH BOTH MOTOR AND COGNITIVE IMPAIRMENT IN AUTOPSIED HONOLULU-ASIA AGING STUDY DECEDENTS

The neuropathologic abnormalities to which aging-related cognitive impairment is commonly attributed include neocortical neurofibrillary tangles, neuritic amyloid plaques, cortical Lewy bodies, hippocampal sclerosis, and vascular brain injury with microinfarcts and/or lacunar infarcts. Motor impairments are very common with aging and occur often but not invariably with dementia. The brain abnormalities generally recognized as common and relevant to motor impairments are infarcts, hemorrhage, and Lewy bodies in the substantia nigra, Repeated cognitive and motor function assessments were carried out over two decades on Japanese-American male Honolulu-Asia Aging Study participants. This analysis was carried out on 774 HAAS decedents who received comprehensive, highly standardized brain autopsies at death. Cognitive assessments utilized the Cognitive Assessment and Screening Instrument. Grip strength, walking speed, stride length, turn around steps, turn around time, chair stands, and standing balance were assessed on 6 occasions. Analyses utilized graphic and tabular visual representation plus linear and logistic regression statistical modeling. Decedents with cognitive impairment but little or no motor impairment were found at autopsy to have neocortical neurofibrillary tangles and amyloid plaques, microinfarcts and/or lacunar infarcts, and hippocampal sclerosis, but negligible striatal, cerebellar, or brainstem abnormalities. Those who had both cognitive and motor impairments had these same lesions plus neocortical Lewy bodies, generalized brain atrophy, and striatal and brainstem neuronal loss and gliosis. In a subset of autopsied cases without neocortical Alzheimer lesions, Lewy bodies (brainstem or neocortex), microinfarcts, or hippocampal sclerosis, neuronal loss and gliosis observed in the brainstem was nonetheless significantly associated with both cognitive and motor impairments. These findings suggest that linked cognitive and motor impairments may be associated with brainstem neuronal injury due in part to currently undefined disease processes distinct from other neuropathologic processes represented by neocortical Alzheimer lesions, Lewy bodies, vascular brain injury, and/or hippocampal sclerosis.

The Temporospatial Evolution of Neuritic Plaque-Related and Independent Tauopathies: Implications for Dementia Staging

Neuritic plaque (NP) formation can be dated in vivo. This analysis attempts to "date" the progression of neurofibrillary tangles (NFT) using the spatial distribution of NP as a reference. Autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) were combined into latent factor measures of NFT and NP counts. The variance in "early" and "late" NP pathology was used to estimate the spatial distribution of "early" and "late" NFT formation. A third latent factor representing "non-NP-related NFT" was also constructed. "Early" NP and "late" NP correlated significantly with objectively early and later cognitive performance, respectively. In contrast to our expectations, neocortical NFT correlated best with "early" NP pathology, while NFT in allocortical structures correlated best with "late" NP pathology. Therefore, the NP-related fraction of NFT appears to be co-localized spatially with NP. However, since the latter evolve corticofugally in time, this suggests that NP-related NFT do so as well. Corticotropic NFT formation must therefore be either unrelated to NP formation, a temporally distinct process, or both.

Disentangling the effects of age and APOE on neuropathology and late life cognitive decline

Age and APOE are the most robust risk factors for dementia and cognitive decline, but the underlying neurobiology remains unclear. We examined the extent to which the hallmark pathologies of Alzheimer's disease, Lewy body disease, and cerebrovascular diseases account for the association of age and APOE with decline in episodic memory versus nonepisodic cognitive abilities. Up to 20 waves of longitudinal cognitive data were collected from 858 autopsied participants in 2 ongoing clinical-pathologic cohort studies of aging. Neuropathologic examinations quantified measures of beta amyloid (Aβ) plaque, mesial temporal and neocortical neurofibrillary tangles, macro- and microinfarcts, and neocortical Lewy bodies. Random coefficient models estimated person-specific slopes of decline in episodic memory and nonepisodic cognition. Path analysis examined the relation of age, APOE, and the 6 pathologic indices to the slopes of cognitive decline. The effect of age on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tau tangles, and macroscopic infarcts; age on decline in nonepisodic cognition was mediated by Aβ, neocortical tangles, and macroscopic infarcts. The effect of APOE on decline in episodic memory was mediated by Aβ, mesial temporal and neocortical tangles, and neocortical Lewy bodies; APOE on nonepisodic cognition was mediated by Aβ, neocortical tangles, and neocortical Lewy bodies. There were no direct effects of age and APOE on decline after accounting for these pathologic pathways.

Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide

Following his discovery of chronic traumatic encephalopathy (CTE) in football players in 2002, Dr. Bennet Omalu hypothesized that posttraumatic stress disorder (PTSD) in military veterans may belong to the CTE spectrum of diseases. The CTE surveillance at the Brain Injury Research Institute was therefore expanded to include deceased military veterans diagnosed with PTSD. The authors report the case of a 27-year-old United States Marine Corps (USMC) Iraqi war veteran, an amphibious assault vehicle crewman, who committed suicide by hanging after two deployments to Fallujah and Ramadi. He experienced combat and was exposed to mortar blasts and improvised explosive device blasts less than 50 m away. Following his second deployment he developed a progressive history of cognitive impairment, impaired memory, behavioral and mood disorders, and alcohol abuse. Neuropsychiatric assessment revealed a diagnosis of PTSD with hyperarousal (irritability and insomnia) and numbing. He committed suicide approximately 8 months after his honorable discharge from the USMC. His brain at autopsy appeared grossly unremarkable except for congestive brain swelling. There was no atrophy or remote focal traumatic brain injury such as contusional necrosis or hemorrhage. Histochemical and immunohistochemical brain tissue analysis revealed CTE changes comprising multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads (ranging from none, to sparse, to frequent) with the skip phenomenon, accentuated in the depths of sulci and in the frontal cortex. The subcortical white matter showed mild rarefaction, sparse perivascular and neuropil infiltration by histiocytes, and mild fibrillary astrogliosis. Apolipoprotein E genotype was 3/4. The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.

Alzheimer Disease Pathology in Subjects Without Dementia in 2 Studies of Aging: The Nun Study and the Adult Changes in Thought Study

Individuals with antemortem preservation of cognition who show autopsy evidence of at least moderate Alzheimer disease (AD) pathology suggest the possibility of brain reserve, that is, functional resistance to structural brain damage. This reserve would, however, only be relevant if the pathologic markers correlate well with dementia. Using data from the Nun Study (n = 498) and the Adult Changes in Thought (ACT) Study (n = 323), we show that Braak staging correlates strongly with dementia status. Moreover, participants with severe(Braak stage V-VI) AD pathology who remained not demented represent only 12% (Nun Study) and 8% (ACT study) of nondemented subjects. Comparison of these subjects to those who were demented revealed that the former group was often significantly memory-impaired despite not being classified as demented. Most of these nondemented participants showed only stage V neurofibrillary pathology and frontal tangle counts that were slightly lower than a comparable (Braak stage V) dementia group. In summary, these data indicate that, in individuals with AD-type pathology who do not meet criteria for dementia, neocortical neurofibrillary tangles are somewhat reduced and incipient cognitive decline is present. Our data provide a foundation for helping to define additional factors that may impair, or be protective of, cognition in older adults.

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.

Preclinical AD Workgroup staging: pathological correlates and potential challenges

The National Institute on Aging Preclinical Alzheimer's disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer's disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in “stage 3”, which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for “intermediate likelihood” that cognitive impairment is due to Alzheimer's disease (AD). We also stress the importance of comorbid non-Alzheimer's disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view.

Neuropathological Associates of Multiple Cognitive Functions in Two Community-Based Cohorts of Older Adults

Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer's disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains.

Cerebrospinal fluid ß-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

The proposed research criteria of prodromal Alzheimer's disease (AD) emphasize the use of biomarkers in addition to the presence of impairment of episodic memory. Atrophy of the medial temporal lobe structures and changes in the levels of CSF tau protein and beta-amyloid 42 (Aß42) peptide in patients with AD are well documented in single center and multicenter studies, and these biomarkers also predict AD in amnestic MCI. However, the relationship between e.g. CSF biomarkers and neuropathologic changes in the brain is not well established. Objective: To study the relationship between antemortem CSF biomarker levels and AD-type neuropathologic changes in the brain. Methods: We studied correlations between levels of CSF Ab42, total tau, and phosphorylated tau (ptau) with neuropathologic changes in the postmortem brain in 123 patients (79 clinically diagnosed AD, 29 other dementia, and 15 other neurologic disease). All study subjects underwent clinical evaluation and provided antemortem lumbar CSF samples. CSF markers were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Aß, hyperphosphorylated tau, and alpha-synuclein. Also vascular pathology was assessed. Results: CSF Aß42, tau and ptau levels were significantly related to amyloid load and the presence of neurofibrillary tangles (NFT) in the brain. CSF Aß42 level correlated inversely with total Aß load in the brain, and CSF tau level correlated with results of immunohistochemistry for tau and with neocortical NFTs. Alpha-synuclein or vascular pathology did not influence CSF biomarker concentrations. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Aß42 level and of increased CSF tau level. Based on the ratio of ptau level to Aß42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of AD-type brain pathology. Conclusions: CSF Aß42 and tau proteins are associated with amyloid and tau pathology but not with alpha-synuclein or vascular pathology. The combination of low Aß42 and high tau levels in CSF predicted AD pathologic features with high accuracy and may be helpful in diagnosing the presence of AD pathologic changes in the brain.

Pathophysiology of vascular cognitive impairment

Insufficiencies of blood supply will more or less lead to brain dysfunction. Cognitive impairment caused by such cerebrovascular insufficiency was called vascular cognitive impairment (VCI), a clinical syndrome composed of a markedly heterogeneous group of diseases rather than a unique pathological process. It includes large vessel disease with strategic single or multiple strokes and small vessel disease with progressive damage to the basal ganglia and/or the white matter. VCI was previously believed to be distinct from Alzheimer’s disease (AD) resulting from a neurodegenerative process. However, such simple dichotomy needs to be reconsidered in light of the shared features between AD and VCI: these two disorders increase in prevalence with age, frequently occur concomitantly, and considerably overlaps in their symptomatology, pathophysiology, and comorbidity. So-called ‘mixed’ brain pathologies, mainly comprising of AD pathology and cerebral infarctions, are reported to account for most dementia cases in community-dwelling elderly people. Consistent with this notion, the contributors to attributable risks at death for dementia include small vessel disease and multiple vascular pathologies, which are no less than those of the main pathological hallmarks of AD, neocortical neuritic plaques and neurofibrillary tangles. Importantly, the multifactorial aspects of cognitive impairment have been incorporated in the dynamic polygon hypothesis, which takes into account the contributions of strokes of all sizes and white matter hyperintensities in parallel to those of plaques and tangles. In terms of the treatment of dementia, it is undoubtedly important to control vascular risk factors for the prevention of VCI. However, even in patients who have AD without cerebrovascular disease, treatment of vascular risk factors is associated with a slower decline in the Mini-Mental State Examination score. Therefore, physicians should always bear in mind that vascular risk factors need to be controlled to achieve a reduction in the risk of dementia, even if the dementia is caused by AD.

Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study

Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS). A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%). Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively "pure," but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia. Please see later in the article for the Editors' Summary.

Neuropathological Correlates of Dementia in Over-80-Year-Old Brain Donors from the Population-Based Cambridge City over-75s Cohort (CC75C) Study

Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimer's disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimer's disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age.

Cerebrospinal Fluid β-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain

There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.

P3-060: Cerebrospinal fluid markers in dementia with Lewy bodies (DLB) in comparison with Alzheimer′s disease (AD)

AD and DLB present with similar clinical features and biological markers to differentiate both disorders are still lacking. Pathologically, most cases with pure DLB exhibit a diffuse plaque-only pathology with rare or absent neocortical neurofibrillary tangles, as opposed to the wide cortical neurofibrillary-tau involvement in AD. We analyzed CSF markers chosen as to reflect some of these underlying pathological differences. CSF samples of 33 cases with probable AD (NINCDS-ADRA criteria) without parkinsonism, 25 cases will all the core features of DLB (Consortium criteria) and 46 age-matched controls were analyzed. Total tau, Ab1–42 amyloid, IL-1b and IL-6 levels were measured by sandwich ELISA using commercially available kits (Innogenetics NV, Belgium and Diaclone Research, France). Tau protein: AD cases had significantly higher levels (500 ± 399 pg/ml, mean ± SD) than DLB cases (213 ± 243) and controls (200 ± 243) (p< 0.0001). There were no differences between DLB and control groups. The most efficient cutoff point (250 pg/ml) provided a 76% specificity to distinguish AD and DLB cases. b-amyloid: AD (348 ± 309 pg/ml) and DLB cases (320 ± 233) had lower b-amyloid levels than controls (462 ± 352) but the differences did not reach statistical significance. The combination of tau/ b-amyloid levels provided the best value to differenciate AD vs controls (cut-off point 0.5, sensitivity 82,5%, specificity 75%) but was worse than tau values alone to discriminate between AD and DLB. Interleukine 1b: IL-1b levels in the three groups were within the lowest values of the standard curve. There were no significant differences among AD (2.17 ± 3.00 pgr/ml), DLB (2.60 ± 2.97) cases and controls (2.02 ± 3.28). Interleukine 6: AD (7.14 ± 5.74 pgr/ml) and DLB (6.14 ± 5.00) cases showed slightly higher IL-6 levels than controls (4.96 ± 4.72) but the differences among the three groups were not significant. Tau levels in CSF may contribute to the clinical distinction between AD and DLB. b-amyloid CSF levels are similar in AD and DLB cases and tend to be lower than in controls. Interleukine CSF concentrations do not distinguish between both dementia disord.

Thyroid function, the risk of dementia and neuropathologic changes: The Honolulu–Asia Aging Study

Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer's disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71–93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology.

Quantitative Proteomics Identifies Surfactant-Resistant α-Synuclein in Cerebral Cortex of Parkinsonism-Dementia Complex of Guam but Not Alzheimer's Disease or Progressive Supranuclear Palsy

Parkinsonism-dementia complex (PDC) remains a significant health burden to the Chamorro population. We tested the hypothesis that quantitative proteomics might provide fresh insight into this enigmatic illness by analyzing proteins resistant to surfactant extraction from patients with Alzheimer's disease (AD) or PDC and their matched controls using isobaric tags for relative and absolute quantification. In addition to the expected increase in abnormal frontal cortical Abeta peptides, tau, ubiquitin, and apolipoprotein E in AD, and tau in PDC, we identified alpha-synuclein (SNCA) as a major abnormal protein in PDC but not AD. We confirmed our isobaric tags for relative and absolute quantification findings by enzyme-linked immunosorbent assay in frontal and temporal cortices. We extended our assays to include a limited number of cases of progressive supranuclear palsy (PSP) and dementia with Lewy bodies; we observed increased abnormal tau but not SNCA in PSP, and abnormal SNCA in dementia with Lewy bodies that was quantitatively similar to PDC. Finally, soluble Abeta oligomers were selectively increased in AD but not PDC or PSP. These results show that frontal and temporal cortex in PDC is distinguished from AD and PSP by its accumulation of abnormal SNCA and suggest that PDC be considered a synucleinopathy as well as a tauopathy.