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An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to integrate information about molecular biology, neuropathology, behavioral aspects of cognitive decline, and cognitive resilience will be of particular importance. In addition, more work is needed to improve our understanding of the effect of systemic factors on brain health and function. It seems likely that, even in later life, the brain's plasticity may allow for a positive response to stimulation. The ultimate goal of this research is to create a validated set of variables and interventions-and to understand the biology underlying them-that are useful not only in describing an individual's cognitive state but also in identifying promising paths for treatment and prevention of cognitive decline., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A primary goal of research in cognitive impairment and dementia is to understand how some individuals retain sufficient cognitive function for a fulfilling life while many others are robbed of their independence, sometimes their essence, in the last years and decades of life. In this commentary, we propose operational definitions of the types of factors that may help individuals retain cognitive function with aging. We propose operational definitions of resistance, resilience, reserve, with an eye toward how these may be measured and interpreted, and how they may enable research aimed at prevention. With operational definitions and quantification of resistance, resilience, and reserve, a focused analytic search for their determinants and correlates can be undertaken. This approach, essentially a search to identify protective risk factors and their mechanisms, represents a relatively unexplored pathway toward the identification of candidate preventive interventions.

Background: Organochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study., Methods: Organochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions., Results: The prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics., Conclusions: Organochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

The most common causes of cognitive impairment and dementia are Alzheimer's disease (AD) and vascular brain injury (VBI), either independently, in combination, or in conjunction with other neurodegenerative disorders. The contribution of VBI to cognitive impairment and dementia, particularly in the context of AD pathology, has been examined extensively yet remains difficult to characterize due to conflicting results. Describing the relative contribution and mechanisms of VBI in dementia is important because of the profound impact of dementia on individuals, caregivers, families, and society, particularly the stability of health care systems with the rapidly increasing age of our population. Here we discuss relationships between pathologic processes of VBI and clinical expression of dementia, specific subtypes of VBI including microvascular brain injury, and what is currently known regarding contributions of VBI to the development and pathogenesis of the dementia syndrome. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels., Methods: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined., Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy., Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life., (© 2016 American Academy of Neurology.)

Objective: To determine how sleep-disordered breathing, nocturnal hypoxia, and changes in sleep architecture in the elderly may be related to the development of the neuropathologic correlates of dementia., Methods: The Honolulu-Asia Aging Study is a prospective cohort study of Japanese American men in Honolulu, HI. We examined brain lesions at autopsy (Braak stage, neurofibrillary tangle and neuritic plaque counts, microinfarcts, generalized brain atrophy, lacunar infarcts, Lewy bodies [LBs], neuronal loss and gliosis in the locus ceruleus) in 167 participants who underwent polysomnography in 1999-2000 (mean age, 84 years) and died through 2010 (mean 6.4 years to death). Polysomnography measures included the apnea-hypopnea index, duration of apnea or hypopnea, duration of hypoxemia, minimum oxygen saturation (SpO₂), duration of slow-wave sleep (SWS, non-REM stage N3), and arousals., Results: Sleep duration with SpO₂ <95% was associated with higher levels of microinfarcts (adjusted odds ratio [OR] 3.88, 95% confidence interval [CI] 1.10-13.76, comparing the highest to lowest quartiles of %sleep with SpO₂ <95%). Greater SWS duration was associated with less generalized atrophy (adjusted OR 0.32, 95% CI 0.10-1.03, comparing highest to lowest quartiles of %sleep in SWS). LBs were less common with greater %sleep with SpO₂ <95% (adjusted OR 0.17, 95% CI 0.04-0.78, comparing highest to lowest quartiles). Higher minimum SpO₂ during REM sleep was associated with less gliosis and neuronal loss in the locus ceruleus. Cognitive scores declined less among men with greater SWS duration., Conclusions: The findings support a role for lower nocturnal oxygenation and SWS in the development of microinfarcts and brain atrophy, but not Alzheimer lesions or LBs., (© 2014 American Academy of Neurology.)

Subjects with Alzheimer's disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium.

Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study., (Copyright © 2012 Movement Disorder Society.)

Latent growth curve (LGC) models estimate change over time in a cohort's serially obtained measurements. We have applied LGC techniques to a spatial distribution of Alzheimer's disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study. Neurofibrillary tangle (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. The gradient of spatial change in neuritic plaque (dNP), was significantly associated with that of neurofibrillary tangle (dNFT), but weakly and inversely (r = -0.12; p < 0.001). Both dNFT and dNP correlated significantly and inversely with Braak stage. Sixty-one percent of the variance in Braak stage was explained by dNFT independent of covariates. Only dNFT was significantly associated with longitudinal change in cognition. Only dNP was associated with apolipoprotein (APOE) e4 burden. This is the first application of LGC models to spatially-ordered data. The result is a quantification of the interindividual variation in the interregional vulnerability to Alzheimer's disease lesions., (Copyright © 2012. Published by Elsevier Inc.)

The Honolulu-Asia Aging Study (HAAS) is a longitudinal epidemiologic investigation of rates, risk factors, and neuropathologic abnormalities associated with cognitive decline and dementia in aged Japanese-American men. The project was established in 1991 and will be brought to closure in 2012. Age-specific rates of total dementia and the major specific types of dementia in HAAS participants are generally similar to those reported from other geographic, cultural, and ethnic populations. Risk factors for dementia in the HAAS include midlife hypertension and other factors previously shown to influence cardiovascular disease. The autopsy component of the project has yielded novel findings, the most illuminating of which is the demonstration of 5 important lesion types linked independently to cognitive impairment. While one of these--generalized atrophy--is strongly associated with both Alzheimer lesions and microinfarcts, it also occurs in the absence of these lesions and is independently correlated with dementia. Each lesion type is viewed as representing a distinct underlying pathogenic process. Their summed influences is an especially robust correlate of dementia in the months and years prior to death.

Objective: This study was untaken to investigate the association of micro brain infarcts (MBIs) with antemortem global cognitive function (CF), and whether brain weight (BW) and Alzheimer lesions (neurofibrillary tangles [NFTs] or neuritic plaques [NPs]) mediate the association., Methods: Subjects were 436 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument, and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on antemortem diagnoses, demented and nondemented subjects were examined together and separately., Results: In those with no dementia, MBIs were strongly associated with the last antemortem CF score; this was significantly mediated by BW, and not NFTs or NPs. In contrast, among those with an antemortem diagnosis of dementia, NFTs had the strongest associations with BW and with CF, and MBIs were modestly associated with CF., Interpretation: This suggests that microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory toward dementia the lesions develop., (Copyright © 2011 American Neurological Association.)

Background: Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies., Objective: To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults., Design: Autopsy study., Setting: Community- and population based., Participants: A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN., Main Outcome Measures: Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts., Results: Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies., Conclusions: These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965-1968) examined for dementia in 1991-1993, including 418 decedents (1992-2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (>/=411.0 mg/d) [corrected] were less likely than men in the lowest quartile (

Abnormal interaction of beta-amyloid 42 (Abeta42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimer's disease (AD). However, in health, Abeta degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of Abeta and biological metals in CSF. We assayed CSF copper, zinc, other metals and Abeta42 in ventricular autopsy samples of Japanese American men (N=131) from the population-based Honolulu Asia Aging Study. There was a significant inverse correlation of CSF Abeta42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF Abeta42. In vitro, the degradation of synthetic Abeta substrate added to CSF was markedly accelerated by low levels (2microM) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical Abeta precipitation in AD, soluble Abeta degradation is normally promoted by physiological copper and zinc concentrations.

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.

This report summarizes findings from 443 autopsies on Japanese-American men followed as active participants in the Honolulu-Asia Aging Study from 1991 through 2003. Five distinct neuropathological lesion types were found to have strong, partially, or completely independent associations with cognitive impairment and/or dementia in the final years of life. They were: Alzheimer lesions (neocortical neurofibrillary tangles and neuritic plaques), microvascular infarcts (microinfarcts and lacunar infarcts), neocortical Lewy bodies, hippocampal sclerosis, and generalized brain atrophy. Atrophy was strongly associated with both Alzheimer lesions and microvascular infarcts, but was also observed in decedents with negligible levels of these and the other lesions. About half of the hippocampal sclerosis cases appeared to be linked to Alzheimer lesions. A weak association of hippocampal sclerosis with microvascular infarcts was also noted. Comparable 3-level indices were defined for each of the five lesion types to facilitate comparisons of associations with cognitive impairment and dementia. Multiple combinations of the five lesion types were observed. The development of dementia in the final years of life was more closely correlated with their combined numbers and severities than with specific lesion types. In this autopsy panel, microvascular infarcts were identified as the sole or dominant lesion in 33.8% of the demented or definitely impaired decedents, compared with Alzheimer lesions in 18.6% and co-dominant lesions (most often Alzheimer and microvascular) in 14.2%. These or one or more of the other lesion types were observed in 87.9% of the demented or definitely impaired decedents.

An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.

It is not known if constipation is associated with the preclinical phase of Parkinson's disease (PD), often characterized by the presence of incidental Lewy bodies (ILB). Such an association could provide evidence that constipation is an early symptom of PD. The purpose of this report is to examine the association between late-life bowel movement frequency and ILB. Bowel movement frequency was assessed from 1991 to 1993 in 245 men aged 71 to 93 years in the Honolulu-Asia Aging Study who later received postmortem examinations. All were without clinical PD and dementia. Brains were examined for ILB in the substantia nigra and locus ceruleus. Among the decedents, 30 men had ILB (12.2%). After age-adjustment, the percent of brains with ILB declined with increasing bowel movement frequency (P=0.013). For men with <1, 1, and >1 bowel movement/day, corresponding percents were 24.1, 13.5, and 6.5%. Findings persisted after additional adjustment for time to death, mid-life pack-years of smoking and coffee intake, physical activity, and cognitive function. Infrequent bowel movements are associated with ILB. Findings provide evidence that constipation can predate the extrapyramidal signs of PD. Constipation could be one of the earliest markers of the beginning of PD processes., (Copyright (c) 2007 Movement Disorder Society.)

Olfactory dysfunction is found in early Parkinson's disease (PD) and in asymptomatic relatives of PD patients. Incidental Lewy bodies (ILB), the presence of Lewy bodies in the brains of deceased individuals without a history of PD or dementia during life, are thought to represent a presymptomatic stage of PD. If olfactory dysfunction were associated with the presence of ILB, this would suggest that olfactory deficits may precede clinical PD. The purpose of this study was to determine the association of olfactory dysfunction during late life with ILB in the substantia nigra or locus ceruleus. Olfaction was assessed during the 1991-1994 and 1994-1996 examinations of elderly Japanese-American men participating in the longitudinal Honolulu-Asia Aging Study. Among those who later died and underwent a standardized postmortem examination, brains were examined for Lewy bodies in the substantia nigra and the locus ceruleus with hematoxylin and eosin stain. Lewy bodies in the brains of individuals without clinical PD or dementia were classified as ILB. There were 164 autopsied men without clinical PD or dementia who had olfaction testing during one of the examinations. Seventeen had ILB. The age-adjusted percent of brains with ILB increased from 1.8% in the highest tertile of odor identification to 11.9% in the mid-tertile to 17.4% in the lowest tertile (P = 0.019 in test for trend). Age-adjusted relative odds of ILB for the lowest versus the highest tertile was 11.0 (P = 0.02). Olfactory dysfunction is associated with ILB. If incidental Lewy bodies represent presymptomatic stage of PD, olfactory testing may be a useful screening tool to identify those at high risk for developing PD., (Copyright 2006 Movement Disorder Society.)

Objective: Type 2 diabetes leads to cognitive impairment and dementia, which may reflect microvascular and macrovascular complications as well as neurodegenerative processes. There are few studies on the anatomical basis for loss of cognitive function in type 2 diabetes. The objective of this study was to investigate the association between type 2 diabetes and markers of brain aging on magnetic resonance images, including infarcts, lacunes, and white matter hyperintensities as markers of vascular damage and general and hippocampal atrophy as markers of neurodegeneration in Japanese-American men born between 1900 and 1919 and followed since 1965 in the Honolulu-Asia Aging Study., Research Design and Methods: Prevalent and incident dementia was assessed. Associations between magnetic resonance imaging markers and diabetic status were estimated with logistic regression, controlling for sociodemographic and other vascular factors., Results: The prevalence of type 2 diabetes in the cohort is 38%. Subjects with type 2 diabetes had a moderately elevated risk for lacunes (odds ratio [OR] 1.6 [95% CI 1.0-2.6]) and hippocampal atrophy (1.7 [0.9-2.9]). The risk for both hippocampal atrophy and lacunes/infarcts was twice as high in subjects with compared with those without type 2 diabetes. Among the group with type 2 diabetes, those with the longest duration of diabetes, those taking insulin, and those with complications had relatively more pathologic brain changes., Conclusions: There is evidence that older individuals with type 2 diabetes have an elevated risk for vascular brain damage and neurodegenerative changes. These pathological changes may be the anatomical basis for an increased risk of cognitive impairment or dementia in type 2 diabetes.

In this study, we compare neuropathological findings at autopsy with clinical dementia diagnoses, such as Alzheimer's disease and vascular dementia. Participants consisted of 363 aged Japanese-American men from the Honolulu-Asia Aging Study. Results indicated that the correspondence between clinical and neuropathologic diagnosis was not great, with 56% of patients diagnosed with probable or possible Alzheimer's disease during life but with only 19% having neuritic plaques and/or neurofibrillary tangles as the sole or dominant dementia-related lesions in the brain at autopsy. Although 16% of cases were attributed to mixed causes during life, almost 40% were found to have significant mixtures of dementia-related lesions at autopsy. Finally, both Alzheimer's disease and non-Alzheimer's disease neuropathologic lesions contributed independently to the explanation of variance on a test of overall cognitive performance. The results suggest that clinical diagnosis of dementia made during life may fail to reflect the pathogenic complexity of this condition in very elderly persons.

Clinicopathologic data from 285 autopsies were analyzed. The decedents were long-standing participants in the Honolulu-Asia Aging Study, a prospective epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We assessed the prevalence at death of four primary neuropathologic processes using specific microscopic lesions as indicators. An algorithm was developed to assign each decedent to one of six subsets, corresponding to pathologic dominance by microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary processes (9%), or without a dominant pathologic process recognized (55%). Definite or probable dementia had been identified in 118 of the decedents. The proportions of men in each subset identified as demented were (in the same order) 57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese-American men, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular lesion type most essentially and inclusively related to dementia was multiple microinfarction.

BackgroundDecedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia.ObjectiveAssess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC.MethodsBrains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC).ResultsAmong 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels.ConclusionPolymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to integrate information about molecular biology, neuropathology, behavioral aspects of cognitive decline, and cognitive resilience will be of particular importance. In addition, more work is needed to improve our understanding of the effect of systemic factors on brain health and function. It seems likely that, even in later life, the brain's plasticity may allow for a positive response to stimulation. The ultimate goal of this research is to create a validated set of variables and interventions-and to understand the biology underlying them-that are useful not only in describing an individual's cognitive state but also in identifying promising paths for treatment and prevention of cognitive decline.

ObjectiveWhile excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up.MethodsIdentification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years.ResultsAlthough EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies.ConclusionsThe association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.

The article discusses the Honolulu Asia Aging Study (HAAS) that investigated the joint association of midlife blood pressure (BP) and amyloid-β (A-beta;) peptide levels with the risk for late-life Alzheimer disease (AD) and vascular dementia (VaD). It states that cerebral amyloid angiopathy, β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in postmortem tissue. The article also concludes that the risk for AD increased with lower level of plasma A-β.

Background There are many variations of the Circle of Willis (COW). The purpose of this study was to compare the prevalence at autopsy of hypoplasticity of the posterior communicating artery (PCoA) in Japanese American men to results from studies involving other ethnic groups. Methods 703 men of the Honolulu Asia-Aging Study (HAAS) were autopsied and the COW was dissected and examined. Hypoplasticity of the PCoA was recorded and compared with previous studies. Results The prevalence of hypoplastic PCoA was found to be greater in HAAS men than in other published reports. Previous studies reported hypoplasia of the PCoA ranging from 16.7% - 81% of cases. In this series, some degree of PCoA hypoplasia was observed in 85% of decedents, including 60.2% with bilateral hypoplasia. The age at death was unassociated with the severity, side, uni-laterality or bilaterality of the hypoplasia. Conclusion A high prevalence of hypoplastic PCoA was observed in this cohort. The lack of any apparent relationship with age at death suggests that brain perfusion sufficient to sustain life was not embarassed by the hypoplasia. Additional analyses will be needed to address the likely origins of the hypoplasia, and to discern any impact on parenchymal brain structure, or relationship with infarcts, hemorrhages, or atrophy. [ABSTRACT FROM AUTHOR]