Cognitive Impairment in Older Adults and Therapeutic Strategies.

Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. SIGNIFICANCE STATEMENT: Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.

Mid- and later-life risk factors for predicting neuropathological brain changes associated with Alzheimer's and vascular dementia: The Honolulu Asia Aging Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.

INTRODUCTION: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological-based risk scores to predict clinical dementia. METHODS: Models were developed for predicting Alzheimer's disease (AD) and non-AD neuropathologies using the Honolulu Asia Aging neuropathological sub-study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non-autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility-Reykjavik Study (n = 4614). RESULTS: Different models were identified for predicting neurodegenerative and vascular neuropathology (c-statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure-related measure. The neurofibrillary tangle and micro-vascular lesion models showed good accuracy for predicting clinical vascular dementia. DISCUSSION: There may be shared risk factors across dementia-related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions.

Modifying effects of race and ethnicity and APOE on the association of physical activity with risk of Alzheimer's disease and related dementias.

INTRODUCTION: We investigated whether the protective association of physical activity with risk of Alzheimer's disease and related dementias (ADRD) has genetic or behavioral variations. METHODS: In the Multiethnic Cohort, we analyzed moderate or vigorous physical activity (MVPA) reported at ages 45 to 75 among 88,047 participants in relation to 13,039 incident diagnoses of late-onset ADRD identified in Medicare claims (1999 to 2014), by five racial and ethnic groups, hours sitting, and in a subset (16%), apolipoprotein E (APOE) genotype. RESULTS: MVPA was inversely associated with ADRD (hazard ratio for ≥14 vs <2.5 hours/week: 0.83, 95% confidence interval [CI]: 0.76 to 0.90 in men; 0.88, 5% CI: 0.81 to 0.95 in women). The association was inverse in all racial and ethnic groups except Black participants (P-heterogeneity = 0.52), but stronger in individuals with lower levels of sitting duration or those who do not carry the APOE e4 risk allele. DISCUSSION: The different effects of physical activity by sitting duration and APOE genotype warrant further research.

Prediction of neuropathologic lesions from clinical data.

INTRODUCTION: Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Risk of Alzheimer's disease and related dementia by sex and race/ethnicity: The Multiethnic Cohort Study.

INTRODUCTION: Data are limited for comparison of sex- and race/ethnicity-specific risks of Alzheimer's disease and related dementia (ADRD). METHODS: In the population-based Multiethnic Cohort, we estimated the age-standardized diagnostic incidence rate (ASDIR) and relative risk of late-onset ADRD (n = 16,410) among 105,796 participants based on Medicare claims (1999-2014) by sex and race/ethnicity. RESULTS: The ASDIR for ADRD was higher for women (17.0 per 1000 person-years) than for men (15.3) and varied across African Americans (22.9 in women, 21.5 in men), Native Hawaiians (19.3, 19.4), Latinos (16.8, 14.7), Whites (16.4, 15.5), Japanese Americans (14.8, 13.8), and Filipinos (12.5, 9.7). Similar risk patterns were observed for AD. Adjustment for education and cardiometabolic diseases attenuated the differences. Accounting for deaths from competing causes increased the sex difference, while reducing the racial/ethnic differences. Less racial/ethnic disparity was detected among apolipoprotein E (APOE) e4 carriers. DISCUSSION: More research is needed to understand the sex and racial/ethnic differences in ADRD.

Military-related experiences and late-life depressive symptomatology among Japanese-American world war II veterans.

Objectives: To examine military service-related variables and late-life depressive symptomatology among older Japanese-American males.Method: This study is a secondary data analysis of a longitudinal, community-based study. A sample of 2669 participants (771 World War II veterans, 1898 civilians) was drawn from the Honolulu-Asia Aging Study. Depressive symptoms were assessed twice across a 9-year period with the Center for Epidemiologic Studies-Depression scale. Covariates included sociodemographic, physical health, health behavior, and psychosocial variables. Combat exposure and symptomatology were examined among a subset of 426 veterans. Cross-sectional and longitudinal designs were analyzed with linear regression.Results: Veterans and civilians did not differ in depression scores. Baseline depression scores significantly predicted follow-up depression scores. For the full sample, lower ratings of quality of life satisfaction, daily activity control and general health were associated with higher depression scores both cross-sectionally and longitudinally. Among veterans, light combat exposure was marginally associated with lower depression scores and longitudinally, previous depression scores and poorer health ratings were significant predictors of depression scores.Conclusion: Results suggest that military service does not affect late-life depressive symptomatology. However, combat exposure may play a marginal role in increased symptoms. Reasons for results include the possibility that other factors are more relevant to late-life depression, symptomatology naturally decreasing over time, or type of combat exposure measurement. Results expand literature by examination of an ethnoracial group not studied often and longitudinal examination of late-life depressive symptoms within a military-related context. Stakeholders should be knowledgeable of the distinct issues presented when serving aging veterans.

Association of brain heptachlor epoxide and other organochlorine compounds with lewy pathology.

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.

The CAIDE Dementia Risk Score and the Honolulu-Asia Aging Study.

INTRODUCTION: The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) dementia risk score is based on demographic, genetic, and modifiable risk factors in midlife and has been shown to be predictive of later-life dementia. OBJECTIVE: To test the predictive capacity of the CAIDE dementia risk score among a cohort of Japanese-American men. METHODS: Midlife measures were obtained from a sample of 3,582 Japanese-American men in the Honolulu Heart Program (1965-1968, average age = 53.1 years). A follow-up exam in 1991 (average age = 77.8 years) assessed cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). Severe cognitive impairment was defined as a CASI score <60. RESULTS: In this cohort, the CAIDE dementia risk score demonstrates significant association with later-life severe cognitive impairment (OR = 1.477, 95% CI: 1.39-1.58). However, the area under the receiver-operating characteristic curve c-statistics suggests poor predictive ability (c = 0.645, 95% CI: 0.62-0.67). Using a score cut-point of 10, the accuracy is acceptable (0.82), but the sensitivity is low (0.50). CONCLUSION: While the CAIDE dementia risk score at midlife is associated with later development of cognitive impairment in Japanese-American men, its predictive capacity in this population is weak.

Clinical-pathologic correlations in vascular cognitive impairment and dementia.

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.

Social vulnerability and survival across levels of frailty in the Honolulu-Asia Aging Study.

PURPOSE: we evaluated mortality risk in relation to social vulnerability across levels of frailty among a cohort of older Japanese-American men. METHODS: in secondary analysis of the Honolulu-Asia Aging Study (HAAS), participants (n = 3,271) were aged 72-93 years at baseline. A frailty index (FI) created using 58 potential health deficits to quantify participants' frailty level at baseline, with four frailty strata: 0.0 < FI ≤ 0.1 (n = 1,074); 0.1 < FI ≤ 0.20 (n = 1,549); 0.2 < FI ≤ 0.30 (n = 472); FI > 0.3 (n = 176). Similarly, a social vulnerability index was created using 19 self-reported social deficits. Cox proportional hazard modelling was employed to estimate the impact of social vulnerability across the four levels of frailty, accounting for age, smoking, alcohol use and variation in health deficits within each frailty level. RESULTS: for the fittest participants, social vulnerability was associated with mortality (hazards ratio (HR) = 1.04, 95% confidence interval (CI) = 1.01, 1.07; P value = 0.008). Similarly, for those considered at risk for frailty, each social deficit was associated with a 5% increased risk of mortality. For frail individuals, the Cox regression analyses indicated that social vulnerability was not significantly associated with mortality (0.2 < FI ≤ 0.3: HR = 1.016, 95% CI = 0.98, 1.06; P value = 0.442; FI > 0.3: HR = 0.98, 95% CI = 0.93, 1.04). CONCLUSIONS: for the fittest and at-risk HAAS participants, the accumulation of social deficits was associated with significant increases in mortality risk. For frail individuals (FI > 0.20), the estimation of mortality risk may depend more so on intrinsic factors related to their health.

Racial and Ethnic Differences in the Population-Attributable Fractions of Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact based on the risk factor prevalence in contemporary surveys. The aim of this study was to determine the race-specific and ethnicity-specific PAF of late-onset Alzheimer disease and related dementias (ADRDs) based on the risk factor prevalence and associations observed on the same individuals within a prospective cohort. METHODS: Data were from Multiethnic Cohort Study participants (African American, Japanese American, Latino, Native Hawaiian, and White) enrolled in Medicare Fee-for-Service. We estimated the PAF based on the prevalence of risk factors at cohort baseline and their mutually adjusted association with subsequent ADRD incidence. Risk factors included low educational attainment and midlife exposures to low neighborhood socioeconomic status, unmarried status, history of hypertension, stroke, diabetes or heart disease, smoking, physical inactivity, short or long sleep duration, obesity, and low-quality diet, as well as APOE ε4 for a subset. RESULTS: Among 91,881 participants (mean age 59.3 at baseline, 55.0% female participants), 16,507 incident ADRD cases were identified from Medicare claims (1999-2016, mean follow-up 9.3 years). The PAF for nongenetic factors combined was similar in men (24.0% [95% CI 21.3-26.6]) and women (22.8% [20.3-25.2]) but varied across Japanese American (14.2% [11.1-17.2]), White (21.9% [19.0-24.7]), African American (27.8% [22.3-33.0]), Native Hawaiian (29.3% [21.0-36.7]), and Latino (33.3% [27.5-38.5]) groups. The combined PAF was attenuated when accounting for competing risk of death, in both men (10.4%) and women (13.9%) and across racial and ethnic groups (4.7%-25.5%). The combined PAF was also different by age at diagnosis and ADRD subtypes, higher for younger (65-74 years: 43.2%) than older (75-84 years: 32.4%; ≥85 years: 11.3%) diagnoses and higher for vascular or unspecified ADRD than for AD or Lewy body dementia. An additional PAF of 11.8% (9.9-13.6) was associated with APOE ε4, which together with nongenetic risk factors accounted for 30.6% (25.8-35.1) of ADRD. DISCUSSION: Known risk factors explained about a third of the ADRD cases but with unequal distributions across racial and ethnic groups.

If Midlife Brain Injury Is a Risk Factor for Alzheimer's Disease and Related Dementias, What Is the Neuropathologic Mechanism?

While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer's Disease and Related Dementias (ADRD). Published analytic conclusions have been mixed. Two reports in the Journal of Alzheimer's Disease reach the same answer: a history of brain injury appears to be a risk factor for generalized brain atrophy, which would likely increase vulnerability to the subsequent development of any variety of ADRD, or to dementia directly attributable to reduced brain mass.

Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia.

Neurodegenerative dementia can result from multiple underlying abnormalities, including neurotransmitter imbalances, protein aggregation, and other neurotoxic events. A major complication in identifying effective treatment targets is the frequent co-occurrence of multiple neurodegenerative processes, occurring either in parallel or sequentially. The path towards developing effective treatments for Alzheimer's disease (AD) and other dementias has been relatively slow and until recently has focused on disease symptoms. Aducanumab and lecanemab, recently approved by the FDA, are meant to target disease structures but have only modest benefit on symptom progression and remain unproven in reversing or preventing dementia. A third, donanemab, appears more promising but awaits FDA approval. Ongoing trials include potential cognition enhancers, new combinations of known drugs for synergistic effects, prodrugs with less toxicity, and increasing interest in drugs targeting neuroinflammation or microbiome. Scientific and technological advances offer the opportunity to move in new therapy directions, such as modifying microglia to prevent or suppress underlying disease. A major challenge, however, is that underlying comorbidities likely influence the effectiveness of therapies. Indeed, the full range of comorbidity, today only definitively identified postmortem, likely contributes to failed clinical trials and overmedication of older adults, since it is difficult to exclude (during life) people unlikely to respond. Our current knowledge thus signals that a paradigm shift towards individualized and multimodal treatments is necessary to effectively advance the field of dementia therapeutics.

Neuropathologic Changes of Alzheimer's Disease and Related Dementias: Relevance to Future Prevention.

BACKGROUND: Decedents 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. OBJECTIVE: Assess 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. METHODS: Brains 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). RESULTS: Among 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. CONCLUSION: Polymorbidity 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.

Quantitative estimate of cognitive resilience and its medical and genetic associations.

BACKGROUND: We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined. METHODS: This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR. RESULTS: CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms. CONCLUSIONS: Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study.

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.

Brain organochlorines and Lewy pathology: the Honolulu-Asia Aging Study.

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.

Rapid growth from 12 to 23 months of life predicts obesity in a population of Pacific Island children.

BACKGROUND: Rapid growth (RG) in early childhood has been associated with increased risk of obesity. The specific intervals when risk is highest have not been well examined and may help identify modifiable risk factors. OBJECTIVE: To determine the correlation between RG in consecutive time intervals during the first 2 years of life with obesity at 4-5 years. METHODS: This was a retrospective study of children attending the largest community health center in Hawaii. Children, aged 4-5 years, with a pre-kindergarten (PreK) well-child physical examination were included; data were abstracted from medical charts. ANALYSES: Children were classified as overweight (BMI for age/sex 85-94%) or obese (BMI for age/sex > or = 95%). Moderate and severe rapid growth was defined as an increase in weight-for-height z-score of .67-1.0 SD and > or = 1.0, respectively. Relationship between RG and PreK obesity was assessed using logistic regression analyses. RESULTS: 389 children were included: 66% Hawaiian, 21.6% Samoan and 12.3% Filipino. At the PreK 19.6% were obese, and 20.9% were overweight. Severe RG from 12 to 23 months was strongly associated with PreK obesity (OR 4.36, 95% CI 1.85-10.27). Of children with severe RG from 12-23 months, 48% were obese at PreK compared with 16.7% of children with moderate RG and 19.3% of children without RG. CONCLUSION: Rapid growth between 12 and 23 months, a key period of nutritional transition in toddlers, was strongly associated with obesity at 4 to 5 years of age in this high-risk population of Pacific Island minority subgroups.