Honolulu-Asia Aging Study Research Articles

Paradoxical association between atrial fibrillation/flutter and high cholesterol over age 75 years: The Kuakini Honolulu Heart Program and Honolulu-Asia Aging Study

IntroductionSeveral studies have indicated high cholesterol is paradoxically associated with low prevalence of atrial fibrillation/flutter (AF). However, the etiology is uncertain. One potential explanation might be the confounding effect of age exemplifying prevalence-incidence (Neyman's) bias. However, this bias has not often been discussed in depth in the literature. Therefore, we conducted a cross-sectional analysis to test the hypothesis that there is a paradoxical association between lipid profile and AF prevalence. MethodsThis is a cross-sectional study design, using data from the Kuakini Honolulu Heart Program. Participants were 3741 Japanese-American men between 71 and 93 years old living in Hawaii. Serum total cholesterol (TC) level was measured and categorized into quartiles. AF was diagnosed by 12‑lead Electrocardiogram. We categorized age into quartiles (71–74, 75–77, 78–80 and 81+ years). ResultsWe observed opposite associations between AF and TC among different age groups. For participants age ≥75, higher TC levels were paradoxically associated with lower prevalence of AF after multivariable adjustment, i.e. the odds ratios of AF comparing the highest TC quartile with the lowest TC quartile for age 75–77, 78–80 and 81+ years were 0.17 (95% confidence interval [CI], 0.06–0.52), 0.28 (95% CI, 0.07–1.09) and 0.14 (95% CI, 0.03–0.62), respectively. Conversely, for those who were 71–74 years old, the odds ratio of AF was 2.09 (95% CI, 0.76–5.75) between the highest and the lowest TC quartiles. ConclusionsThere is a paradoxical association of TC with AF in Japanese-American men age ≥75, but not <75 years. The paradox might be explained by Neyman's bias.

Lifelong Engagement: The Role of Cognitive Reserve and Physical Health in Very Late Life

At the end of a very long life, older adults often experience a significant decline in cognitive function. However, there are older adults who have maintained high levels of cognition and physical health. The purpose of this symposium is to illuminate interdisciplinary findings of cognitive engagement with late-life benefits of cognitive functioning and physical health. Components of cognitive reserve include sociodemographic variables (e.g., education, occupational complexity and responsibility), psychosocial variables (e.g., engaged life style and activity) and physical and genetic reserve (e.g., strength, APOE4). Based on three major research studies (the Japanese SONIC study; the Honolulu Asia Aging Study, HAAS; and the Georgia Centenarian Study, GCS), we highlight important aspects of building cognitive reserve and the implications for cognitive and physical health. The first presentation evaluates the importance of work complexity as a predictor of cognitive and physical health among participants of the SONIC study. Multiple group analyses yielded strong associations of occupational complexity with cognitive functioning for men. The second presentation reports logistic regression findings from the HAAS including education, strength and genetic markers, as well as mental health and their relatedness to cognitive abilities and physical health. The final presentation evaluates a structural equation model from the GCS, highlighting the interrelationship of cognitive reserve components (i.e., education, occupational responsibility, engaged lifestyle, social support, and activity) with cognitive and physical health in very late life. We will summarize and integrate the findings for their theoretical and practical implications and provide future directions.

Risk and Protective Factors for Cognitive Reserve in Oldest-Old Japanese Americans

3,734 Japanese-American male oldest-old (aged 85+ years), from the Kuakini Honolulu Asia Aging Study, were assessed for prevalent cognitive impairment (CI). CI was defined as scoring <74 on the 100-point Cognitive Abilities Screening Instrument (CASI; 80% sensitivity, 90% specificity for dementia). CASI tests from 1991 (Exam 4) to 2012 (Exam 12) identified 1496 cases of CI (i.e. low cognitive reserve) and 1222 non-CI controls (mean diagnosis age: 85.7 ± 5.3; range 71-100 years). Baseline risk factors were compared between groups, adjusted for age at onset of CI or last CASI. Step-wise conditional logistic regression was used to assess risk for CI. Among other factors, education (0.88; 0.85-0.9, p<0.0001), hand-grip strength (0.98; 0.97-0.99, p=0.03), and height (0.97; 0.96-0.99, p=0.002) had protective effects; whereas APOE4 carriage (1.31; 1.04-1.63, p=0.02) and depression (1.4; 1.06-1.96, p=0.02) were risk factors for CI. The implications of these data for cognitive and physical health will be discussed.

Electrocardiographic changes predate Parkinson\u2019s disease onset

Autonomic nervous system involvement precedes the motor features of Parkinson’s disease (PD). Our goal was to develop a proof-of-concept model for identifying subjects at high risk of developing PD by analysis of cardiac electrical activity. We used standard 10-s electrocardiogram (ECG) recordings of 60 subjects from the Honolulu Asia Aging Study including 10 with prevalent PD, 25 with prodromal PD, and 25 controls who never developed PD. Various methods were implemented to extract features from ECGs including simple heart rate variability (HRV) metrics, commonly used signal processing methods, and a Probabilistic Symbolic Pattern Recognition (PSPR) method. Extracted features were analyzed via stepwise logistic regression to distinguish between prodromal cases and controls. Stepwise logistic regression selected four features from PSPR as predictors of PD. The final regression model built on the entire dataset provided an area under receiver operating characteristics curve (AUC) with 95% confidence interval of 0.90 [0.80, 0.99]. The five-fold cross-validation process produced an average AUC of 0.835 [0.831, 0.839]. We conclude that cardiac electrical activity provides important information about the likelihood of future PD not captured by classical HRV metrics. Machine learning applied to ECGs may help identify subjects at high risk of having prodromal PD.

Factor analysis of the Cognitive Abilities Screening Instrument: Kuakini Honolulu-Asia Aging Study.

The Cognitive Abilities Screening Instrument (CASI) is a screening test of global cognitive function used in research and clinical settings. However, the CASI was developed using face validity and has not been investigated via empirical tests such as factor analyses. Thus, we aimed to develop and test a parsimonious conceptualization of the CASI rooted in cognitive aging literature reflective of crystallized and fluid abilities. Secondary data analysis implementing confirmatory factor analyses where we tested the proposed two-factor solution, an alternate one-factor solution, and conducted a χ2 difference test to determine which model had a significantly better fit. N/A. Data came from 3,491 men from the Kuakini Honolulu-Asia Aging Study. The Cognitive Abilities Screening Instrument. Findings demonstrated that both models fit the data; however, the two-factor model had a significantly better fit than the one-factor model. Criterion validity tests indicated that participant age was negatively associated with both factors and that education was positively associated with both factors. Further tests demonstrated that fluid abilities were significantly and negatively associated with a later-life dementia diagnosis. We encourage investigators to use the two-factor model of the CASI as it could shed light on underlying cognitive processes, which may be more informative than using a global measure of cognition.

Association between central sleep apnea and atrial fibrillation/flutter in Japanese-American men: The Kuakini Honolulu Heart Program (HHP) and Honolulu-Asia Aging Study (HAAS)

IntroductionWhile several studies have indicated that central sleep apnea (CSA) is associated with atrial fibrillation and atrial flutter (AF) in older populations, few studies have focused on older Asian populations. MethodsWe conducted a cross- sectional analysis using data from the 1999–2000, 7th exam cycle of the Kuakini Honolulu-Asia Aging Study. Participants were 718 Japanese-American men between 79 and 97 years old, who had overnight polysomnography. Obstructive Apnea-Hypopnea Index (OAHI) was the measure of the number of obstructive apneas and hypopneas with >4% oxygen desaturation. Additionally, the Central Apnea Index (CAI) was the measure of the number of central apneas. Obstructive sleep apnea (OSA) was categorized as none (OAHI <5), mild (OAHI 5–14), moderate (OAHI 15–29) and severe (OAHI ≥30). CSA was defined by CAI of 5 or more. Cheyne-Stokes Breathing (CSB) was defined as a minimum consecutive 5-minute period of a crescendo-decrescendo respiratory pattern associated with CSA. ResultsAF prevalence was 5.5% (39 of 709). The prevalence proportions of severe OSA, CSA, and CSB were 20.2% (143 of 709), 6.4% (43 of 673) and 3.2% (22 of 673), respectively. In multivariable-adjusted logistic regression models, CSA and CSB were significantly associated with AF prevalence: odds ratio (OR) 5.15, 95% confidential interval (CI), 2.21–12.52 and OR 6.26, 95% CI, 2.05–19.14, respectively. However, OSA was not significantly associated with AF prevalence. ConclusionAF prevalence is associated with CSA and CSB but not OSA in older Japanese-American men. This information could help target AF prevention strategies in this population.

Incident prolonged QT interval in midlife and late-life cognitive performance.

Measures of cardiac ventricular electrophysiology have been associated with cognitive performance in cross-sectional studies. We sought to evaluate the association of worsening ventricular repolarization in midlife, as measured by incident prolonged QT interval, with cognitive decline in late life. Midlife QT interval was assessed by electrocardiography during three study visits from 1965/68 to 1971/74 in a cohort of Japanese American men aged 46-68 at Exam 1 from the Honolulu Heart Study. We defined incident prolonged QT as the QT interval in the upper quartile at Exam 2 or 3 after QT interval in lower three quartiles at Exam 1. Cognitive performance was assessed at least once using the Cognitive Abilities Screening Instrument (CASI), scored using item response theory (CASI-IRT), during four subsequent visits from 1991/93 to 1999/2000 among 2,511 of the 4,737 men in the Honolulu-Asia Aging Study otherwise eligible for inclusion in analyses. We used marginal structural modeling to determine the association of incident prolonged QT with cognitive decline, using weighting to account for confounding and attrition. Incident prolonged QT interval in midlife was not associated with late-life CASI-IRT at cognitive baseline (estimated difference in CASI-IRT: 0.04; 95% CI: -0.28, 0.35; p = 0.81), or change in CASI-IRT over time (estimated difference in annual change in CASI-IRT: -0.002; 95%CI: -0.013, 0.010; p = 0.79). Findings were consistent across sensitivity analyses. Although many midlife cardiovascular risk factors and cardiac structure and function measures are associated with late-life cognitive decline, incident prolonged QT interval in midlife was not associated with late-life cognitive performance or cognitive decline.

Brain Injury and Later-Life Cognitive Impairment and Neuropathology: The Honolulu-Asia Aging Study.

Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes. Examine the relationship between head injury and later cognitive impairment. A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared. Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance in the adjusted model (OR = 1.320, CI: 0.90-1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68-3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00-1.01). We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury.

Late life insulin resistance and Alzheimer's disease and dementia: The Kuakini Honolulu heart program

IntroductionRecent findings outline negative effects of brain insulin signaling on memory due to hyperinsulinemia. We investigated the association between insulin resistance (IR) with AD and dementia. MethodsLater life Japanese men (N = 1544, mean age = 79.9 years) with normal cognitive function were followed from exam 4 to 5 of the Kuakini Honolulu Asia Aging Study. Subjects underwent physical exams, blood draws, and neuropsychological testing. IR status was determined at exam 4 using the McAuley and HOMA indices. Subjects with prevalent diabetes and dementia were excluded. Incident dementia and AD cases were determined at exam 5. ResultsIR was associated with decreased odds of AD and dementia using both IR indices. Carriers of the APOE ε4 allele had 15% increased odds of AD and dementia. DiscussionOur findings provide insight regarding possible inverse relationship between IR and AD in elderly Japanese men, and support biologic studies showing short term hyperinsulinemia improves memory and cognitive function.

Most cases with Lewy pathology in a population-based cohort adhere to the Braak progression pattern but ‘failure to fit’ is highly dependent on staging system applied

Braak et al.’s 2003 paper detailing the caudo-rostral progression of Lewy body pathology (LP) formed the foundation of current understanding of disease spread in Parkinson's disease (PD); however, its methods are difficult to recreate and consequently multiple new staging systems emerged to recapitulate Braak's staging system using standard neuropathological methods and to account for other patterns of LP. Studies using these systems have documented widely variable rates of cases that ‘fail to fit’ expected patterns of LP spread. This could be due to population differences, features of individual systems, or may constitute under-recognized patterns of disease. We examined 324 neuropathological cases from the Honolulu Asia Aging Study and applied four different LP staging systems to determine the proportion of cases adhering to different staging methodologies and those that ‘fail to fit’ expected patterns of LP. Of 141 cases with LP (24: PD, 8: Dementia with Lewy bodies (DLB), 109: Incidental Lewy body disease (ILBD)), our application of Braak et al., 2003 classified 83.7%, Müller et al., 2005 classified 87.9%, Beach et al., 2009 classified 100%, and Leverenz et al., 2008 classified 98.6%. There were significant differences in the cases classifiable by the Leverenz and Beach systems versus the Braak and Müller systems (p < 0.001 for each). In this population-based autopsy cohort with a high prevalence of ILBD, the majority of cases were consistent with the progression characterized by the Braak et al. however, the determination of cases as atypical is highly dependent on the staging system applied.

Abstract P005: Related Factors for Cognitive Impairment in Older Japanese Men in Hawaii and Japan

Background: The number of people with dementia is increasing in the world and it is of great public health concern. Previous observational studies, mainly from western countries, have reported that modifiable factors for development of dementia were cardiometabolic risk factors, related to genetically determined metabolic abilities and lifestyle. There are no studies comparing which modifiable factors relate to low cognitive scores among populations with the same genetic background but different lifestyle. Objective: The purpose of the present study is to describe factors related to low cognitive scores in Japanese men in two cohorts that are genetically similar but with different lifestyle exposures. Methods: Population-based cross-sectional data from the Kuakini Honolulu-Asia Aging Study (HAAS) in Hawaii and Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) in Japan were analyzed. Participants were Japanese men aged 71-81 years (2,628 men in Hawaii and 349 men in Japan). Cognitive function was assessed using the Cognitive Abilities Screening Instrument (CASI), with low CASI score &lt; 82. Related factors were obtained by questionnaire and measurements. Multivariable adjusted odds ratios of low CASI score by different factors among the two cohorts were calculated by logistic regression analysis. Results: Low CASI score was more common in elderly men in Hawaii compared to Japan (21.2% or 556/2,628 versus 12.3% or 43/349, p&lt;0.001). After adjustment for age and educational attainment, these differences were no longer significant (Hawaii 20.3% versus Japan 17.9%, p=0.328). Odds ratios for low cognitive scores were 1.65 in Hawaii with history of stroke, and 1.93 in Japan with history of CHD. Higher odds of low cognitive score were seen with diabetes in Hawaii (OR=1.20), and with BMI≥25 in Japan (OR=1.88). Conclusion: We found different strengths of associations between cardiovascular diseases and cardiometabolic factors with low cognitive scores among genetically similar men in Hawaii and Japan with different lifestyles.

Abstract P274: Association Between Atrial Fibrillation and Central Sleep Apnea in Older Japanese-American Men

Introduction: Several studies have indicated that central sleep apnea (CSA) is associated with atrial fibrillation (AF) in older populations. However, there are few studies of this association in older Asian populations. Hypothesis: The hypothesis being tested is that there is an association between AF and CSA in older Japanese-American men. Methods: The Kuakini Honolulu-Asia Aging Study is a longitudinal cohort study of Japanese-American men living in Hawaii. We did a cross- sectional analysis using data from the 1999- 2000 7th exam cycle. Participants were 718 Japanese-American men between 79 and 97 years old, who had overnight polysomnography (PSG) conducted in their homes using criteria established by the large multicenter Sleep Heart Health Study. Obstructive Apnea-Hypopnea Index (OAHI) was the measure of the number of obstructive apneas and hypopneas with &gt;4% oxygen desaturation. Additionally, the Central Apnea Index (CAI) was the measure of the number of central apneas. Obstructive sleep apnea (OSA) was categorized as none (OAHI &lt;5), mild (OAHI 5-14), moderate (OAHI 15-29) and severe (OAHI 30 or more). CSA was defined by CAI of 5 or more. Cheyne-Stokes Breathing (CSB) was defined as a minimum consecutive 10-minute period of a crescendo-decrescendo respiratory pattern associated with CSA. A board-certified physician confirmed AF by single lead electrocardiography of PSG. Results: The mean age of participants was 83.2±0.2 years. The prevalence of AF was 5.5% (39 of 709). The prevalence proportions of severe OSA, CSA, and CSB were 20.5% (145 of 709), 6.3% (43 of 681) and 3.2%, (22 of 681) respectively. In multivariable-adjusted logistic regression models, CSA and CSB were significantly associated with AF prevalence [Odds Ratio (OR) 4.78; 95% Confidential interval (CI), 1.91-11.95] and [OR 5.48; 95% CI, 1.70-17.66], respectively. In contrast, OSA was not significantly associated with AF prevalence (severe OSA [OR 1.17; 95% CI, 0.44-3.11], moderate OSA [OR 0.72; 95% CI, 0.26-2.05], mild OSA [OR 0.97; 95% CI, 0.39-2.44]). Conclusion: There is an association of AF prevalence with CSA and CSB in older Japanese-American Men. In older Japanese men, screening for CSA and CSB might be important to prevent AF.

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.

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. 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. 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. 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.

TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study.

Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

CAN WE AGE SUCCESSFULLY? MEASURES OF COMORBIDITY AND HEALTHY AGING IN THE KUAKINI HONOLULU ASIA AGING STUDY

There are several methods for measuring healthy or “successful” aging utilizing different measures of comorbidity. Each can lead to different conclusions about how “successfully” one is aging. To bring more clarity, we compared 3,741 American men of Japanese ancestry (mean age 77.8 ± 4.7, range 71–93 years) from the 1991–94 exam of the Kuakini Honolulu Asia Aging Study in a cross-sectional analysis, utilizing the Rowe and Kahn criteria versus a modified Charlson Index. With Rowe and Kahn criteria, 50.4%, 34.3% and 7.3% of men in their 70s, 80s and 90s, were successful agers, respectively (p<0.0001 for age trend). Utilizing a modified Charlson Index, 12.0%, 5.8% and 0.0% of men in their 70s, 80s and 90s, were disease-free successful agers. 49.0%, 58.7%, and 79.7%, had two-plus diseases, respectively (p<0.0001 for age trend). These data suggest that much of the “success” in successful aging depends upon the criteria used to define that success.

Session 411 - Research in Dementia and Depression in Elderly Japanese-American Men: The Kuakini Honolulu-Asia Aging Study

Session 411 - Research in Dementia and Depression in Elderly Japanese-American Men: The Kuakini Honolulu-Asia Aging Study

Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

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.

Resistance to Alzheimer Disease Neuropathologic Changes and Apparent Cognitive Resilience in the Nun and Honolulu-Asia Aging Studies.

Two population-based studies key to advancing knowledge of brain aging are the Honolulu-Asia Aging Study (HAAS) and the Nun Study. Harmonization of their neuropathologic data allows cross comparison, with findings common to both studies likely generalizable, while distinct observations may point to aging brain changes that are dependent on sex, ethnicity, environment, or lifestyle factors. Here, we expanded the neuropathologic evaluation of these 2 studies using revised NIA-Alzheimer's Association guidelines and compared directly the neuropathologic features of resistance and apparent cognitive resilience. There were significant differences in prevalence of Alzheimer disease neuropathologic change, small vessel vascular brain injury, and Lewy body disease between these 2 studies, suggesting that sex, ethnicity, and lifestyle factors may significantly influence resistance to developing brain injury with age. In contrast, hippocampal sclerosis prevalence was very similar, but skewed to poorer cognitive performance, suggesting that hippocampal sclerosis could act sequentially with other diseases to impair cognitive function. Strikingly, despite these observed differences, the proportion of individuals resistant to all 4 diseases of brain or displaying apparent cognitive resilience was virtually identical between HAAS and Nun Study participants. Future in vivo validation of these results awaits comprehensive biomarkers of these 4 brain diseases.