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INTRODUCTION: Dietary patterns are associated with dementia risk, but the underlying molecular mechanisms are largely unknown. METHODS: We used RNA sequencing data from post mortem prefrontal cortex tissue and annual cognitive evaluations from 1204 participants in the Religious Orders Study and Memory and Aging Project. We identified a transcriptomic profile correlated with the MIND diet (Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay) among 482 individuals who completed ante mortem food frequency questionnaires; and examined its associations with cognitive health in the remaining 722 participants. RESULTS: We identified a transcriptomic profile, consisting of 50 genes, correlated with the MIND diet score (p = 0.001). Each standard deviation increase in the transcriptomic profile score was associated with a slower annual rate of decline in global cognition (ß = 0.011, p = 0.003) and lower odds of dementia (odds ratio = 0.76, p = 0.0002). Expressions of several genes (including TCIM and IGSF5) appeared to mediate the association between MIND diet and dementia. DISCUSSION: A brain transcriptomic profile for healthy diets revealed novel genes potentially associated with cognitive health. HIGHLIGHTS: Why healthy dietary patterns are associated with lower dementia risk are unknown. We integrated dietary, brain transcriptomic, and cognitive data in older adults. Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet intake is correlated with a specific brain transcriptomic profile. This brain transcriptomic profile score is associated with better cognitive health. More data are needed to elucidate the causality and functionality of identified genes.
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OBJECTIVE: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology. METHODS: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses. RESULTS: Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT308AKT1/total AKT1, but not with pS307IRS-1/total IRS-1 or the density of cells stained positive for pS616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts. INTERPRETATION: Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.
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Inibidores da Enzima Conversora de Angiotensina , Proteínas Substratos do Receptor de Insulina , Insulina , Sistema Renina-Angiotensina , Transdução de Sinais , Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Idoso , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Insulina/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Antagonistas de Receptores de Angiotensina/farmacologiaRESUMO
INTRODUCTION: There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings. METHODS: In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis. RESULTS: Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR] = 2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR = 1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR = 0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR = 0.94, 95% CI: 0.89 to 0.98) had lower odds. DISCUSSION: We identified characteristics of individuals who may miss the optimal window for dementia treatment and support. HIGHLIGHTS: We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system.
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Diagnóstico Tardio , Demência , Medicare , Humanos , Masculino , Feminino , Demência/diagnóstico , Demência/epidemiologia , Idoso , Diagnóstico Tardio/estatística & dados numéricos , Medicare/estatística & dados numéricos , Estados Unidos , Estudos Prospectivos , Idoso de 80 Anos ou mais , Diagnóstico Ausente/estatística & dados numéricos , Fatores de TempoRESUMO
BACKGROUND: Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to affect functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of Alzheimer's disease (AD) and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. METHODS: Participants were 1 509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and 3 other AD indices were examined, in addition to 4 non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43, and Lewy bodies, and 4 cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. RESULTS: Alzheimer's disease and the other neuropathologies were associated with impaired IADL (all psâ <â .001) and with impaired BADL (psâ <â .01), except for atherosclerosis and CAA, which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHF-tau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. CONCLUSIONS: Alzheimer's disease and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.
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Atividades Cotidianas , Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Feminino , Masculino , Idoso de 80 Anos ou mais , Idoso , Demência , Angiopatia Amiloide Cerebral/patologia , Corpos de Lewy/patologia , Hipocampo/patologia , Avaliação da DeficiênciaRESUMO
BACKGROUND: Everyday discrimination-experiences of being treated unfairly based on background characteristics like race-is linked to poor physical and mental health throughout the lifespan. Whether more experiences of discrimination are associated with higher odds of being hospitalized in older African Americans has not been explored. METHODS: Community-dwelling participants from 3 longitudinal cohort studies (Nâ =â 446, age 65+ years) with discrimination scores and ≥12 months of linked Medicare claims were included. Hospitalizations were identified using Medicare fee-for-service claims, available for an average of 6.2 (SD: 3.7) years of follow-up after baseline. RESULTS: In mixed-effects ordinal logistic regression models (outcomes of 0, 1, or 2+ hospitalizations per year) adjusted for age, sex, education, and income, higher discrimination was associated with higher odds of total annual hospitalizations (odds ratio [OR] per point higherâ =â 1.09, 95% confidence intervals [95% CI]: 1.02-1.17). Results were similar when accounting for depressive symptoms. CONCLUSIONS: Higher exposure to everyday discrimination is associated with higher odds of hospitalization among older African Americans. Mechanisms underlying associations should be explored further to understand how hospitalizations may be reduced in older African Americans.
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Negro ou Afro-Americano , Hospitalização , Humanos , Masculino , Hospitalização/estatística & dados numéricos , Feminino , Idoso , Negro ou Afro-Americano/estatística & dados numéricos , Estados Unidos/epidemiologia , Estudos Longitudinais , Medicare/estatística & dados numéricos , Idoso de 80 Anos ou mais , Racismo/estatística & dados numéricos , Racismo/psicologiaRESUMO
BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Epilepsia , Esclerose Hipocampal , Estados Unidos/epidemiologia , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Medicare , Angiopatia Amiloide Cerebral/patologia , Autopsia , Epilepsia/diagnóstico por imagem , Epilepsia/epidemiologia , Epilepsia/patologia , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
OBJECTIVE: To examine associations of serum insulin and related measures with neuropathology and cognition in older persons. METHODS: We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio. Using adjusted regression analyses, we examined the associations of serum measures with neuropathology of cerebrovascular disease and Alzheimer's disease, and with the level of cognition proximate-to-death. RESULTS: Higher HOMA-IR was associated with the presence of brain infarcts and specifically microinfarcts, and higher HOMA-IR and leptin were each associated with subcortical infarcts. Further, higher leptin levels and lower adiponectin-to-leptin ratios were associated with the presence of moderate-to-severe atherosclerosis. Serum insulin and related measures were not associated with the level of Alzheimer's disease pathology, as assessed by global, as well as amyloid burden or tau tangle density scores. Regarding cognitive outcomes, higher insulin and leptin levels, and lower adiponectin and receptors for advanced glycation-end products levels, respectively, were each associated with lower levels of global cognition. INTERPRETATION: Peripheral insulin resistance indicated by HOMA-IR and related serum measures was associated with a greater burden of cerebrovascular neuropathology and lower cognition. ANN NEUROL 2024;95:665-676.
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Doença de Alzheimer , Diabetes Mellitus , Resistência à Insulina , Doenças do Sistema Nervoso , Humanos , Idoso , Idoso de 80 Anos ou mais , Leptina , Doença de Alzheimer/patologia , Adiponectina , Cognição , InsulinaRESUMO
BACKGROUND: Lower hippocampal volume is associated with late-life cognitive decline and is an important, but nonspecific marker for clinical Alzheimer's dementia. Cerebrovascular disease may also be associated with hippocampal volume. Here we study the role of intracranial large vessel disease (atherosclerosis) in association with hippocampal volume and the potential role of age, average late-life blood pressure across all visits, and other factors (sex, apolipoprotein ε4 [APOE ε4], and diabetes). METHODS AND RESULTS: Data came from 765 community-based older people (91 years old on average at death; 72% women), from 2 ongoing clinical-pathologic cohort studies. Participants completed baseline assessment, annual standardized blood pressure measurements, vascular risk assessment for diabetes, and blood draws to determine APOE genotype, and at death, brains were removed and underwent ex vivo magnetic resonance imaging and neuropathologic evaluation for atherosclerosis pathology and other cerebrovascular and neurodegenerative pathologies. Linear regression models examined the association of atherosclerosis and hippocampal to hemisphere volume ratio and whether age at death, blood pressure, and other factors modified associations. In linear regression models adjusted for demographics and neurodegenerative and other cerebrovascular pathologies, atherosclerosis severity was associated with a lower hippocampal to hemisphere volume ratio. In separate models, we found the effect of atherosclerosis on the ratio of hippocampal to hemisphere volume was attenuated among advanced age at death or having higher systolic blood pressure (interaction terms P≤0.03). We did not find confounding or interactions with sex, diabetes, or APOE ε4. CONCLUSIONS: Atherosclerosis severity is associated with lower hippocampal volume, independent of neurodegenerative and other cerebrovascular pathologies. Higher systolic blood pressures and advanced age attenuate associations.
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Doença de Alzheimer , Aterosclerose , Diabetes Mellitus , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Pressão Sanguínea/fisiologia , Apolipoproteína E4/genética , Doença de Alzheimer/patologia , Hipocampo/diagnóstico por imagem , Diabetes Mellitus/patologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/epidemiologia , Aterosclerose/patologiaRESUMO
BACKGROUND: Evidence indicates the health care system disproportionately misses dementia in African American compared to White individuals. In preliminary data, we examined factors related to dementia identification by the health care system among African Americans. METHODS: We leveraged linked Medicare fee-for-service claims and detailed annual cohort evaluations in African Americans from 4 cohorts at Rush Alzheimer's Disease Center. RESULTS: Among 88 African Americans with cognitive impairment (meanâ =â 10 years follow-up), Medicare claims identified dementia <2 years from cohort diagnosis in 55%; 27% were identified 2-9.9 years after cohort diagnosis, and in 18% there was either no claims diagnosis during the study period, or claims identified dementia 10+ years after cohort diagnosis. Claims identification of dementia was related to older age at cohort diagnosis (eg, <2 years between cohort and claims: meanâ =â 82 years; 10+ years/no diagnosis: meanâ =â 77 years, pâ =â .04), lower Mini-Mental State Examination (MMSE) score (<2 years: meanâ =â 24; 10+ years/no diagnosis: meanâ =â 26, pâ =â .04), more depressive symptoms (<2 years: meanâ =â 2.1 symptoms; 10+ years/no diagnosis: meanâ =â 1.2, pâ =â .04), and more comorbidity (<2 years: meanâ =â 5.6 comorbidities; 10+ years/no diagnosis, meanâ =â 3.0, pâ =â .02). CONCLUSIONS: Among African Americans, preliminary data indicate the health care system most rapidly identifies dementia in older individuals, with worse cognitive and physical health. The health care system may miss opportunities for early support of African Americans with dementia, and caregivers.
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Doença de Alzheimer , Disfunção Cognitiva , Demência , Idoso , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Negro ou Afro-Americano , Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Demência/epidemiologia , Medicare , Estados Unidos/epidemiologia , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Previous research suggests a decline in body mass index (BMI) among older adults is associated with negative health outcomes, including mild cognitive impairment (MCI) and incident dementia. However, no studies have examined the effects of education or developing MCI on BMI trajectories over time. The purpose of this investigation was to characterize trajectories of change in BMI among older adults who develop MCI. METHODS: Participants were from the Minority Aging Research Study (MARS), a longitudinal cohort study of cognitive decline and Alzheimer's disease in older African Americans living in the greater Chicago, Illinois, area. The study included annual clinical evaluations of cognitive status, as well as measurements of height and weight for BMI calculation. Older African American participants without cognitive impairment at baseline were included in the present analysis (Nâ =â 436, 78% women, mean baseline ageâ =â 72 [SDâ =â 5.7], mean educationâ =â 15 [SDâ =â 3.5]). RESULTS: In piecewise linear mixed-effects models that included a random intercept and 2 random slopes, BMI declined over time (Bâ =â -0.20, SEâ =â 0.02, pâ <â .001), with a faster decline after MCI diagnosis (additional decline, Bâ =â -0.15, SEâ =â 0.06, pâ =â .019). Older age was associated with lower baseline BMI (Bâ =â -0.19, SEâ =â 0.05, pâ <â .001), as was higher education (Bâ =â -0.34, SEâ =â 0.09, pâ <â .001). Further, higher education was associated with a slower decline in BMI before MCI (Bâ =â 0.02, SEâ =â 0.006, pâ =â .001), but a faster decline after MCI (Bâ =â -0.06, SEâ =â 0.022, pâ =â .003). CONCLUSIONS: These results suggest an accelerated decline in BMI following an MCI diagnosis, with higher education related to an even faster BMI decline.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Feminino , Idoso , Masculino , Índice de Massa Corporal , Negro ou Afro-Americano , Estudos Longitudinais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologiaRESUMO
At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (â¼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals. Mixed effects regression models tested whether ARTS scores increased over time, while simultaneous mixed effects regression models estimated the simultaneous rates of change in both ARTS and cognition and the correlation of these changes. ARTS scores increased over time (estimate=0.030, SE=0.002, p < 0.0001). Faster increases in ARTS were associated with faster rates of global cognitive decline (r = -0.447, p = 0.006) and domain-specific cognitive functions. Applying an in-vivo marker of arteriolosclerosis in an African American cohort revealed that the likelihood of arteriolosclerosis increases over time, and participants whose ARTS scores increased more rapidly tended to have faster than average rates of cognitive decline.
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Arteriolosclerose , Disfunção Cognitiva , Humanos , Arteriolosclerose/patologia , Negro ou Afro-Americano , Cognição , Disfunção Cognitiva/diagnóstico , IdosoRESUMO
BACKGROUND: The use of mixed effect models with a specific functional form such as the Sigmoidal Mixed Model and the Piecewise Mixed Model (or Changepoint Mixed Model) with abrupt or smooth random change allows the interpretation of the defined parameters to understand longitudinal trajectories. Currently, there are no interface R packages that can easily fit the Sigmoidal Mixed Model allowing the inclusion of covariates or incorporating recent developments to fit the Piecewise Mixed Model with random change. RESULTS: To facilitate the modeling of the Sigmoidal Mixed Model, and Piecewise Mixed Model with abrupt or smooth random change, we have created an R package called nlive. All needed pieces such as functions, covariance matrices, and initials generation were programmed. The package was implemented with recent developments such as the polynomial smooth transition of the piecewise mixed model with improved properties over Bacon-Watts, and the stochastic approximation expectation-maximization (SAEM) for efficient estimation. It was designed to help interpretation of the output by providing features such as annotated output, warnings, and graphs. Functionality, including time and convergence, was tested using simulations. We provided a data example to illustrate the package use and output features and interpretation. The package implemented in the R software is available from the Comprehensive R Archive Network (CRAN) at https://CRAN.R-project.org/package=nlive . CONCLUSIONS: The nlive package for R fits the Sigmoidal Mixed Model and the Piecewise Mixed: abrupt and smooth. The nlive allows fitting these models with only five mandatory arguments that are intuitive enough to the less sophisticated users.
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Algoritmos , Software , HumanosRESUMO
Type-2 diabetes is associated with an increased risk of dementia, and the underlying mechanism might involve abnormal insulin signaling in the brain. The objective of this study was to examine the association of postmortem brain insulin signaling with late-life cognitive decline. Among participants of Religious Orders Study, a community-based clinical-pathological cohort, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had postmortem brain insulin signaling measurements collected in the prefrontal cortex using ELISA and immunohistochemistry. By using adjusted linear mixed-effects models, we examined the association of postmortem brain insulin signaling with late-life cognitive function assessed longitudinally (mean follow-up duration = 9.4 years) using a battery of neuropsychological tests. We found that a higher level of serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) was associated with a faster decline in global cognition (estimate = -0.023, p = 0.030), and three domains: episodic memory (estimate = -0.024, p = 0.032), working memory (estimate = -0.018, p = 0.012), and visuospatial abilities (estimate = -0.013, p = 0.027). The level of insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) was not associated with decline in global cognition or most cognitive domains, except for perceptual speed (estimate = 0.020, p = 0.020). The density of pS616IRS1-stained cells was not associated with decline in global cognition or any of the domains. In conclusion, these findings provide novel evidence for an association between brain insulin signaling and late-life cognitive decline. AKT phosphorylation is associated with a decline in global cognition and memory in particular, whereas IRS1 phosphorylation is associated with a decline in perceptual speed.
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Medical and epidemiological researchers commonly study ordinal measures of symptoms or pathology. Some of these studies involve two correlated ordinal measures. There is often an interest in including both measures in the modeling. It is common to see analyses that consider one of the measures as a predictor in the model for the other measure as outcome. There are, however, issues with these analyses including biased estimate of the probabilities and a decreased power due to multicollinearity (since they share some predictors). These issues create a necessity to examine both variables as simultaneous outcomes, by assessing the marginal probabilities for each outcome (i.e. using a proportional odds model) and the association between the two outcomes (i.e. using a constant global odds model). In this work we extend this model using a parsimonious option when the constraints imposed by assumptions of proportional marginal odds and constant global odds do not hold. We compare approaches by using simulations and by analyzing data on brain infarcts in older adults. Age at death is a marginal predictor of gross infarcts and also a marginal predictor of microscopic infarcts, but does not modify the association between gross and microscopic infarcts.
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Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.
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Identifying novel mechanisms underlying dementia is critical to improving prevention and treatment. As an approach to mechanistic discovery, we investigated whether MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), a consistent risk factor for dementia, is correlated with a specific profile of cortical gene expression, and whether such a transcriptomic profile is associated with dementia, in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). RNA sequencing (RNA-Seq) was conducted in postmortem dorsolateral prefrontal cortex tissue from 1,204 deceased participants; neuropsychological assessments were performed annually prior to death. In a subset of 482 participants, diet was assessed ~6 years before death using a validated food-frequency questionnaire; in these participants, using elastic net regression, we identified a transcriptomic profile, consisting of 50 genes, significantly correlated with MIND diet score (P=0.001). In multivariable analysis of the remaining 722 individuals, higher transcriptomic score of MIND diet was associated with slower annual rate of decline in global cognition (ß=0.011 per standard deviation increment in transcriptomic profile score, P=0.003) and lower odds of dementia (odds ratio [OR] =0.76, P=0.0002). Cortical expression of several genes appeared to mediate the association between MIND diet and dementia, including TCIM, whose expression in inhibitory neurons and oligodendrocytes was associated with dementia in a subset of 424 individuals with single-nuclei RNA-seq data. In a secondary Mendelian randomization analysis, genetically predicted transcriptomic profile score was associated with dementia (OR=0.93, P=0.04). Our study suggests that associations between diet and cognitive health may involve brain molecular alterations at the transcriptomic level. Investigating brain molecular alterations related to diet may inform the identification of novel pathways underlying dementia.
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Cerebral microbleeds (CMBs) appearing as hypointense foci on T2*-weighted magnetic resonance images are small hemorrhages that have been linked to cognitive decline and increased mortality. However, the neuropathologic correlates of CMBs in community-based older adults are poorly understood. The present study investigated the association of age-related neuropathologies with CMBs in community-based older adults. Cerebral hemispheres from 289 participants of the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Rush Alzheimer's Disease Clinical Core underwent ex vivo MRI and detailed neuropathologic examination. Following Bonferroni correction, CMBs in the cerebrum overall and in the frontal lobe were associated with cerebral amyloid angiopathy, CMBs in the frontal lobe were also associated with arteriolosclerosis, and CMBs in the basal ganglia showed a borderline significant association with microinfarcts. These findings suggest that CMBs can aid in the prediction of small vessel disease in community-based older adults. Finally, CMBs were not associated with dementia, suggesting that CMBs in community-based older adults may not be linked to substantial cognitive impairment.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Disfunção Cognitiva , Humanos , Idoso , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Doença de Alzheimer/diagnóstico , Envelhecimento , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer's disease dementia may provide insights into much needed dementia therapeutics. OBJECTIVE: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC). METHODS: We obtained biologic samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer's disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls). RESULTS: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUCâ=â91.8%; 95% CI, 82.9-100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUCâ=â87.9%; 95% CI, 77.5-98.3%). CONCLUSION: We demonstrate in this small sample, the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes.
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Doença de Alzheimer , Ácidos Nucleicos Livres , Diabetes Mellitus , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Metilação de DNA , 5-Metilcitosina/metabolismo , Diabetes Mellitus/genética , Ácidos Nucleicos Livres/metabolismoRESUMO
Background: The use of mixed effect models with a specific functional form such as the Sigmoidal Mixed Model and the Piecewise Mixed Model (or Changepoint Mixed Model) with abrupt or smooth random change allow the interpretation of the defined parameters to understand longitudinal trajectories. Currently, there are no interface R packages that can easily fit the Sigmoidal Mixed Model allowing the inclusion of covariates or incorporate recent developments to fit the Piecewise Mixed Model with random change. Results: To facilitate the modeling of the Sigmoidal Mixed Model, and Piecewise Mixed Model with abrupt or smooth random change, we have created an R package called nlive. All needed pieces such as functions, covariance matrices, and initials generation were programmed. The package was implemented with recent developments such as the polynomial smooth transition of piecewise mixed model with improved properties over Bacon-Watts, and the stochastic approximation expectation-maximization (SAEM) for efficient estimation. It was designed to help interpretation of the output by providing features such as annotated output, warnings, and graphs. Functionality, including time and convergence, was tested using simulations. We provided a data example to illustrate the package use and output features and interpretation. The package implemented in the R software is available from the Comprehensive R Archive Network (CRAN) at https://CRAN.R-project.org/package=nlive. Conclusions: The nlive package for R fits the Sigmoidal Mixed Model and the Piecewise Mixed: abrupt and smooth. The nlive allows fitting these models with only five mandatory arguments that are intuitive enough to the less sophisticated users.
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Introduction: Acculturation-related characteristics, that is, factors directly connected to culture and familial relationships, are associated with engaged research participation within Latino communities. Despite this, little empirical data exists on whether acculturation changes over time in older Latinos, which has potential implications for Alzheimer's disease and related dementias (ADRD) research study design including longer duration clinical trial implementation. Methods: Self-identified Latinos (n = 222; mean age = 71, 76% female) participating in one of three ongoing longitudinal community-based cohort studies of aging who reported their nativity outside of the United States/District of Columbia (US/DC) contributed, on average, 4.0 ± 1.2 years of annually collected data. This included acculturation-related characteristics of total, language-, and social-based scores from the Short Acculturation Scale for Hispanics (SASH) and total and domain-specific scores from an abbreviated Sabogal Familism questionnaire. We used ordinal mixed effects models and linear mixed effects models (as appropriate) to assess change in acculturation metrics after adjusting for age, sex, education, income, and duration of time in the US/DC. Results: Although none of the SASH metrics changed over time (P-values ≥ 0.25), all Familism metrics declined over time (P-values ≤ 0.044). Additionally, select participant-based characteristics including years of education were significantly (and differentially) associated with level of, but not change in, acculturation-related outcomes. Discussion: Results suggest that specific acculturation-related factors (i.e., familism) change over time in older Latinos, and participant-based characteristics associated with baseline levels of (but not change in) acculturation more generally. Thus, acculturation-related characteristics are not all static, trait-like qualities but rather a multi-faceted, and at times evolving, construct. Considering this dynamic phenotyping is important when contextualizing older Latinos' lived experience, and when designing, adapting, and conducting ADRD clinical trials and other health-related interventions.