Neighborhood Perceptions Are Associated With Intrinsic Amygdala Activity and Resting-State Connectivity With Salience Network Nodes Among Older Adults.

OBJECTIVE: Neighborhood perceptions are associated with physical and mental health outcomes; however, the biological associates of this relationship remain to be fully understood. Here, we evaluate the relationship between neighborhood perceptions and amygdala activity and connectivity with salience network (i.e., insula, anterior cingulate, thalamus) nodes. METHODS: Forty-eight older adults (mean age = 68 [7] years, 52% female, 47% non-Hispanic Black, 2% Hispanic) without dementia or depression completed the Perceptions of Neighborhood Environment Scale. Lower scores indicated less favorable perceptions of aesthetic quality, walking environment, availability of healthy food, safety, violence (i.e., more perceived violence), social cohesion, and participation in activities with neighbors. Participants separately underwent resting-state functional magnetic resonance imaging. RESULTS: Less favorable perceived safety ( ß = -0.33, pFDR = .04) and participation in activities with neighbors ( ß = -0.35, pFDR = .02) were associated with higher left amygdala activity, independent of covariates including psychosocial factors. Less favorable safety perceptions were also associated with enhanced left amygdala functional connectivity with the bilateral insular cortices and the left anterior insula ( ß = -0.34, pFDR = .04). Less favorable perceived social cohesion was associated with enhanced left amygdala functional connectivity with the right thalamus ( ß = -0.42, pFDR = .04), and less favorable perceptions about healthy food availability were associated with enhanced left amygdala functional connectivity with the bilateral anterior insula (right: ß = -0.39, pFDR = .04; left: ß = -0.42, pFDR = .02) and anterior cingulate gyrus ( ß = -0.37, pFDR = .04). CONCLUSIONS: Taken together, our findings document relationships between select neighborhood perceptions and amygdala activity as well as connectivity with salience network nodes; if confirmed, targeted community-level interventions and existing community strengths may promote brain-behavior relationships.

Cerebral arteriolosclerosis, lacunar infarcts, and cognition in older Black adults.

INTRODUCTION: Older Black adults are at risk of cerebral small vessel disease (CSVD), which contributes to dementia risk. Two subtypes of CSVD, arteriolosclerosis and ischemic lacunar infarcts, have been independently linked to lower cognition and higher dementia risk, but their combined effects on cognition in older Black adults are unclear. METHODS: Mixed models were used to examine the associations of in vivo measures of arteriolosclerosis (ARTS) and ischemic lacunar infarcts to cognitive level and change in 370 older Black adults without dementia.  RESULTS: Modeled together, higher ARTS load accounted for lower levels of global cognition, episodic memory, semantic memory, and perceptual speed, whereas higher infarct load accounted for lower levels of working memory. There were no associations with rate of cognitive change. DISCUSSION: Both arteriolosclerosis and ischemic infarcts impact the cognitive health of older Black adults, but arteriolosclerosis affects cognition more broadly and offers promise as an in vivo biomarker of dementia risk. HIGHLIGHTS: Older Black adults are at risk of cerebral small vessel disease (CSVD) and dementia. Examined magnetic resonance imaging-derived measure of arteriolosclerosis (ARTS), infarcts, and cognition. ARTS load was widely associated with lower cognition after adjusting for infarct load. Infarct load was specifically associated with lower complex attention. More within-Black in vivo studies of CSVD subtypes and cognition are needed.

Psychosocial factors associated with 7-year change in cognition among middle-aged and older Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) and Sociocultural ancillary studies.

INTRODUCTION: Few studies have examined the associations of psychosocial factors with cognitive change in Hispanics/Latinos. METHODS: Data from the Hispanic Community Health Study/Study of Latinos-Investigation of Neurocognitive Aging (HCHS/SOL INCA) and Sociocultural studies were used (n = 2,155; ages ≥45 years). Psychosocial exposures included intrapersonal (ethnic identity, optimism, purpose in life), interpersonal (family cohesion, familism, social networks, social support), and social factors (ethnic discrimination, loneliness, subjective social status). Survey-linear regression models examined associations between psychosocial exposures and 7-year cognitive change (global cognition [GC], verbal learning, memory, word fluency [WF], and digit symbol substitution [DSS]). RESULTS: Familism predicted decline in GC, verbal learning, and memory; family cohesion predicted DSS decline; and loneliness predicted memory decline. Ethnic identity was protective against decline in GC and memory, optimism and social support were protective against decline in memory, and purpose in life was protective against WF decline. DISCUSSION: Psychosocial factors are differentially related to cognitive changes. Culturally relevant factors should be explored in Hispanic/Latino cognitive aging research. HIGHLIGHTS: Psychosocial factors are differentially related to cognitive changes in Latinos. Role of culturally relevant factors on cognition should be further explored. Familism predicted decline in global cognition, verbal learning, and memory. Ethnic identity predicted increase in global cognition and memory.

Connections between reproductive health and cognitive aging among women enrolled in the HCHS/SOL and SOL-INCA.

INTRODUCTION: Reproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women. METHODS: Participants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence). RESULTS: Younger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence. DISCUSSION: Several aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Factors Associated With Healthcare and Financial Decision Making Among Older Black Adults Without Dementia.

OBJECTIVES: The study aims to identify factors associated with health care and financial decision-making among older Black adults without dementia. METHODS: Participants (N = 326) underwent assessments of decision-making and completed measurements of factors from four categories: cognitive, contextual, psychosocial, and personality. We performed separate linear regression models to examine the association between each factor and decision-making and created a fully adjusted model. RESULTS: Higher global cognition (estimate = 1.92, SE = 0.21, p < .0001) was associated with better decision-making. Contextual factors including higher current annual income (estimate = 0.23, SE = 0.05, p < .0001), higher childhood socioeconomic status (estimate = 0.48, SE = 0.18, p = .006), higher health and financial literacy (estimate = 0.08, SE = 0.01, p < .0001), and lower financial stress (estimate = -0.19, SE = 0.07, p = .01) were associated with better decision-making. More psychological well-being (estimate = 0.07, SE = 0.22, p = .001), a psychosocial factor, and less neuroticism (estimate = -0.06, SE = 0.02, p = .002), a personality factor, were associated with better decision-making. In the fully adjusted model, two factors, higher global cognition and higher literacy (health and financial), remained associated with better decision-making. CONCLUSIONS: Cognitive and contextual factors serve as drivers of decision-making among older Black adults. CLINICAL IMPLICATIONS: Clinicians may implement strategies to bolster cognition and improve health and financial literacy to facilitate optimal decision-making among older Black adults.

The Relationship of MRI-Derived Alzheimer's and Cerebrovascular-Related Signatures With Level of and Change in Health and Financial Literacy.

OBJECTIVE: The cortical thickness "signature" of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden have each been associated with cognitive aging and incident AD and related dementias. Less is known about how these structural neuroimaging markers associate with other critical behaviors. We investigated associations of AD-CT and WMH volumes with a composite index of health and financial literacy given that the ability to access, understand, and utilize health and financial information significantly influences older adults' health outcomes. DESIGN, SETTING, PARTICIPANTS: Participants were 303 adults without dementia (age∼80 years; 74% women) from the Rush Memory and Aging Project. MEASUREMENTS: Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess AD-CT and WMH volumes, respectively. Literacy was measured using questions designed to assess comprehension of health and financial information and concepts, yielding a total literacy score. Multivariable linear mixed effects regression models determined the relationship of each neuroimaging marker, first separately and then combined, with the level of and change in literacy. RESULTS: Reduced AD-CT and higher WMH at baseline were each associated with lower levels of literacy; only AD-CT was associated with the rate of decline in literacy over time. The association of AD-CT with change in literacy persisted when both neuroimaging markers were included in the same model. CONCLUSIONS: The cortical thickness signature of AD predicts changes in health and financial literacy in nondemented older adults suggesting that the multidimensional construct of health and financial literacy relies on specific brain networks implicated in AD.

Dissociating Statistically Determined Normal Cognitive Abilities and Mild Cognitive Impairment Subtypes with DCTclock.

OBJECTIVE: To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia. METHOD: Patients (n = 123) were classified into the following groups: cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning. RESULTS: Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (p < .050, all analyses); and lower than the SbCI group on drawing efficiency (p = .011). The aMCI group scored lower than the CN group on spatial reasoning (p = .019). Smaller effect sizes were obtained for the four copy indices. CONCLUSIONS: These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.

Childhood socioeconomic status interacts with cognitive function to impact scam susceptibility among community-dwelling older adults.

OBJECTIVES: We examined whether childhood socioeconomic status (SES) is related to scam susceptibility in old age and tested the hypothesis that childhood SES interacts with cognitive function to impact scam susceptibility. METHODS: This study employed a cross-sectional design. All data were collected in participants' community-based residences. Participants were 1071 older adults (mean age = 81.05 years, SD = 7.53) without dementia (median MMSE score = 28.29, IQR = 27.86-30.00). Participants completed assessments of childhood SES, cognitive function, and scam susceptibility. We used linear regression models to examine the associations of childhood SES and cognitive function with scam susceptibility. RESULTS: In a regression model adjusted for age, gender, and education, poorer cognitive function was associated with higher scam susceptibility, but childhood SES was not. However, in an additional model that included the interaction of childhood SES and cognitive function, the interaction was significant, such that lower childhood SES was associated with higher scam susceptibility among participants with lower cognitive function. CONCLUSION: Lower childhood SES is associated with higher scam susceptibility among older adults with lower levels of cognitive function. Thus, older adults who experienced limited resources in childhood and have lower cognitive function may represent a specific group for interventions to increase scam awareness and prevent financial exploitation.

The structural and social determinants of Alzheimer's disease related dementias.

INTRODUCTION: The projected growth of Alzheimer's disease (AD) and AD-related dementia (ADRD) cases by midcentury has expanded the research field and impelled new lines of inquiry into structural and social determinants of health (S/SDOH) as fundamental drivers of disparities in AD/ADRD. METHODS: In this review, we employ Bronfenbrenner's ecological systems theory as a framework to posit how S/SDOH impact AD/ADRD risk and outcomes. RESULTS: Bronfenbrenner defined the "macrosystem" as the realm of power (structural) systems that drive S/SDOH and that are the root cause of health disparities. These root causes have been discussed little to date in relation to AD/ADRD, and thus, macrosystem influences, such as racism, classism, sexism, and homophobia, are the emphasis in this paper. DISCUSSION: Under Bronfenbrenner's macrosystem framework, we highlight key quantitative and qualitative studies linking S/SDOH with AD/ADRD, identify scientific gaps in the literature, and propose guidance for future research. HIGHLIGHTS: Ecological systems theory links structural/social determinants to AD/ADRD. Structural/social determinants accrue and interact over the life course to impact AD/ADRD. Macrosystem is made up of societal norms, beliefs, values, and practices (e.g., laws). Most macro-level determinants have been understudied in the AD/ADRD literature.

Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship With Cognitive Decline.

BACKGROUND AND PURPOSE: Cerebrovascular disease (CVD) pathologies including vessel disease (atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and tissue injury (macroinfarcts and microinfarcts) each contribute to Alzheimer and other forms of dementia. CVD is often a complex mix of neuropathologies, with little known about the frequencies of differing combinations or their associations with cognition. METHODS: We investigated 32 possible CVD combinations (3 types of vessel disease and 2 types of tissue injury) using autopsy data from 1474 decedents (≈88 years at death; 65% female) of Rush Alzheimer's Disease Center studies. We determined frequencies of all 32 CVD combinations and their relationships with global and domain-specific cognitive decline using mixed-effect models adjusted for demographics, neuropathologies, time before death, and interactions of these variables with time. RESULTS: Of the 1184 decedents with CVD neuropathology (80% of the total sample), 37% had a single CVD (67-148 decedents/group) while 63% had mixed CVD profiles (11-54 decedents/group). When considered as 2 distinct groups, the mixed CVD profile group (but not the single CVD profile group) showed a faster cognitive decline across all domains assessed compared with decedents without CVD neuropathology. Most mixed CVD profiles, especially those involving both atherosclerosis and arteriolosclerosis, showed faster cognitive decline than any single CVD profile considered alone; specific mixed CVD profiles differentially associated with individual cognitive domains. CONCLUSIONS: Mixed CVD, more common than single CVD, is associated with cognitive decline, and distinct mixed CVD profiles show domain-specific associations with cognitive decline. CVD is not monolithic but consists of heterogenous person-specific combinations with distinct contributions to cognitive decline.

Cognitive decline and hippocampal functional connectivity within older Black adults.

While there has been a proliferation of neuroimaging studies on cognitive decline in older non-Hispanic White adults, there is a dearth of knowledge regarding neuroimaging correlates of cognitive decline in Black adults. Resting-state functional neuroimaging approaches may be particularly sensitive to early cognitive decline, but there are no studies that we know of that apply this approach to examining associations of brain function to cognition in older Black adults. We investigated the association of cognitive decline with whole-brain voxel-wise functional connectivity to the hippocampus, a key brain region functionally implicated in early Alzheimer's dementia, in 132 older Black adults without dementia participating in the Minority Aging Research Study and Rush Memory and Aging Project, two longitudinal studies of aging that include harmonized annual cognitive assessments and magnetic resonance imaging brain imaging. In models adjusted for demographic factors (age, education, sex), global cognitive decline was associated with functional connectivity of the hippocampus to three clusters in the right and left frontal regions of the dorsolateral prefrontal cortex. In domain-specific analyses, decline in semantic memory was associated with functional connectivity of the hippocampus to bilateral clusters in the precentral gyrus, and decline in perceptual speed was inversely associated with connectivity of the hippocampus to the bilateral intracalcarine cortex and the right fusiform gyrus. These findings elucidate neurobiological mechanisms underlying cognitive decline in older Black adults and may point to specific targets of intervention for Alzheimer's disease.

Relationship of Blood Pressure and White Matter Hyperintensity Burden With Level of and Change in Cognition in Older Black Adults.

OBJECTIVE: Elevations in blood pressure (BP) and associated white matter hyperintensities (WMHs) are chronic comorbid conditions among older Black adults. We investigated whether WMHs modify the association between late-life BP and cognition within older Black adults. METHODS: A total of 167 Black adults (age, ~75 years; without dementia at baseline) participating in neuroimaging studies at the Rush Alzheimer's Disease Center were evaluated for BP markers of cardiovascular health, including systolic BP, diastolic BP, pulse pressure, mean arterial pressure (MAP), and hypertension, and were assessed for global and domain-specific cognition at baseline and annually for up to 8 years. WMHs adjusted for intracranial volume were quantified at baseline. RESULTS: Models adjusted for relevant confounders and the interaction of these variables with time revealed differential associations between BP markers and baseline cognition; however, only elevated diastolic BP predicted faster cognitive, that is, episodic memory, decline (estimate = -0.002, standard error = 0.0009, p = .002). Although WMH burden did not modify the association between diastolic BP and episodic memory decline, it did interact with diastolic BP to lower episodic memory at baseline (estimate = -0.051, standard error = 0.012, p = .0001); that is, greater WMHs combined with higher diastolic BP resulted in the lowest baseline episodic memory scores. A similar profile was noted for WMHs, MAP, and baseline episodic memory. Hypertension was neither associated with cognition nor modified by WMH burden after multiple comparisons correction. CONCLUSION: Late-life diastolic BP was associated with faster rates of episodic memory decline in older Black adults; together with higher WMH burden, it (and MAP) lowered the point at which individuals begin their course of decline toward pathological aging.

Acute versus chronic inflammatory markers and cognition in older black adults: Results from the Minority Aging Research Study.

Peripheral inflammation is elevated in older Black adults, an elevation which prior work has suggested may be due to chronic stress associated with systemic racism and related adverse cardiovascular health conditions. Inflammation is also involved in the pathogenic processes of dementia; however, limited (and mixed) results exist concerning inflammation and cognitive decline in Black adults. We characterized patterns of inflammation and their role in cognitive decline in 280 older Black adults (age = 72.99 ± 6.00 years; 69.6% female) from the Minority Aging Research Study (MARS) who were without dementia at baseline and followed between 2 and 15 years (mean = 9 years). Participants completed a blood draw at baseline and annual cognitive evaluations. Serum was assayed for 9 peripheral inflammatory markers; 19 neuropsychological test scores were used to create indices of global cognition and five cognitive domains. Principal component analysis with varimax rotation characterized patterns of inflammation with factor loadings > 0.6 per component contributing to two composite scores representing acute/upstream and chronic/downstream inflammation. These composites were used as separate predictors in linear mixed regression models to determine associations with level and change in cognition adjusting for relevant covariates. Higher baseline upstream/acute inflammation associated with lower baseline semantic memory (p = .040) and perceptual speed (p = .046); it was not related to cognitive decline. By contrast, higher baseline downstream/chronic inflammation associated with faster declines in global cognition (p = .010), episodic (p = .027) and working memory (p = .006); it was not related to baseline cognition. For older Black adults, chronic, but not acute, inflammation may be a risk factor for changes in cognition.

Exercise Training and Cognitive Function in Kidney Disease: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Chronic kidney disease (CKD) is extremely common in older adults and is associated with cognitive impairment. It is hypothesized that accelerated cognitive decline in CKD results from a vascular dysfunction-induced reduction in the integrity of the brain white matter. OBJECTIVE: The aim of this study was to describe the protocol for a study to evaluate whether exercise training provides a cerebroprotective effect by improving cerebrovascular health. METHODS: This is a randomized controlled trial investigating feasibility and effect size. RESULTS: Participants will be randomized to either a 24-week, home-based, walking program or a usual care group. Participants will undergo evaluation of cognitive function, brain structure via magnetic reasoning imaging, physical function, physical activity, and vascular function. The primary outcome is change in cognitive function. DISCUSSION: The findings of this study will help determine whether exercise training influences cognitive function during a therapeutic window in the disease process of cognitive impairment in older adults with CKD. CONCLUSION: This protocol describes a study to evaluate cognition and brain structure following a home-based exercise program to an at-risk population.

Association of physical activity levels and brain white matter in older Latino adults.

OBJECTIVE: Investigate the associations between self-reported physical activity (PA) engagement and white matter (WM) health (i.e. volume, integrity, and hyperintensities) in older Latinos. DESIGN: Cross-sectional study with community-dwelling older adults from predominantly Latino neighborhoods. Participants: Thirty-four cognitively healthy older Latinos from two different cohorts. Measurements: Participants self-reported demographic information, PA engagement [Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults] and magnetic resonance imaging (MRI). We used high-resolution three-dimensional T1- and T2-FLAIR weighted images and diffusion tensor imaging acquired via 3 T MRI. We performed a series of hierarchical linear regression models with the addition of relevant covariates to examine the associations between self-reported PA levels and WM volume, integrity, and hyperintensities (separately). We adjusted p-values with the use of the Benjamini-Hochberg's false discovery rate procedure. RESULTS: Higher reported levels of leisure-time moderate-to-vigorous PA were significantly associated with higher WM volume of the posterior cingulate (ß = 0.220, SE = 0.125, 95% CI 0.009-0.431, p = 0.047) and isthmus cingulate (ß = 0.212, SE = 0.110, 95% CI 0.001-0.443, p = 0.044) after controlling for intracranial volume. Higher levels of total PA were significantly associated with higher overall WM volume of these same regions (posterior cingulate: ß = 0.220, SE = 0.125, CI 0.024-0.421, p = 0.046; isthmus cingulate: ß = 0.220, SE = 0.125, 95% CI 0.003-0.393; p = 0.040). Significant p-values did not withstand Benjamini-Hochberg's adjustment. PA was not significantly associated with WM integrity or WM hyperintensities. CONCLUSION: Higher levels of PA, particularly higher leisure-time moderate-to-vigorous PA, might be associated with greater WM volume in select white matter regions key to brain network integration for physical and cognitive functioning in older Latinos. More research is needed to further confirm these associations.

The Spanish-English bilingual experience and cognitive change in Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos-Investigation of Neurocognitive Aging.

INTRODUCTION: Studies suggest bilingualism may delay behavioral manifestations of adverse cognitive aging including Alzheimer's dementia. METHODS: Three thousand nine hundred sixty-three participants (unweighted mean population age ≈56 years) at Hispanic Community Health Study/Study of Latinos baseline (2008-2011) self-reported their and their parents' birth outside the United States, Spanish as their first language, and used Spanish for baseline and comparable cognitive testing 7 years later (2015-2018). Spanish/English language proficiency and patterns of use were self-rated from 1 = only Spanish to 4 = English > Spanish. Cognitive testing included test-specific and global composite score(s) of verbal learning, memory, word fluency, and Digit Symbol Substitution (DSS). Survey linear regression models examined associations between baseline bilingualism scores and cognition. RESULTS: Higher second-language (English) proficiency and use were associated with higher global cognition, fluency, and DSS at follow-up and better than predicted change in fluency. DISCUSSION: The bilingual experience was more consistently related to 7-year level versus change in cognition for Hispanics/Latinos.

APOE alleles' association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL).

INTRODUCTION: Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry-specific genetic effects. METHODS: We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations. RESULTS: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P-value = 0.03), with the strongest association in Cubans (OR = 1.46, P-value = 0.007). APOE-ε2 was associated with decreased risk of MCI (OR = 0.37, P-value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline. DISCUSSION: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

Hospitalization, Alzheimer's Disease and Related Neuropathologies, and Cognitive Decline.

OBJECTIVE: To test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age. METHODS: As part of a longitudinal clinical-pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed ß-amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa. RESULTS: Over a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = -0.042, standard error [SE] = 0.012, p < 0.001), and after controlling for all 7 neuropathologic markers, the association was essentially the same (estimate = -0.040, SE = 0.013, p = 0.002). In a multivariable model with 3-way interactions of neuropathologic markers with hospitalization rate and time, the association between hospitalization rate and faster cognitive decline was greater in persons with more tangle pathology (estimate for interaction = -0.007, SE = 0.002, p = 0.002) and in persons with neocortical Lewy bodies (estimate for interaction = -0.117, SE = 0.042, p = 0.005). INTERPRETATION: Older persons with more hospitalizations experienced faster rates of cognitive decline, and this association was more pronounced in persons with more tau tangle density and with neocortical Lewy body pathologies. ANN NEUROL 2019;86:844-852.

Common Brain Structural Alterations Associated with Cardiovascular Disease Risk Factors and Alzheimer's Dementia: Future Directions and Implications.

Recent reports suggest declines in the age-specific risk of Alzheimer's dementia in higher income Western countries. At the same time, investigators believe that worldwide trends of increasing mid-life modifiable risk factors [e.g., cardiovascular disease (CVD) risk factors] coupled with the growth of the world's oldest age groups may nonetheless lead to an increase in Alzheimer's dementia. Thus, understanding the overlap in neuroanatomical profiles associated with CVD risk factors and AD may offer more relevant targets for investigating ways to reduce the growing dementia epidemic than current targets specific to isolated AD-related neuropathology. We hypothesized that a core group of common brain structural alterations exist between CVD risk factors and Alzheimer's dementia. Two co-authors conducted independent literature reviews in PubMed using search terms for CVD risk factor burden (separate searches for 'cardiovascular disease risk factors', 'hypertension', and 'Type 2 diabetes') and 'aging' or 'Alzheimer's dementia' with either 'grey matter volumes' or 'white matter'. Of studies that reported regionally localized results, we found support for our hypothesis, determining 23 regions commonly associated with both CVD risk factors and Alzheimer's dementia. Within this context, we outline future directions for research as well as larger cerebrovascular implications for these commonalities. Overall, this review supports previous as well as more recent calls for the consideration that both vascular and neurodegenerative factors contribute to the pathogenesis of dementia.