Showing papers by "Charles DeCarli published in 2022"

Association of Loneliness With 10-Year Dementia Risk and Early Markers of Vulnerability for Neurocognitive Decline

Abstract: Background and Objectives Loneliness is common, and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability. Methods This was a retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (September 9, 1948–December 31, 2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded with the Center for Epidemiologic Studies Depression Scale, defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white matter injury. Results Of 2,308 participants (mean age 73 [SD 9] years, 56% women) who met eligibility in the dementia sample, 14% (329 of 2,308) developed dementia and 6% (144 of 2,308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio 1.54, 95% CI 1.06–2.24). Lonely participants <80 years of age without APOE ε4 alleles had a 3-fold greater risk (adjusted hazard ratio 3.03, 95% CI, 1.63–5.62). Among 1,875 persons without dementia who met eligibility in the cognition sample (mean age 62 [SD 9] years, 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white matter injury. Discussion Over 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low on the basis of age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends. Classification of Evidence This study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.

Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease

Abstract: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Instrumental validation of free water, peak‐width of skeletonized mean diffusivity, and white matter hyperintensities: MarkVCID neuroimaging kits

Abstract: To describe the protocol and findings of the instrumental validation of three imaging‐based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1‐weighted imaging.

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

Abstract: The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease

Abstract: Alzheimer's disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care.We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called "Alzheimer's Predictive Vector" (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO).The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimer's related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and SNPrs2075650 is significantly altered in patients with ADrp-like phenotype.This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.Alzheimer’s disease is the most common cause of dementia, impacting memory, thinking and behaviour. It can be challenging to diagnose Alzheimer’s disease which can lead to suboptimal patient care. During the development of Alzheimer’s disease the brain shrinks and the cells within it die. One method that can be used to assess brain function is magnetic resonance imaging, which uses magnetic fields and radio waves to produce images of the brain. In this study, we develop a method that uses magnetic resonance imaging data to identify differences in the brain between people with and without Alzheimer’s disease, including before obvious shrinkage of the brain occurs. This method could be used to help diagnose patients with Alzheimer’s Disease.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort *

Abstract: We investigated cross‐sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort.

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Abstract: Alzheimer's disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer's Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study.

Abstract: BACKGROUND Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. METHODS The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. RESULTS Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p < 0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p < 0.001; β= 1.59±0.38, p < 0.001, and β= 1.52±0.54, p = 0.008, respectively). CONCLUSION This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Manifestations of Alzheimer’s disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90

Abstract: Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Imaging Markers of Vascular Brain Health: Quantification, Clinical Implications, and Future Directions

Abstract: Cerebrovascular disease (CVD) manifests through a broad spectrum of mechanisms that negatively impact brain and cognitive health. Oftentimes, CVD changes (excluding acute stroke) are insufficiently considered in aging and dementia studies which can lead to an incomplete picture of the etiologies contributing to the burden of cognitive impairment. Our goal with this focused review is 3-fold. First, we provide a research update on the current magnetic resonance imaging methods that can measure CVD lesions as well as early CVD-related brain injury specifically related to small vessel disease. Second, we discuss the clinical implications and relevance of these CVD imaging markers for cognitive decline, incident dementia, and disease progression in Alzheimer disease, and Alzheimer-related dementias. Finally, we present our perspective on the outlook and challenges that remain in the field. With the increased research interest in this area, we believe that reliable CVD imaging biomarkers for aging and dementia studies are on the horizon.

Examination of Neurofilament Light Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults

Abstract: This cohort study uses data from the Chicago Health and Aging Project to examine associations between physical activity and cognitive decline by serum concentrations of neurofilament light (NfL) chain among older adults.

Aging, prevalence and risk factors of MRI-visible enlarged perivascular spaces

Abstract: Background and purpose: Cerebral small vessel disease (CSVD) increases with age and is associated with stroke and cognitive decline. Enlarged Perivascular Spaces (ePVS) is an emerging marker of CSVD, but its prevalence over the life span remain unclear. We characterized the age and sex-specific prevalence of ePVS and relation to age-specific risk factors, in a large community-based sample. Methods: We included 3,710 Framingham Heart Study participants with available brain MRI (average age 61.4±14.6, 46% men). ePVS burden was rated in the centrum semiovale (CSO) and basal ganglia (BG) regions. Individual vascular risk factors were related to ePVS burden in the CSO, BG, and mixed CSO-BG regions using multivariable adjusted ordinal logistic regression analysis. Results: Severe ePVS prevalence increased with age in men and women, and paralleled increase in vascular risk factors, and prevention treatment use. Older age, hypertension (and resulting higher treatment use), higher systolic and diastolic blood pressure, and smoking were associated with higher burden of ePVS in the CSO, BG and mixed regions. Conclusions: Our observations reinforce the hypothesis that ePVS may be a marker of aging-driven brain vascular pathologies, and its association with vascular risk factors support their role as CSVD imaging biomarker.

Dissection of the polygenic architecture of neuronal Aβ production using a large sample of individual iPSC lines derived from Alzheimer’s disease patients

Abstract: Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer’s disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1. Using more than 100 independent iPSC lines derived from patients with Alzheimer’s disease, the authors discovered loci associated with the neuronal production of amyloid β and confirmed their influence using RNA interference.

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife

Abstract: Background and Objectives Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype. Methods We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes. Results We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers. Discussion Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

Accounting for lack of representation in dementia research: Generalizing KHANDLE study findings on the prevalence of cognitive impairment to the California older population

Abstract: Most dementia studies are not population‐representative; statistical tools can be applied to samples to obtain critically‐needed population‐representative estimates, but are not yet widely used.

Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels

Abstract: Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

MRI-Visible Perivascular Spaces and Risk of Incident Dementia

Abstract: Background and Objectives Perivascular spaces (PVS) visible on MRI scans may represent key aspects in the pathophysiology of stroke and dementia, including cerebral small vessel disease and glymphatic dysfunction. This study aimed to determine the association between MRI-visible PVS burden and the risk of incident dementia. Methods This study included community-dwelling Framingham Heart Study Original and Offspring cohort participants with available brain MRI-PVS ratings, free of stroke and dementia. Multivariable Cox proportional hazard regression was used to obtain hazard ratios (HRs) and 95% CIs of the association between MRI-visible PVS and incident dementia. PVS were rated using validated methods in the basal ganglia (BG) and centrum semiovale (CSO). The outcomes included all-cause dementia, Alzheimer dementia (AD), and vascular dementia (VaD). Results One thousand four hundred forty-nine participants 50 years or older (46% male) were included. Over a median follow-up period of 8.3 years, the incidence of all-cause dementia, AD, and VaD was 15.8%, 12.5%, and 2.5%, respectively. In models that adjusted for vascular risk factors and cardiovascular disease, the hazard for dementia increased steadily as PVS burden increased, rising 2-fold for those with grade II PVS (HR 2.44, 95% CI 1.51–3.93) to 5-fold in participants with grade IV (HR 5.05, 95% CI 2.75–9.26) compared with grade I PVS in CSO. In the BG, hazards increased 1.6-fold (HR 1.62, 95% CI 1.15–2.27) for grade II to 2.6-fold (HR 2.67, 95% CI 1.04–6.88) for grade IV compared with grade I PVS. The association remained significant for CSO but not for BG, after adjustment for white matter hyperintensity volume (WMHV), covert infarcts, and total brain volume. Similar findings were observed for AD, but VaD, limited by a small number of events, was not statistically significant. Discussion Higher burden of PVS in CSO was associated with increased risk of developing dementia, independent of vascular risk factors, total brain volume, WMHVs, and covert infarcts. This finding supports a role for PVS as a subclinical MRI marker to identify individuals in subclinical stages at high risk of developing dementia who may benefit from early intervention.

Association of Apolipoprotein E ɛ4 Allele with Enlarged Perivascular Spaces

Abstract: Enlarged perivascular spaces have emerged as markers of cerebral small vessel disease and are linked to perivascular drainage dysfunction. The apolipoprotein E‐ɛ4 (APOE‐ɛ4) allele is the strongest genetic risk factor for cerebral amyloid angiopathy and Alzheimer's neuropathology, but the underlying mechanisms remain unclear. We studied the relationship between APOE‐ɛ4 and the topography and burden of enlarged perivascular spaces to elucidate underlying mechanisms between APOE‐ɛ4 and adverse clinical outcomes.

Association of Subjective Memory Complaints With White Matter Hyperintensities and Cognitive Decline Among Older Adults in Chicago, Illinois

Abstract: Importance Subjective memory complaints (SMCs) are associated with a faster cognitive decline; whether this association is also associated with structural brain alterations, such as white matter hyperintensity (WMH) volumes, requires investigation. Objective To evaluate the association of SMCs with WMH volumes and cognitive decline and investigate the role of WMH volumes in the association between SMCs and cognitive decline. Design, Setting, and Participants The Chicago Health and Aging Project, a population-based cohort study, enrolled adults aged 65 years or older. Data collection occurred in 3-year cycles from 1993 until 2012. Our study comprised 975 participants with magnetic resonance imaging assessments, of which 900 participants had data on SMCs and covariates, and 713 participants provided 2 or more cognitive assessments during the follow-up. Statistical analyses were conducted from May to October 2021. Exposures SMCs were obtained from self-reported questionnaire data during clinical evaluations, and the cycle, when reported, constituted the baseline of our study. Based on the frequency and severity of concerns, we categorized participants into 3 groups, (1) no concerns, (2) moderate concerns, and (3) very worried. Main Outcomes and Measures Volumetric magnetic resonance imaging measures of WMH volume and neuropsychological testing assessments of global cognition. Linear regression analysis was used to investigate the association between SMCs and WMH volumes in a multivariable model adjusted for age, sex, race and ethnicity, education, APOE4 status, and total intracranial volume. The association of SMCs with cognitive decline was investigated using linear mixed-effects models for age, sex, race and ethnicity, education, APOE4 status, follow-up time, and each variable in interaction with time to estimate the annual longitudinal change in cognitive function. Results Of the 900 participants with data on SMCs, covariates, and WMH volumes, 553 (61.4%) were women, 539 (59.9%) were African American, and the mean (SD) age was 79.5 (6.2) years. SMCs were associated with a larger WMH volume and faster cognitive decline. Compared with participants with no concerns, participants who were very worried had higher WMH volumes (β = 0.833; 95% CI, 0.203-1.463) and 174% faster cognitive decline (β = −0.049; 95% CI, −0.076 to −0.022). The association between SMCs and cognitive decline remained statistically significant among individuals with large WMH volumes (ie, within the fourth quartile). Within the fourth quartile of WMH volumes, participants who were very worried had 428% faster cognitive decline (β = −0.077; 95% CI, −0.144 to −0.011) compared with participants with no concerns. Conclusions and Relevance This cohort study suggests that SMCs, frequently reported by older individuals, are an important sign of cognitive impairment, especially among people with abnormalities in brain structure, such as larger WMH volumes.

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Abstract: Abstract Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer’s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden.

Abstract: BACKGROUND Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. OBJECTIVE We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. METHODS We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. CONCLUSION Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition

Abstract: We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.

Subclinical left ventricular systolic dysfunction and incident stroke in the elderly: long-term findings from Cardiovascular Abnormalities and Brain Lesions.

Abstract: AIMS Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort. METHODS AND RESULTS Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes. CONCLUSION LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies.

Impact of cardiovascular risk factors in adolescence, young adulthood, and mid-life on late-life cognition

Abstract: Using the Study of Healthy Aging in African Americans (STAR), we assessed cardiovascular risk factors (CVRFs) in adolescence, young adulthood, and midlife with late-life cognition. Among 755 participants, body mass index, blood pressure, glucose, and total cholesterol were collected during Multiphasic Health Checkups (1964-1985). At STAR baseline (2018-2019; mean age=69(SD=9)), executive function (EF), verbal episodic memory (VEM), and semantic memory (SM) were measured using the Spanish and English Neuropsychological Assessment Scales. Linear regression models associated CVRFs with cognition. Hypertension was associated with worse late-life EF (β[95% CI]:-0.14[-0.28, -0.00]) and VEM (β[95% CI]:-0.22[-0.37, -0.07]). Diabetes was associated with worse EF (β[95% CI]: -0.43[-0.83, -0.03]). In age-stratified analyses, adolescent hypertension was associated with lower late-life EF (β[95% CI]:-0.39[-0.67, -0.11]). Young adulthood hypertension (β[95% CI]:-0.29[-0.49, -0.09]) and midlife hyperlipidemia (β[95% CI]:-0.386[-0.70, -0.02]) were associated with lower VEM. These results emphasize the importance of lifecourse cardiovascular health on the aging brain among Black Americans.

Progression of cerebral white matter hyperintensities is related to leukocyte gene expression.

Abstract: Cerebral white matter hyperintensities (WMH) are an important contributor to aging brain pathology. Progression in WMH volume is associated with cognitive decline and gait impairment. Understanding the factors associated with WMH progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression and thus evaluated the relationship of blood leukocyte gene expression to progression of cerebral WMH. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (IQR 3.5-8.2 years). WMH volumes were measured by semi-automated segmentation and percent change in WMH per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in WMH volumes over time and baseline leukocyte gene expression was analyzed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median WMH volume was 13.4 mL (SD 17.4 mL). The mean change in WMH volume was 12% per year. Patients were divided in quartiles by percent change in WMH volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3, and 33.6% per year in quartile 4. There were 148 genes associated with changing WMH volumes over time (p < 0.05 r>|0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, FAK, and SIGLEC1 were among the identified genes. Progression of WMH volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of WMH progression and the contribution to cognitive decline.

High-Density Lipoprotein Changes in Alzheimer’s Disease Are APOE Genotype-Specific

Abstract: High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

Abstract: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings.