Seshadri, Sudha

Abstract INTRODUCTION Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi‐site study, using a predefined hypothesis. METHODS We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. Highlights This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.

Background: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. Objective: To study the cross-sectional associations of pulmonary function with structural brain variables. Methods: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. Results: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. Conclusion: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

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.

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID’s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as neurofibrillary degeneration generally restricted to the medial temporal region (Braak stage I–IV) with complete or near absence of diffuse and neuritic plaques. Symptoms range in severity but are generally milder and later in onset than in Alzheimer disease (AD). Recently, an early predilection for neurofibrillary degeneration in the hippocampal CA2 subregion has been demonstrated in PART, whereas AD neuropathologic change (ADNC) typically displays relative sparing of CA2 until later stages. In this study, we utilized a semiquantitative scoring system to evaluate asymmetry of neurofibrillary degeneration between left and right hippocampi in 67 PART cases and 17 ADNC cases. 49% of PART cases demonstrated asymmetric findings in at least one hippocampal subregion, and 79% of the asymmetric cases displayed some degree of CA2 asymmetry. Additionally, 19% of cases revealed a difference in Braak score between the right and left hippocampi. There was a significant difference in CA2 neurofibrillary degeneration (p = 0.0006) and CA2/CA1 ratio (p &lt; 0.0001) when comparing the contralateral sides, but neither right nor left was more consistently affected. These data show the importance of analyzing bilateral hippocampi in the diagnostic evaluation of PART and potentially of other neurodegenerative diseases.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

AbstractBackgroundSenescent cells accumulate with advanced age and contribute to dysfunction and disability. We recently discovered that tau protein accumulation induces cellular senescence in Alzheimer’s disease and other tauopathies, a group of brain diseases characterized by the deposition of tau protein (Musi et al., 2018). Treating mice with senolytics, drugs that specifically target senescent cells for their removal, reduced pathology and improved brain structure and function in tauopathy mice. Our initial study focused on dasatinib plus quercetin (D+Q). We now report results from directly comparing D+Q to fisetin (FIS) to determine differences in efficacy, toxicity, and sex and genotype as we work to translate this therapy to clinical studies.MethodFourteen‐month old male and female wild type (WT) and tau transgenic (rTg4510) mice were treated intermittently (3 days on, 11 days off, for 6 cycles) with D+Q, FIS, or vehicle by oral gavage. Physical and behavioral outcomes were measured before and after treatment.ResultBoth senolytic therapies significantly enhanced female rTg4510 mouse performance in the y‐maze (increased preference for novel arm (p = 0.00093 and p = 0.0015, D+Q and FIS, respectively); no treatment changes were noted in WT females or male mice. Pre‐ and post‐treatment comparisons of body weight revealed that D+Q uniquely increased body weight in female mice (WT: p=0.0005 and t: p = 0.024). Similarly, body length was increased by D+Q in WT (p= 0.0012) and rTg4510 (p= 0.0457) females, and WT males (p= 0.0481). Physical performance measures included run speed whereby D+Q increased WT female (p= 0.0002) and male (p=0.0267) velocity. FIS only affected WT males (p= 0.0022) but not females; and rTg4510 male (p=0.0015) but not female mice. Additional genotype, sex and treatment specific effects were observed in measures of frailty, grip strength, stride length, and nerve conduction. Our on‐going analyses of brain volumetry changes (MRI), axon integrity, transcriptomics, tau pathology, and inflammatory changes among the groups will provide mechanistic insights responsible for these behavioral phenotypes.ConclusionOur study suggests that tailoring senolytic therapies to specific individuals based on sex and disease state may provide the most benefit as we translate this promising therapy to clinical use.