Kimberly R. Pechman

Lower cardiac index levels relate to lower cerebral blood flow in older adults

Objective: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. Methods: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. Results: Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. Conclusions: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.

The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview

BACKGROUND Vascular health factors frequently co-occur with Alzheimers disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults

Background Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults. Methods and Results Vanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73±7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and APOE*ε4 status. Models were repeated with a cardiac×cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (β=−0.07, P=0.04), visuospatial immediate recall (β=−0.83, P=0.03), visuospatial delayed recall (β=−0.22, P=0.03), and verbal delayed recall (β=−0.11, P=0.007). LVEF did not relate to worse performance on any measure (P>0.18). No diagnostic interactions were observed. Conclusions Our study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function.

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals (n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

POSTERIOR COMMUNICATING ARTERY VARIATION IN THE CIRCLE OF WILLIS IS ASSOCIATED WITH COMPROMISED TEMPORAL LOBE HEMODYNAMICS IN OLDER ADULTS

which mean diffusivity(MD), fractional anisotropy(FA) and white matter hyperintensity(WMH) were calculated. Cerebrospinal fluid was obtained for 63 subjects and Ab, tau and phosphorylated-tau levels were measured. Subjects were classified as low-binders when rs6971 homozygous and high-binders when rs6971 homozygous. Chi-square and t-tests were used for demographic description whereas linear models adjusted for covariates were used to assess the effect of rs6971 on the available phenotypes. Results: The rs6971 minor-allele frequency in our study population is 0.30 (48,8% CC,41.7% CT,9.4% TT) (Figure 1), which is in accordancewith frequencies described for Caucasian populations in public databases. Differences in gender, diagnosis and APOE-e4 status were not observed across rs6971 genotypes. The rs6971 was not associated with any cognitive score as well as with none of the CSF or imaging biomarkers tested here. Conclusions:The study population under investigation is genetically representative of the Caucasian population –for the rs6971–and the SNP showed no effect in any dementia-related phenotypes analyzed here. Results confirm that the cohort is appropriate for neuroimaging studies linking dementia and neuroinflammation.

VERBAL EPISODIC MEMORY IS PREFERENTIALLY RELATED TO WHITE MATTER INTEGRITY IN COGNITIVELY NORMAL OLDER ADULTS: THE VANDERBILT MEMORY & AGING PROJECT

Second, a longitudinal analysis was performed to evaluate intrasubject difference between visits.Results:The result revealed differential aging and education effects on lexical performance across tasks. The cross-sectional analysis showed that age significantly predicted the performance on BNT & Semantic Fluency Test. This indicates that older elderly performed poorly than younger elderly at these tasks. Longitudinally, the year of education only significantly predicted the accuracy decline on Vocabulary and Semantic Fluency but not the accuracy changes on BNT and Phonemic Fluency Test. Participants with fewer years of education showed more decline on the accuracy of these tests. It suggests that individuals with higher education better compensate their lexical ability decline on selective tasks.Conclusions:The education effect on lexical production tasks is not the same across tasks and amount of education plays different roles in cognitive reserve. This effect has to be considered in identification of early cognitive changes in healthy elderly or people with pre-dementia phase.

ANATOMICAL VARIATION IN THE CIRCLE OF WILLIS IS ASSOCIATED WITH WHITE MATTER HYPERINTENSITIES IN OLDER ADULTS

Entorhinal -0.26 (.17) 0.137 -0.61, 0.09 -0.17 (.23) 0.461 -0.63, 0.29 Fusiform -0.21 (.09) 0.020 -0.38, -0.04 -0.16 (.12) 0.182 -0.39, 0.08 Parahippocampal -0.20 (.14) 0.157 -0.48, 0.08 0.01 (.18) 0.946 -0.38, 0.35 Cingulate Isthmus -0.25 (.11) 0.026 -0.47, -0.03 -0.10 (.14) 0.477 -0.39, 0.18 Posterior Cingulate -0.21 (.10) 0.042 -0.42, -0.01 -0.17 (.14) 0.229 -0.44, 0.11 Precuneus -0.48 (.07) 0.000 -0.63, -0.34 -0.35 (.09) 0.000 -0.53, -.016

APOE GENOTYPE INFLUENCES HOW CEREBRAL BLOOD FLOW AND VASOREACTIVITY PREDICT NEUROPSYCHOLOGICAL DECLINE OVER AN 18-MONTH FOLLOW-UP: THE VANDERBILT MEMORY AND AGING STUDY

other groups, including sAD.Conclusions:Our results suggest a high frequency of microhemorrhages in DSAD cases in the occtx, more so than sAD. This along with the increased amount of CAA suggests that cerebrovascular pathology may be an under-recognized, yet significant contributor to aging and the development of dementia in peoplewith DS.We are currently in the process of quantifying microbleeds using MRI in the occtx in our aging DS cohort to link this pathology with cognitive decline. Funding from NIH/NICHD R01HD064993.

INTRACRANIAL ARTERY LUMEN DIAMETER RELATES TO CEREBRAL BLOOD FLOW AND CEREBROVASCULAR REACTIVITY IN MCI

independent steps. First, for each scan session (subject), the normalized signal intensity for each voxel was assessed for fit to the same session’s CSF signal across the 4 sequences (T, T, FLAIR, PD) (Fig. 2). Second, clusters ( 4 contiguous voxels) with positive vCSF regression coefficients were submitted to the morphological assessment component of the algorithm (Fig 3). For clusters surviving linearity and volume thresholds, morphological features including linearity, width, and volume of each cluster (ePVS) were extracted (Fig 3). Results:A significant correlation was found between visual counts and 1) clusters detected in the same slice (r(26)1⁄4 0.65, p<0.001; r(26)1⁄4 0.69, p<0.001; r(26)1⁄40.54, p<0.01) and 2) with total burden volume (r(26)1⁄4 0.58, p<0.01) and total ePVS number detected by mMAPS (r(26)1⁄4 0.76, p<0.01, Figure 4C). Average ePVS was 24.6 (range 3 to 71) and total burden volume (SD) 303.0 (267.74) mm per dataset. Average width of ePVS was 3.12 mm (min 1.7, max 13.5). Whole brain counts were 7.1 times that of a single slice, a nearly 100-fold increase in the range of the measured proxy variable for burden. In this limited dataset, no significant relationships were observed between

SUBJECTIVE COGNITIVE DECLINE AND NEUROIMAGING AND CEREBROSPINAL FLUID MARKERS OF CEREBROVASCULAR HEALTH: THE VANDERBILT MEMORY AND AGING PROJECT

Marcia Radanovic, Orestes Vicente Forlenza, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of S~ao Paulo, S~ao Paulo, Brazil; UNESP Universidade Estadual Paulista, Biosciences Institute, Rio Claro, Sao Paulo, Brazil; Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of S~ao Paulo, S~ao Paulo, Brazil; Gerontology Program, Pontif ıcia Universidade Cat olica de S~ao Paulo, S~ao Paulo, Brazil; Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of S~ao Paulo, S~ao Paulo, Brazil; Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of S~ao Paulo, Brazil, S~ao Paulo, Brazil. Contact e-mail: juliacunhaloureiro@ gmail.com