L. Taylor Davis

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.

Planning-free cerebral blood flow territory mapping in patients with intracranial arterial stenosis

A noninvasive method for quantifying cerebral blood flow and simultaneously visualizing cerebral blood flow territories is vessel-encoded pseudocontinuous arterial spin labeling MRI. However, obstacles to acquiring such information include limited access to the methodology in clinical centers and limited work on how clinically acquired vessel-encoded pseudocontinuous arterial spin labeling data correlate with gold-standard methods. The purpose of this work is to develop and validate a semiautomated pipeline for the online quantification of cerebral blood flow maps and cerebral blood flow territories from planning-free vessel-encoded pseudocontinuous arterial spin labeling MRI with gold-standard digital subtraction angiography. Healthy controls (n = 10) and intracranial atherosclerotic disease patients (n = 34) underwent 3.0 T MRI imaging including vascular (MR angiography) and hemodynamic (cerebral blood flow-weighted arterial spin labeling) MRI. Patients additionally underwent catheter and/or CT angiography. Variations in cross-territorial filling were grouped according to diameters of circle of Willis vessels in controls. In patients, Cohen’s k-statistics were computed to quantify agreement in perfusion patterns between vessel-encoded pseudocontinuous arterial spin labeling and angiography. Cross-territorial filling patterns were consistent with circle of Willis anatomy. The intraobserver Cohens k-statistics for cerebral blood flow territory and digital subtraction angiography perfusion agreement were 0.730 (95% CI = 0.593–0.867; reader one) and 0.708 (95% CI = 0.561–0.855; reader two). These results support the feasibility of a semiautomated pipeline for evaluating major neurovascular cerebral blood flow territories in patients with intracranial atherosclerotic disease.

Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements: CSF Flow Suppression in Intracranial VWI

Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo.

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.

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

Clinical Reasoning: A 57-year-old man with unilateral anosmia, papilledema, and meningismus

A 57-year-old previously healthy man was referred to our clinic for bilateral vision loss.

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

ABNORMAL CARDIAC STRUCTURE AND FUNCTION MEASURES ARE ASSOCIATED WITH INCREASED PERIVASCULAR SPACES IN OLDER ADULTS

Background:Three different 18F-labeled radiotracers for b-amyloid PET are available, which demonstrated similar performance as 11C-PiB. The leaflets of the three tracers indicate 3 different visual criteria for PET reporting based on controlled trials, but it’s not yet verified in clinical practice if these criteria are equivalent in term of diagnostic accuracy or if there is a reading criteria better than an other. The aim of this study is to determine the inter-rater variabilityof the visual interpretation of 18F-Florbetapir PET/CT among 6 independent readers for 3 different visual criteria recommended by the 3 companies. We studied the intra-reader variability. Methods: We analyzed 252 18F-Florbetapir PET/CT (228 patients with cognitive impairment and 24 normal cognitive control), obtained from subjects participating at INDIA-FBP study and performed in 2 PET centers. Six independent blinded readers (2 experts in amyloid imaging and 4 who followed reading educational programs but without direct clinical experience) examined each PET-scan three times according to 3 different visual reading criteria, classifying them with a subjective confidence level of 5 point score (4:definitely positive; 3:doubt positive; 2:doubt; 1:doubt negative or 0:definitely negative) and then attributing a numeric score for each region analyzed that formed anoverallobjective score. We compared the mean of the results obtained by the 2 experts readers (considered as “gold standard”) with those obtained by the others 4 readers. Results: Substantial to almost perfect agreement was observed for visual interpretation by the six readers’ confidence level (mean weighted Kappa) for all 3 radiotracers: mwK1⁄40.82 for 18F-Florbetapir lecture; mwK1⁄40.84 for 18F-Florbetaben; mwK1⁄40.85 for 18F-Flutemetamol. Overall objective score showed a low inter-readers variability: mwK1⁄40.73 for 18F-Florbetapir lecture; mwK1⁄40.82 for 18F-Florbetaben and mean Spearman’s rho1⁄40.82 for 18F-Flutemetamol. Comparison between the “gold standard” showed a high confidence level: wK ranging 0.80-0.94. Intra-rater agreement has Spearman’s rho ranging 0.89-1.00 (p<0.001) about confidence level and Spearman’srho ranging 0.75-0.90 (p<0.001) about overall score. Conclusions: There is a high inter-rater and intra-reader agreement using the three different visual criteria for amyloid images. All the criteria proposed are useful and valid to determine the positivity or negativity of amyloid deposition and when compared with a “gold standard” there aren’t statistical differences between the three criteria.