Vascular Risk Burden Research Articles

Higher intraindividual variability in neuropsychological test performance is associated with reduced cerebral blood flow in older adults

AbstractBackgroundIntraindividual variability (IIV) across neuropsychological measures within a single testing session has become a promising sensitive marker predictive of cognitive decline and development of Alzheimer’s disease (AD). We have previously shown that higher IIV is associated with medial temporal lobe atrophy. However, to our knowledge, IIV has yet to be examined in relation to cerebral blood flow (CBF). Therefore, we examined associations between IIV and regional CBF among older adults free of dementia.Method141 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent neuropsychological testing, magnetic resonance imaging (MRI), and florbetapir positron emission tomography (PET) imaging. The IIV index was calculated as the intraindividual standard deviation across 6 demographically‐corrected neuropsychological measures. Mean neuropsychological performance was computed as the mean of the 6 z‐scores. Pulsed arterial spin labeling MRI was used to quantify CBF. Six free‐surfer derived a priori CBF regions of interest were examined: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. PET amyloid‐β (Aβ) positivity was determined using the recommended threshold for cross‐sectional florbetapir of 1.11 using whole cerebellum as the reference region.ResultIn the entire sample, linear regression models showed that after adjusting for age, sex, mean neuropsychological performance, and regional cortical thickness, greater IIV was significantly associated with lower inferior parietal CBF (β=‐2.712, p=.004), inferior temporal CBF (β=‐3.259, p=.001), and reduced entorhinal CBF at trend level (β=‐.407, p=.073). Sensitivity analyses showed that among Aβ+ individuals, greater IIV was significantly associated with lower CBF in inferior parietal (β=‐2.729, p=.018) and inferior temporal regions (β=‐2.704, p=.043). In Aβ‐ individuals, there were no significant associations between IIV and CBF (all ps>.05).ConclusionIIV may be sensitive to early cerebrovascular changes in AD‐vulnerable regions above and beyond demographics, mean neuropsychological performance, and cortical thickness. These relationships were seen among Aβ+ individuals, suggesting that IIV may be a marker of early brain changes among those individuals on the AD continuum. Future studies should examine how IIV may predict future brain and cognitive changes in more diverse samples and among those with greater vascular risk burden.

The Impact of Multimorbidity Burden, Frailty Risk Scoring, and 3-Directional Morphological Indices vs. Testing for CSF Responsiveness in Normal Pressure Hydrocephalus.

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes.Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer’s Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness.Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008).Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Arterial stiffening acts synergistically with APOE genotype and AD biomarker status to influence memory in older adults without dementia

BackgroundArterial stiffening has emerged as an important risk factor for Alzheimer’s disease (AD) and related dementias. Carotid-femoral pulse wave velocity has been proposed as a non-invasive and reproducible method to assess arterial stiffness. However, the association of pulse wave velocity with performance across multiple cognitive domains as well as interactions with in vivo AD biomarkers and apolipoprotein E (APOE) genotype has received limited study.MethodWe studied 193 older adult volunteers (167 with normal cognition and 26 with mild cognitive impairment) who underwent comprehensive medical and neuropsychological evaluation at the University of California, San Diego Alzheimer’s Disease Research Center. Cerebrospinal fluid (CSF) biomarkers were available on 123 participants (63%). Linear models examined whether pulse wave velocity significantly interacted with APOE ε4 status and CSF AD biomarker positivity (based on the ratio of total tau over beta-amyloid [tau/Aβ42]) on memory, language, executive functioning, attention, and visuospatial abilities.ResultsAfter adjusting for demographic characteristics and vascular risk burden, across the entire sample, pulse wave velocity was associated with poorer executive functioning but not the performance in the other cognitive domains. When the modifying effects of AD genetic risk and CSF AD biomarkers were considered, pulse wave velocity interacted with APOE genotype and CSF tau/Aβ ratio such that a stronger association between elevated pulse wave velocity and poorer memory performance was found among those positive for CSF and genetic AD markers. There were no significant interaction effects for non-memory cognitive domains.ConclusionThe findings suggest that pulse wave velocity, a non-invasive method to assess arterial wall properties, may be a useful marker of risk for cognitive decline, particularly among individuals who are APOE ε4 carriers or CSF AD biomarke0r-positive.

A Pilot Study of Online Yoga to Improve Fatigue and Quality of Life in Myeloproliferative Neoplasm Patients

Introduction: Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are myeloproliferative neoplasms (MPNs) with impact on patients that include cytopenias, vascular risk, and disease specific symptom burden. Fatigue is the most commonly reported symptom among MPN patients, contributing to a reduced overall quality of life (QoL). Fatigue and reduced QoL are often left unresolved with current pharmacologic therapy. Our prior work has demonstrated the feasibility of online-streamed yoga and its preliminary effects for improving total symptom burden (including fatigue) in MPN patients. The purpose of this study was to further examine the effects of a 12-wk online yoga intervention for fatigue and QoL in MPN patients as compared to a wait-list control group as well as the feasibility of collecting remote blood samples, for remote assessment of corresponding biomarkers, in a national sample of MPN patients.Methods: MPN patients were recruited nationally using social media and MPN patient group partners. Participants were randomized to either an intervention (i.e., yoga) group or a wait-list control group. The intervention group was asked to complete 60 min/wk of online yoga (via Udaya.com, an online yoga streaming platform) for 12 wks as well as a blood draw (complete blood cell count (CBC), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a)) at both wk 0 and post-intervention wk 12. Those in the control group were asked to maintain their normal level of activity for 16 wks. All study participants were asked to complete online self-report surveys administered via Qualtrics. Survey measures included demographics, MPN Symptom Assessment Form (MPN SAF) as well as National Institutes of Health Patient Reported Outcomes Measurement Information System (NIH PROMIS). Surveys were administered at baseline (wk 0), mid-point (wk 7), and post-intervention (wk 12). Weekly yoga minutes were collected with online self-report and objectively with an online web analytics tool (i.e., Clicky). The feasibility of the remote blood draw was defined as a ≥70% completion rate at both wk 0 and wk 12. Questionnaire outcomes were compared between groups at 12 wks using analysis of covariance adjusting for baseline and changes in blood draw variables were analyzed using dependent t-tests.Results:Patients: Two hundred and sixty MPN patients completed the eligibility survey, of which 96 were eligible, 62 completed the informed consent, and 48 MPN patients completed the 12-wk intervention. There were no significant differences in demographic variables or outcome variables (i.e., fatigue and QoL) between the intervention group (n=27) and the control group (n=21) at baseline. Table 1 describes study participant demographics.Yoga Participation: Over the course of the 12-wk intervention, objective yoga participation averaged 40.8 min/wk whereas self-report yoga participation averaged 56.1 min/wk. Figure 1 depicts the trends in objective and self-report yoga participation throughout the 12-wk intervention.Impact of Yoga Intervention: There were no significant differences at wk 12 in MPN SAF fatigue (ES=0.18; p=0.72) or MPN SAF QoL (ES=-0.53; p=0.19), however, NIH PROMIS QoL was significantly better in the yoga group at wk 12 (ES=0.7; p=0.03) when compared to the control group. Table 2 describes the changes in fatigue and QoL throughout the 12-wk intervention.Blood Draw Feasibility: At baseline, 92.6% (n=25/27) of yoga group participants completed the blood draw and 70.4% (n=19/27) completed the blood draw at post-intervention. There was a significant decrease in TNF-a from wk 0 to wk 12 (-1.3±1.5; p=0.005) but no significant differences in CBC or IL-6 from wk 0 to wk 12.Conclusions: This study builds upon our prior work demonstrating the feasibility of online yoga as well as its preliminary effects for improving symptom burden in MPN patients. In light of the improvements in QoL compared to the control group and significant decreases in TNF-a as well as the feasibility of remote blood draws in the present study, a future randomized controlled trial is warranted. It is possible that we did not see significant improvements in fatigue due to small sample sizes; therefore, a larger, more representative (i.e., more men) sample size is warranted in order to further investigate the effectiveness of online yoga on MPN patient symptom burden, QoL, and pro-inflammatory biomarkers. [Display omitted] DisclosuresMesa:Ariad: Consultancy; Incyte Corporation: Research Funding; Gilead Sciences, Inc.: Research Funding; CTI BioPharma Corp.: Research Funding; Celgene Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Galena Biopharma, Inc.: Consultancy; Promedico: Research Funding.

Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly: A Meta-Analysis.

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Tau Pathologies Mediate the Associations of Vascular Risk Burden with Cognitive Impairments in Non-demented Elders: The CABLE Study.

Studies suggested that vascular dysfunction might increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms still remain obscure. To evaluate the associations of vascular risk burden with AD core pathologies and investigate the effects of AD core pathologies on relationships between vascular risk burden and cognitive impairments. The Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study was principally focusing on aging, as well as the risk factors and biomarkers of AD initiated in 2017. The CABLE study was a large cohort study established in Qingdao, China. A total of 618 non-demented elders were obtained from CABLE study. The general vascular risk burden was assessed by the Framingham General Cardiovascular Risk Score (FGCRS). Multivariate linear regression analyses were performed to evaluate the associations of FGCRS with cerebrospinal fluid (CSF) AD biomarkers and cognition. Casual mediation analyses were performed to investigate the mediating effects of AD biomarkers on cognition. Increased FGCRS was related to higher levels of CSF total tau (t-tau, p < 0.001), phosphorylated tau (p-tau, p < 0.001) as well as the ratio of t-tau and amyloid-β 42 (t-tau/Aβ42, p = 0.010), and lower Chinese-Modified Mini-Mental State Examination (CM-MMSE, p = 0.010) score. Stratified analysis indicated that age modified the associations, with FGCRS being significantly associated with tau pathology (p < 0.001 for t-tau and p-tau) in middle-aged group (<65 years old), instead of older group. The influences of FGCRS on cognitive impairments were partially mediated by tau pathologies (a maximum proportion of 20.9%). Tau pathology might be a pivotal mediator for effects of vascular risk on cognitive decline. Early and comprehensive intervention for vascular risk factors might be a potential approach to delaying or preventing cognitive impairment and AD.

Regional Differences in Blood-Brain Barrier Permeability in Cognitively Normal Elderly Subjects: A Dynamic Contrast-Enhanced MRI-Based Study.

ObjectiveThis study aimed to determine whether there are regional differences in the blood-brain barrier (BBB) permeability of cognitively normal elderly participants and to identify factors influencing BBB permeability with a clinically feasible, 10-minute dynamic contrast-enhanced (DCE) MRI protocol.Materials and MethodsThis IRB-approved prospective study recruited 35 cognitively normal adults (26 women; mean age, 64.5 ± 5.6 years) who underwent DCE T1-weighted imaging. Permeability maps (Ktrans) were coregistered with masks to calculate the mean regional values. The paired t test and Friedman test were used to compare Ktrans between different regions. The relationships between Ktrans and the factors of age, sex, education, cognition score, vascular risk burden, vascular factors on imaging, and medial temporal lobar atrophy were assessed using Pearson correlation and the Spearman rank test.ResultsThe mean permeability rates of the right and left hippocampi, as assessed with automatic segmentation, were 0.529 ± 0.472 and 0.585 ± 0.515 (Ktrans, × 10−3 min−1), respectively. Concerning the deep gray matter, the Ktrans of the thalamus was significantly greater than those of the putamen and hippocampus (p = 0.007, p = 0.041). Regarding the white matter, the Ktrans value of the occipital white matter was significantly greater than those of the frontal, cingulate, and temporal white matter (p < 0.0001, p = 0.0007, p = 0.0002). The variations in Ktrans across brain regions were not related to age, cognitive score, vascular risk burden, vascular risk factors on imaging, or medial temporal lobar atrophy in the study group.ConclusionOur study demonstrated regional differences in BBB permeability (Ktrans) in cognitively normal elderly adults using a clinically acceptable 10-minutes DCE imaging protocol. The regional differences suggest that the integrity of the BBB varies across the brains of cognitively normal elderly adults. We recommend considering regional differences in Ktrans values when evaluating BBB permeability in patients with neurodegenerative diseases.

Association of Cardiovascular Risk Factors with Cerebral Perfusion in Whites and African Americans.

Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for APOE genotype and race. When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither APOE genotype nor race moderated relationships between risk factors and perfusion. Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.

Mid-life and late-life vascular risk factor burden and neuropathology in old age.

ObjectiveTo determine whether vascular risk factor burden in mid‐ or late‐life associates with postmortem vascular and neurodegenerative pathologies in a community‐based sample.MethodsWe studied participants from the Framingham Heart Study who participated in our voluntary brain bank program. Overall vascular risk factor burden was calculated using the Framingham Stroke Risk Profile (FSRP). Mid‐life FSRP was measured at 50 to 60 years of age. Following death, brains were autopsied and semi‐quantitatively assessed by board‐certified neuropathologists for cerebrovascular outcomes (cortical infarcts, subcortical infarcts, atherosclerosis, arteriosclerosis) and Alzheimer’s disease pathology (Braak stage, cerebral amyloid angiopathy, and neuritic plaque score). We estimated adjusted odds ratios between vascular risk burden (at mid‐life and before death) and neuropathological outcomes using logistic and proportional‐odds logistic models.ResultsThe median time interval between FSRP and death was 33.4 years for mid‐life FSRP and 4.4 years for final FSRP measurement before death. Higher mid‐life vascular risk burden was associated with increased odds of all cerebrovascular pathology, even with adjustment for vascular risk burden before death. Late‐life vascular risk burden was associated with increased odds of cortical infarcts (OR [95% CI]: 1.04 [1.00, 1.08]) and arteriosclerosis stage (OR [95% CI]: 1.03 [1.00, 1.05]). Mid‐life vascular risk burden was not associated with Alzheimer’s disease pathology, though late‐life vascular risk burden was associated with increased odds of higher Braak stage (OR [95% CI]: 1.03 [1.01, 1.05]).InterpretationMid‐life vascular risk burden was predictive of cerebrovascular but not Alzheimer’s disease neuropathology, even after adjustment for vascular risk factors before death.

Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life

Midlife vascular risk burden is associated with late-life dementia. Less is known about if and how risk exposure in early adulthood influences late-life brain health. To determine the associations between vascular risk in early adulthood, midlife, and late life with late-life brain structure and pathology using measures of white matter-hyperintensity volume, β-amyloid load, and whole-brain and hippocampal volumes. This prospective longitudinal cohort study, Insight 46, is part of the Medical Research Council National Survey of Health and Development, which commenced in 1946. Participants had vascular risk factors evaluated at ages 36 years (early adulthood), 53 years (midlife), and 69 years (early late life). Participants were assessed with multimodal magnetic resonance imaging and florbetapir-amyloid positron emission tomography scans between May 2015 and January 2018 at University College London. Participants with at least 1 available imaging measure, vascular risk measurements at 1 or more points, and no dementia were included in analyses. Office-based Framingham Heart study-cardiovascular risk scores (FHS-CVS) were derived at ages 36, 53, and 69 years using systolic blood pressure, antihypertensive medication usage, smoking, diabetic status, and body mass index. Analysis models adjusted for age at imaging, sex, APOE genotype, socioeconomic position, and, where appropriate, total intracranial volume. White matter-hyperintensity volume was generated from T1/fluid-attenuated inversion recovery scans using an automated technique and whole-brain volume and hippocampal volume were generated from automated in-house pipelines; β-amyloid status was determined using a gray matter/eroded subcortical white matter standardized uptake value ratio threshold of 0.61. A total of 502 participants were assessed as part of Insight 46, and 463 participants (236 male [51.0%]) with at least 1 available imaging measure (mean [SD] age at imaging, 70.7 [0.7] years; 83 β-amyloid positive [18.2%]) who fulfilled eligibility criteria were included. Among them, FHS-CVS increased with age (36 years: median [interquartile range], 2.7% [1.5%-3.6%]; 53 years: 10.9% [6.7%-15.6%]; 69 years: 24.3% [14.9%-34.9%]). At all points, these scores were associated with smaller whole-brain volumes (36 years: β coefficient per 1% increase, -3.6 [95% CI, -7.0 to -0.3]; 53 years: -0.8 [95% CI, -1.5 to -0.08]; 69 years: -0.6 [95% CI, -1.1 to -0.2]) and higher white matter-hyperintensity volume (exponentiated coefficient: 36 years, 1.09 [95% CI, 1.01-1.18]; 53 years, 1.02 [95% CI, 1.00-1.04]; 69 years, 1.01 [95% CI, 1.00-1.02]), with largest effect sizes at age 36 years. At no point were FHS-CVS results associated with β-amyloid status. Higher vascular risk is associated with smaller whole-brain volume and greater white matter-hyperintensity volume at age 69 to 71 years, with the strongest association seen with early adulthood vascular risk. There was no evidence that higher vascular risk influences amyloid deposition, at least up to age 71 years. Reducing vascular risk with appropriate interventions should be considered from early adulthood to maximize late-life brain health.

Homocysteine, rather than age of onset, is a better predictor for cognitive function in older adults with bipolar disorder.

The association between older-age bipolar disorder and cognitive impairments may be mediated by vascular burden. The aim of the study was to examine the difference of cognitive function between older people with late-onset bipolar disorder (LOBD) and early-onset bipolar disorder (EOBD) by considering rigorous vascular risk burden evaluation, comprehensive cognitive tests, and relevant biochemistry data. We recruited 95 outpatients aged over 55 with a DSM-IV-TR diagnosis of bipolar I disorder. Fifty had LOBD, defined by age of onset after 40. Cognitive function was evaluated through a battery of tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility. Vascular risk assessments included individual disorders, 10-year Framingham cardiovascular risk scores, and serum levels of homocysteine, vitamin B12, folate, and triiodothyronine. No differences were observed between LOBD and EOBD on any cognitive test after adjusting for potential confounders. In addition to age and educational years, multiple linear regression analyses indicated significantly negative associations between serum homocysteine levels and cognitive performances in attention, psychomotor speed, verbal memory, and executive function. Among older people with bipolar disorder, LOBD is not associated with more cognitive dysfunction in this study. However, higher serum homocysteine levels were significantly associated with worse cognitive performance in this particular group. Clinicians therefore have to pay attention to the cognitive function in older bipolar patients with higher levels of homocysteine.

The Altered Reconfiguration Pattern of Brain Modular Architecture Regulates Cognitive Function in Cerebral Small Vessel Disease.

Background: Cerebral small vessel disease (SVD) is a common cause of cognitive dysfunction. However, little is known whether the altered reconfiguration pattern of brain modular architecture regulates cognitive dysfunction in SVD.Methods: We recruited 25 cases of SVD without cognitive impairment (SVD-NCI) and 24 cases of SVD with mild cognitive impairment (SVD-MCI). According to the Framingham Stroke Risk Profile, healthy controls (HC) were divided into 17 subjects (HC-low risk) and 19 subjects (HC-high risk). All individuals underwent resting-state functional magnetic resonance imaging and cognitive assessments. Graph-theoretical analysis was used to explore alterations in the modular organization of functional brain networks. Multiple regression and mediation analyses were performed to investigate the relationship between MRI markers, network metrics and cognitive performance.Results: We identified four modules corresponding to the default mode network (DMN), executive control network (ECN), sensorimotor network and visual network. With increasing vascular risk factors, the inter- and intranetwork compensation of the ECN and a relatively reserved DMN itself were observed in individuals at high risk for SVD. With declining cognitive ability, SVD-MCI showed a disrupted ECN intranetwork and increased DMN connection. Furthermore, the intermodule connectivity of the right inferior frontal gyrus of the ECN mediated the relationship between periventricular white matter hyperintensities and visuospatial processing in SVD-MCI.Conclusions: The reconfiguration pattern of the modular architecture within/between the DMN and ECN advances our understanding of the neural underpinning in response to vascular risk and SVD burden. These observations may provide novel insight into the underlying neural mechanism of SVD-related cognitive impairment and may serve as a potential non-invasive biomarker to predict and monitor disease progression.

DTI Profiles for Rapid Description of Cohorts at the Clinical-Research Interface.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.

Vascular Risk and β-Amyloid Are Synergistically Associated with Cortical Tau.

Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden. Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aβ (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan. We observed a significant interaction between FHS-CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

Neuromuscular Attributes are Associated with Poor Mobility in Older Adults with Vascular Risk Conditions

BackgroundThe mobility of older adults is limited by the compounding effects of vascular health conditions, or vascular risk burden. However, little is known about the role of neuromuscular attributes among those in which vascular risk burden contributes to mobility limitations.ObjectiveWe investigated (1) the relationship between the absence/presence of type 2 diabetes, hypertension, and/or obesity and mobility measures and neuromuscular attributes, and (2) whether the association between vascular risk burden and mobility is mediated by lower limb neuromuscular attributes.DesignCross-sectional analysis of baseline data from 430 older adults within the Boston RISE Study.MeasurementsMeasures of mobility were the Short Physical Performance Battery, habitual gait speed, and functional mobility as measured by the Late Life Function Instrument. We also evaluated lower limb neuromuscular attributes, namely leg strength, leg velocity, trunk extensor muscle endurance, knee and ankle range of motion, and sensory loss.ResultsParticipants self-reported the presence of None (n=93), One (n=179), Two (n=114), or Three (n=44) of the following conditions: diabetes, hypertension, and obesity. Multivariable regression models indicated that those with a greater vascular risk burden had worse performance on the Short Physical Performance Battery (p=0.01), slower gait speed (p=0.0003) and lower Basic and Advanced Late Life Function Instrument scores (p<0.003). These associations were independent of multiple covariates. Vascular risk burden was also found to be negatively associated with leg strength (p=0.0002) and knee flexion range of motion (p<0.0001) and an associated non-significant trend was observed with leg velocity (p=0.06). In addition, the association between vascular risk burden and mobility outcomes were found to be partially mediated by leg strength, leg velocity, and knee flexion range of motion.ConclusionsAmong older adults with vascular risk burden and mobility problems, neuromuscular impairments in attributes such as leg strength, leg velocity, and knee range of motion may need to be treatment priorities.

Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals

Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) pathology commonly co-occur in older adults and are significant causes of cognitive impairment. To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease. In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017. Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status. Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = -0.064; 95% CI, -0.094 to -0.033; P < .001) and higher Aβ burden (β = -0.058; 95% CI, -0.079 to -0.037; P < .001). The interaction of the FHS-CVD risk score and Aβ burden with time was significant (β = -0.040, 95% CI, -0.062 to -0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (β = -0.055; 95% CI, -0.086 to -0.024; P < .001), even after adjustment for Aβ burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities. In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.

White matter hyperintensities and vascular risk factors in monozygotic twins

Cerebral white matter hyperintensities (WMHs) have been associated with vascular risk factors, both of which are under genetic influence. We examined in a monozygotic twin sample whether the association between vascular risk and WMHs is influenced by overlapping genetic factors. We included 195 cognitively normal monozygotic twins (age = 70 ± 7 years), including 94 complete pairs. Regional WMH load was estimated using an automated algorithm. Vascular risk was summarized with the Framingham score. The within–twin pair correlation for total WMHs was 0.76 and for Framingham score was 0.77. Within participants, Framingham score was associated with total and periventricular WMHs (r = 0.32). Framingham score in 1 twin was also associated with total WMHs in the co-twin (r = 0.26). Up to 83% of the relation between both traits could be explained by shared genetic effects. In conclusion, monozygotic twins have highly similar vascular risk and WMH burden, confirming a genetic background for these traits. The association between both traits is largely driven by overlapping genetic factors.

Brain tissue pulsatility is related to clinical features of Parkinson's disease.

IntroductionThis study investigated whether brain tissue pulsatility is associated with features of disease severity in Parkinson's disease (PD).MethodsData were extracted from the Parkinson's Progression Markers Initiative among 81 adults with PD (confirmed with DATSCAN™). Brain tissue pulsatility was computed using resting state blood oxygenation level dependent (BOLD) MRI in white matter (WM), referred to as BOLDTP. Motor impairment was assessed using the Movement Disorders Society unified Parkinson's disease rating scale. Factor analysis generated composite scores for cognition and vascular risk burden. A linear regression model examined the association of BOLDTP with age, sex, motor impairment, cognition, vascular risk burden and PD duration. In addition, we investigated whether BOLDTP relates to WM hyperintensity (WMH) volume, WM fractional anisotropy (WM-FA) and striatal binding ratio (SBR) of dopamine transporter.ResultsMotor impairment (t = 2.3, p = .02), vascular burden (t = 2.4, p = .02) and male sex (t = 3.0, p = .003) were independently associated with BOLDTP (r2 = 0.40, p < .001). BOLDTP was correlated with WMH volume (r = 0.22, p = .05) but not WM-FA nor SBR (p > .1). In addition, BOLDTP (t = 2.76, p = .008) and SBR (t = −2.04, p = .04) were independently related to motor impairment (r2 = 0.18, p = .006).ConclusionOur findings show that brain tissue pulsatility from BOLD images in WM is related to neurological and vascular features in PD. BOLDTP may be useful in PD to study small vessel alterations that appear distinct from WM structural changes.

Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion.

Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment. To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion. Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells). Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels. Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.