Cross-sectional epidemiological and clinical research suggest lower cardiac index is related to markers of abnormal brain aging, such as smaller brain volume, increased white matter hyperintensities, and worse cognitive performance. It is unknown whether lower resting cardiac index is a risk factor for incident dementia or Alzheimer's disease (AD). 1034 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia constituted our sample (69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for age, sex, education, systolic blood pressure, diabetes mellitus, prevalent cardiovascular disease (CVD), and apolipoprotein E4 status were used to relate cardiac MRI-assessed cardiac index (cardiac output/body surface area, L/min/m 2) to incident all-cause dementia and AD. Over a median 7.3 year follow-up period, 26 participants developed dementia, including 21 AD cases. In multivariable-adjusted models, each one standard deviation unit decrease in cardiac index increased the relative risk of dementia (HR=1.77, p=0.01) and AD (HR=1.73, p=0.03). If participants with clinically prevalent CVD and atrial fibrillation were excluded (n=209), each one standard deviation unit decrease in cardiac index continued to increase the relative risk of dementia (HR=3.54, p=0.01) and AD (HR=3.45, p=0.02). Among community dwelling adults age 60 years and older, lower cardiac index is associated with increased risk of incident dementia and AD over a median follow-up period of 7 years. When participants with prevalent CVD and atrial fibrillation were excluded from analyses, lower cardiac index was still associated with increased risk of incident dementia and AD. Systemic hemodynamics may affect cerebral hemodynamics in older adults with a lifetime burden of vascular risk factors and subsequent modest compromises in cerebral circulation control. Such age-related changes may contribute to the pathogenesis or exacerbation of amyloid deposition, subsequent neuronal injury, and vascular pathology. Further investigation into the mechanisms underlying this increased risk is merited for identifying targets for primary prevention or therapeutic interventions.
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Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.
Abstract Background There is growing recognition that white matter microstructural integrity is affected in Alzheimer’s disease. The goal of this study was to characterize sex, racial/ethnic, and apolipoprotein (APOE)‐ε4 allele differences in white matter integrity. Methods This study included participants from ADNI, BLSA, ROS/MAP/MARS, and VMAP, all longitudinal cohorts of aging. This combined dataset included 6,837 imaging sessions from 2,619 participants age 50+ with diffusion MRI (dMRI) and demographic and clinical data (60% female, 31.4% APOE‐ε4 carriers, 78.9% White). dMRI was preprocessed using the PreQual pipeline. Free‐water (FW) correction was used to generate FW and FW‐corrected intracellular metrics including fractional anisotropy (FA FWcorr ), mean diffusivity (MD FWcorr ), axial diffusivity (AxD FWcorr ), and radial diffusivity (RD FWcorr ). Conventional and FW‐corrected metrics were harmonized using the Longitudinal ComBat package. Linear mixed‐effects models related sex, race/ethnicity, and APOE‐ε4 allele status to longitudinal diffusion metrics in 48 white matter tracts, adjusting for age at baseline, sex, education, race/ethnicity, APOE‐ε4 carrier status, cognitive status at baseline, and converter status. All models were corrected for multiple comparisons using the FDR approach. Result Sex differences in white matter were most notable in projection tracts (Figure 1A) and were primarily in FW‐corrected metrics. Females had lower FA FWcorr and higher RD FWcorr , indicative of worse microstructure, but lower AxD FWcorr . This sex difference was most pronounced for FA FWcorr in the ventral premotor projection tract (p=1.53x10 ‐62 ). There were global differences in white matter integrity by race/ethnicity (Figure 1B). Non‐Hispanic White participants tended to have higher conventional FA, FA FWcorr and AxD FWcorr and lower RD FWcorr . There was no association between APOE‐ε4 status and white matter integrity and no significant sex x race/ethnicity, sex x APOE‐ε4, or race/ethnicity x APOE‐ε4 interactions for conventional or FW‐corrected metrics when corrected for multiple comparisons. Conclusion There were striking sex and racial/ethnic (but not APOE‐ε4) differences in white matter tract integrity in a large cohort of aging adults. Female participants tended to have measures reflective of worse white matter integrity, and non‐Hispanic White participants tended to have measures reflective of greater integrity. Additional research exploring the etiology of these differences will be important to better understand disparities in Alzheimer’s disease.
As interventions targeted at treating Alzheimer's disease during the early stages of cognitive decline increase, more individuals with mild cognitive impairment (MCI) are being recruited for clinical trials. Their capacity to provide consent for such participation has not been measured, and relationships between their capacity and cognitive functioning has not been explored. We hypothesized that participants with MCI would perform more poorly on a capacity measure than normal controls (NC), and decisional capacity would have unique cognitive associations. We prospectively gathered pilot data from 14 NC and 7 MCI participants (62% women), ages ranged 60–90 years (74±7). Cognitive measures assessed global cognitive function (MMSE), executive function (DKEFS TMT–B, COWA, DKEFS 20 Questions, WAIS–III Similarities, WAIS–III Matrix Reasoning, NAB Judgment), language (BNT, Token Test), literacy (WRAT–III Reading), and memory (CVLT–II). Capacity research consent was measured for a hypothetical, but ecologically valid, clinical trial utilizing the MacArthur Competence Assessment Tool for Clinical Research (MacCAT–CR). Analyses of covariance (ANCOVAs), adjusting for age and education, were utilized to test between–group comparisons on the decisional capacity measures: Understanding, Appreciation, Reasoning, and Expression of Choice. Pearson correlations were conducted between all cognitive measures and decisional capacity measures. ANCOVAs revealed significant differences between NC and MCI on the MacCAT–CR Understanding (F(1,16)=9.45, p=.007) and Reasoning (F(1,16)=4.74, p=.04) measures. On both dimensions, the NC group outperformed the MCI group. Bivariate correlations yielded multiple associations; however, the strongest correlations were observed between Understanding and NAB Judgment (r=.67, p=.001), Appreciation and MMSE (r=.63, p=.002), Reasoning and CVLT–II Trial 1–5 total (r=.60, p=.004). Expression of Choice was unrelated to any cognitive measure. When correlations were repeated utilizing just the MCI subsample, results were unchanged. Our findings suggest that individuals with MCI perform significantly worse than NC on selected measures of decisional capacity. Unique cognitive associations were noted between several decisional capacity measures, suggesting that judgment is associated with Understanding, global cognition is associated with Appreciation, and memory is associated with Reasoning.
Introduction: We have previously demonstrated that impaired endothelial vascular reactivity is associated with acute brain dysfunction in the ICU. The role of endothelial activation and blood brain barrier (BBB) injury in this acute brain dysfunction is unclear. Methods: In our cohort of patients with respiratory failure and/or shock with peripheral artery tonometry assessments of endothelial vascular reactivity, we further measured baseline plasma concentrations of PAI-1, E-selectin, Ang-2 and S100B. Delirium and coma were assessed daily using the CAM-ICU and RASS. Multivariable linear regression with robust sandwich variance-covariance estimator was used to study the independent associations between endothelial activation and BBB injury with delirium/coma-free days (DCFDs) and with delirium duration in survivors, adjusting for confounders including age, illness severity and sepsis. We further assessed if BBB injury mediated the effects of endothelial dysfunction on DCFDs using the multivariable regression models. Results: Our 134-patient cohort had a median age of 57 years and APACHE II score of 26. Higher PAI-1 (p=0.002), E-selectin (p=0.02) and S100B (p<0.001) concentrations were independently associated with worse brain dysfunction (fewer DCFDs). Higher PAI-1 (p=0.01) and S100B (p=0.01) concentrations were also independently associated with longer duration of delirium in survivors. Adjusting for S100B did not affect the independent associations of endothelial vascular reactivity, PAI-1 and E-selectin with acute brain dysfunction, suggesting no mediation. Conclusions: These pilot data support that both endothelial dysfunction and BBB injury are independently associated with acute brain dysfunction during critical illness and that BBB injury does not mediate the effects of endothelial dysfunction on acute brain dysfunction.
Imaging findings inconsistent with those expected at specific chronological age ranges may serve as early indicators of neurological disorders and increased mortality risk. Estimation of chronological age, and deviations from expected results, from structural magnetic resonance imaging (MRI) data has become an important proxy task for developing biomarkers that are sensitive to such deviations. Complementary to structural analysis, diffusion tensor imaging (DTI) has proven effective in identifying age-related microstructural changes within the brain white matter, thereby presenting itself as a promising additional modality for brain age prediction. Although early studies have sought to harness DTI's advantages for age estimation, there is no evidence that the success of this prediction is owed to the unique microstructural and diffusivity features that DTI provides, rather than the macrostructural features that are also available in DTI data. Therefore, we seek to develop white-matter-specific age estimation to capture deviations from normal white matter aging. Specifically, we deliberately disregard the macrostructural information when predicting age from DTI scalar images, using two distinct methods. The first method relies on extracting only microstructural features from regions of interest (ROIs). The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are non-linearly registered and warped to a template to minimize macrostructural variations. When tested on unseen data, the first method yields mean absolute error (MAE) of 6.11 ± 0.19 years for cognitively normal participants and MAE of 6.62 ± 0.30 years for cognitively impaired participants, while the second method achieves MAE of 4.69 ± 0.23 years for cognitively normal participants and MAE of 4.96 ± 0.28 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction.
Cognitive complaint is one of the diagnostic criteria for mild cognitive impairment (MCI) and may reflect an early clinical marker of Alzheimer's disease (AD) pathology. The source of cognitive complaint, or who is reporting cognitive changes, has prognostic implications, such that informant-report seems more predictive of conversion or cognitive decline than self-complaint. This study a ssessed how the presence of a self-report, informant-report, or mutual-report (self and informant) of cognitive complaint is related to neuropathological markers of AD and cerebrovascular disease. Data were drawn from the National Alzheimer's Coordinating Center Uniform and Neuropathology Datasets. Using last clinical visit before death, participants included individuals diagnosed with MCI divided into one of four mutually exclusive complaint status groups: no-complaint (n=26, 86 ±9, 42% female), self-complaint (n=24, 91 ±6, 62% female); informant-complaint (n=22, 88 ±10, 55% female), and mutual complaint (n=83, 88 ± 8, 54% female). Neuropathological outcomes included amyloid, tau, and vascular pathology. Adjusting for age, sex, education, race, Mini-Mental State Examination, depression, and time between last visit and death, logistic regression related each complaint group (using no complaint as the referent) to neuropathological outcomes. Compared to no-complaint, MCI participants with mutual complaint evidenced more diffuse amyloid plaques (OR=6.8, p=0.01), a trend for a higher BRAAK stage (OR=3.0, p=0.086), and a trend to meet NIA/Reagan (OR=3.2, p=0.068) and CERAD criteria (OR=3.7, p=0.09). In a secondary analysis, logistic regression related the combination of AD and vascular pathology (using 'vascular pathology only' as the referent) to the presence of any complaint prior to death (self, informant, and mutual), yielding a significant observation (OR=7.2, p=0.006). MCI individuals with a mutual (both self- and informant-) complaint are more likely to have AD pathology at death than their peers with no-complaint. This finding is consistent with research suggesting mutual complaint is most predictive of cognitive trajectory and conversion. Additionally, MCI individuals with concomitant vascular and AD pathology are more likely to have some type of cognitive complaint than their peers with only vascular pathology. Funding: R01-HL11516, R01-AG034962, K12-HG043483, NIRG-13-283276, K24-AG046373, U01-AG016976.
Abstract Background Recent research emphasizes the significance of white matter tracts and the free‐water (FW) component in understanding cognitive decline. The goal of this study is to conduct a large‐scale assessment on the role of white matter microstructure on longitudinal cognitive decline. Method This study used a cohort collated from seven longitudinal cohorts of aging (ADNI, BIOCARD, BLSA, NACC, ROS/MAP/MARS, VMAP, and WRAP). In total, this dataset included 2,220 participants aged 50+ who had both diffusion MRI and harmonized composites of memory performance and executive function. This dataset included a total of 4,918 imaging sessions with corresponding cognitive data (mean number of visits per participant: 1.69 ± 1.67, interval range: 1‐10 years). Diffusion MRI was preprocessed using the PreQual pipeline and FW correction was used to create FW and FW‐corrected intracellular metrics. Conventional and FW‐corrected measures were harmonized using the Longitudinal ComBat package. Linear mixed effects regression was used for longitudinal analysis, in which we covaried for age, age squared, education, sex, race/ethnicity, diagnosis at baseline, APOE‐ε4 status, and APOE‐ε2 status. All models were corrected for multiple comparisons using the FDR approach. Result For longitudinal memory performance, we found global associations with conventional diffusion MRI metrics, in which abnormalities were associated with lower memory performance. Following FW correction, we found that the FW metric itself was strongly associated with memory performance, in which higher FW was associated with lower memory performance and exacerbated decline. Interestingly, following FW‐correction the intracellular contributions were largely mitigated. As illustrated in Figure 1A, the most significant effects were found in the limbic tracts, with the most significant associations found for cingulum bundle FW (p=5.80x10 ‐45 ). Figure 1B illustrates the association between cingulum FW and longitudinal memory performance. Findings for longitudinal executive function performance are shown in Figure 2. Conclusion To date, this is the largest study combining FW‐corrected diffusion MRI data and harmonized cognitive composites to understand cognitive trajectories in aging. Future studies evaluating how white matter microstructure may be incorporated into models of AD may further our knowledge into the neurodegenerative cascade of AD.
Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes.Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively.BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients.Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI.
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