Regional White Matter Hyperintensities Research Articles

Association of gait speed with regional brain volumes and risk of dementia in older Japanese: The Hisayama study

BackgroundTo investigate the association of gait speed with regional brain volumes and the risk of incident dementia. MethodsA total of 1112 dementia-free Japanese residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years (median). The participants were classified into the age- and sex-specific quartile levels of maximum gait speed. Regional gray matter volumes (GMV) and white matter hyperintensities volumes (WMHV) were measured by applying voxel-based morphometry methods. The cross-sectional association of maximum gait speed with regional GMV was examined using an analysis of covariance. We also estimated the association between maximum gait speed level and the risk of developing dementia using a Cox proportional hazards model. Mediation analyses were conducted to determine the contribution of regional brain volumes to the association between maximum gait speed and dementia. ResultsLower maximum gait speed was significantly associated with lower GMV of the total brain, frontal lobe, temporal lobe, cingulate gyrus, insula, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum, and increased WMHV at baseline. During the follow-up, 108 participants developed dementia. The incidence rate of all dementias increased significantly with decreasing maximum gait speed after adjusting for potential confounders (P for trend = 0.03). The mediating effects of the GMV of the hippocampus, GMV of the insula, and WMHV were significant. ConclusionsLower maximum gait speed was significantly associated with an increased risk of dementia. Reduced GMV of the hippocampus or insula, and an increase in WMHV was likely to be involved in this association.

The effect of age on mnemonic discrimination is fully mediated by posterior cerebral artery‐defined white matter hyperintensities

AbstractBackgroundPrevious work has observed a decline in memory performance with age on mnemonic discrimination tasks (MDT). Other studies have recognized the contributions of white matter hyperintensities (WMH), a marker of cerebrovascular disease, on age and Alzheimer’s disease‐related memory decline. Here, we asked whether WMH, defined within vascular territories, particularly the posterior cerebral artery (PCA) defined territory, would mediate the association between age and MDT performance.MethodA sample of 120 older adults (mean age (SD) = 76.6 (10.43) years, age range: 59‐98 years, 74 (61.7%) females) were included in these analyses. Regional WMH volumes were derived from T2‐FLAIR (Figure 1A) images using ANTs, a vascular territory atlas (Figure 1B) and manual editing. The MDT was administered to assess episodic memory and pattern separation ability within both the object (MDT‐O) and spatial (MDT‐S) domains. Adjusting for sex and education, we tested for associations among age, regional WMH volumes, MDT‐S, and MDT‐O scores, correcting for multiple comparisons. Results were then used to assess the mediating role of regional WMH on the relationship between age and MDT. Lastly, we compared the accuracy of the different vascular territory WMH volumes, along with total WMH volume, in classifying cognitive impairment (MCI, QCI, CIND) using area under the receiver operating characteristic curve (ROC).ResultAge was associated with MDT‐S (β=‐0.247, p=0.005), but not MDT‐O performance (β=‐0.130, p=0.177). Only PCA‐defined WMH volume was associated with MDT‐S (β=‐0.252, p=0.005) and MDT‐O (b=‐0.229, p=0.016). PCA‐defined WMH fully mediated the association between age and MDT‐S (indirect effect: β=‐0.001, 95% CI (‐0.003, ‐0.001); Figure 2A). Similarly, PCA‐defined WMH fully mediated the association between age and MDT‐O (β=‐0.001, 95% CI (‐0.002, ‐0.003); Figure 2B). PCA‐defined WMH volume more accurately classified cognitively impaired from non‐impaired (AUC=0.780, p<0.001; Figure 3) compared with total WMH (AUC=0.624, p=0.113), ACA‐defined WMH volume (AUC=0.618, p=.130) or MCA‐defined WMH (AUC=0.592, p=0.237).ConclusionPCA‐defined WMH mediate the relationship between age and memory performance and is a better diagnostic of cognitive impairment than whole brain or other vascular territory WMH volumes. This study demonstrates that defining WMH within vascular territories provides a useful way to characterize the impact of aging on memory impairment.

A longitudinal investigation of physical and cognitive activities and the outcome of trajectories of AD neuroimaging biomarkers: The Mayo Clinic Study of Aging

AbstractBackgroundPhysical and cognitive activities are associated with decreased risk of mild cognitive impairment and dementia. However, the longitudinal associations between physical and cognitive activities with trajectories of Alzheimer’s disease (AD) neuroimaging biomarkers among older adults free of dementia remain unclear.MethodWe conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants had information on physical and cognitive activity engagement in midlife (ages 30‐45 for participants aged 50‐69; ages 50‐65 for participants aged ≥ 70) and late‐life (12 months prior to baseline assessment), and AD biomarker assessments. We calculated linear mixed‐effect models to examine the association between baseline physical and cognitive activity composite scores for mid‐ and late‐life, and trajectories for individual yearly change in amyloid deposition (measured by PiB‐PET), tau burden (measured by Tau‐PET), regional glucose hypometabolism (measured by FDG‐PET), cortical thickness (measured by MRI), and white matter hyper intensities (WMH, measured by FLAIR‐MRI). The models were adjusted for age, sex, and APOE ɛ4 carrier status.ResultThe sample included 2755 persons (52% males; 2462 cognitively unimpaired, 293 with MCI). The mean [SD] age was 72.7 [9.8] years; 774 participants were APOE ɛ4 carriers. Although, overall, participants showed an increase in amyloid deposition, tau burden, WMH, and a decrease in glucose metabolism and cortical thickness over time, those with higher late‐life physical activity experienced less pronounced increase in Tau‐PET SUVR over time [estimate for late‐life physical activity with time interaction: ‐0.002; 95% CI ‐0.004, ‐0.000; p = 0.034]. In addition, participants with higher cognitive activities in midlife [est. for midlife cognitive activity with time interaction: 0.001; 95% CI 0.000, 0.003; p = 0.026] and late‐life [est. for late‐life cognitive activity with time interaction 0.002; 95% CI 0.001, 0.003; p = 0.005] had less pronounced decrease in FDG‐PET SUVR over time. There were no further significant interactions.ConclusionPreliminary findings suggest significant associations between 1) late‐life physical activity and less tauopathy, and 2) cognitive activities in mid‐ and late‐life with less synaptic dysfunction over time. Further research is needed to validate study findings.

White matter hyperintensity load varies depending on subjective cognitive decline criteria.

Increased age and cognitive impairment is associated with an increase in cerebrovascular pathology often measured as white matter hyperintensities (WMHs) on MRI. Whether WMH burden differs between cognitively unimpaired older adults with subjective cognitive decline (SCD +) and without subjective cognitive decline (SCD -) remains conflicting, and could be related to the methods used to identify SCD. Our goal was to examine if four common SCD classification methods are associated with different WMH accumulation patterns between SCD + and SCD - . A total of 535 cognitively unimpaired older adults with 1353 time points from the Alzheimer's Disease Neuroimaging Initiative were included in this study. SCD was operationalized using four different methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry. Linear mixed-effects models were used to investigate the associations between SCD and overall and regional WMH burden. Overall temporal WMH burden differences were only observed with the Worry questionnaire. Higher WMH burden change over time was observed in SCD + compared to SCD - in the temporal and parietal regions using the CCI (temporal, p = .01; parietal p = .02) and ECog (temporal, p = .02; parietal p = .01). For both the ECog + Worry and Worry questionnaire, change in WMH burden over time was increased in SCD + compared to SCD - for overall, frontal, temporal, and parietal WMH burden (p < .05). These results show that WMH burden differs between SCD + and SCD - depending on the questionnaire and the approach (regional/global) used to measure WMHs. The various methods used to define SCD may reflect different types of underlying pathologies.

Polygenic coronary artery disease association with brain atrophy in the cognitively impaired.

While a number of low-frequency genetic variants of large effect size have been shown to underlie both cardiovascular disease and dementia, recent studies have highlighted the importance of common genetic variants of small effect size, which, in aggregate, are embodied by a polygenic risk score. We investigate the effect of polygenic risk for coronary artery disease on brain atrophy in Alzheimer's disease using whole-brain volume and put our findings in context with the polygenic risk for Alzheimer's disease and presumed small vessel disease as quantified by white-matter hyperintensities. We use 730 subjects from the Alzheimer's disease neuroimaging initiative database to investigate polygenic risk score effects (beyond APOE) on whole-brain volumes, total and regional white-matter hyperintensities and amyloid beta across diagnostic groups. In a subset of these subjects (N = 602), we utilized longitudinal changes in whole-brain volume over 24 months using the boundary shift integral approach. Linear regression and linear mixed-effects models were used to investigate the effect of white-matter hyperintensities at baseline as well as Alzheimer's disease-polygenic risk score and coronary artery disease-polygenic risk score on whole-brain atrophy and whole-brain atrophy acceleration, respectively. All genetic associations were examined under the oligogenic (P = 1e-5) and the more variant-inclusive polygenic (P = 0.5) scenarios. Results suggest no evidence for a link between the polygenic risk score and markers of Alzheimer's disease pathology at baseline (when stratified by diagnostic group). However, both Alzheimer's disease-polygenic risk score and coronary artery disease-polygenic risk score were associated with longitudinal decline in whole-brain volume (Alzheimer's disease-polygenic risk score t = 3.3, P FDR = 0.007 over 24 months in healthy controls) and surprisingly, under certain conditions, whole-brain volume atrophy is statistically more correlated with cardiac polygenic risk score than Alzheimer's disease-polygenic risk score (coronary artery disease-polygenic risk score t = 2.1, P FDR = 0.04 over 24 months in the mild cognitive impairment group). Further, in our regional analysis of white-matter hyperintensities, Alzheimer's disease-polygenic risk score beyond APOE is predictive of white-matter volume in the occipital lobe in Alzheimer's disease subjects in the polygenic regime. Finally, the rate of change of brain volume (or atrophy acceleration) may be sensitive to Alzheimer's disease-polygenic risk beyond APOE in healthy individuals (t = 2, P = 0.04). For subjects with mild cognitive impairment, beyond APOE, a more inclusive polygenic risk score including more variants, shows coronary artery disease-polygenic risk score to be more predictive of whole-brain volume atrophy, than an oligogenic approach including fewer larger effect size variants.

The effect of regional white matter hyperintensities on essential tremor subtypes and severity.

To investigate the effect of regional white matter hyperintensities (WMHs) on Essential tremor (ET) subtypes and to explore the association between WMHs load and the severity of motor and non-motor symptoms in patients with ET. A cohort of 176 patients with ET (including 86 patients with pure ET and 90 patients with ET plus) and 91 normal controls (NC) was consecutively recruited. Demographic, clinical, and imaging characteristics were compared between individuals with pure ET, ET plus, and NC. The cross-sectional association among regional WMHs and the severity of tremor and non-motor symptoms were assessed within each group. Compared with the pure ET subgroup, the ET plus subgroup demonstrated higher TETRAS scores, NMSS scores, and lower MMSE scores (all P < 0.05). Periventricular and lobar WMHs' loads of pure ET subgroup intermediated between NC subjects and ET plus subgroup. WMHs in the frontal horn independently increased the odds of ET (OR = 1.784, P < 0.001). The age (P = 0.021), WMHs in the frontal lobe (P = 0.014), and WMHs in the occipital lobe (P = 0.020) showed a significant impact on TETRAS part II scores in the ET plus subgroup. However, only the disease duration was positively associated with TETRAS part II scores in patients with pure ET (P = 0.028). In terms of non-motor symptoms, NMSS scores of total patients with ET were associated with disease duration (P = 0.029), TETRAS part I scores (P = 0.017), and WMH scores in the frontal lobe (P = 0.033). MMSE scores were associated with age (P = 0.027), body mass index (P = 0.006), education level (P < 0.001), and WMHs in the body of the lateral ventricle (P = 0.005). Our results indicated that the WMHs in the frontal horn could lead to an increased risk of developing ET. WMHs may be used to differentiate pure ET and ET plus. Furthermore, WMHs in the frontal and occipital lobes are strong predictors of worse tremor severity in the ET plus subgroup. Regional WMHs are associated with cognitive impairment in patients with ET.

Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD.

White matter hyperintensities (WMHs) are pathological changes that occur with increased age and are associated with cognitive decline. Most WMH research has not examined regional differences and focuses on a whole-brain approach. This study examined regional WMHs between normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimer's disease (AD). We also examined whether WMHs were associated with cognitive decline. Participants from the Alzheimer's Disease Neuroimaging Initiative were included if they had at least one WMH measurement and cognitive scores examining global cognition, executive functioning, and memory. Only amyloid-positive MCI and AD participants were included. A total of 1573 participants with 7381 timepoints over a maximum period of 13years were included. Linear mixed-effects models examined group differences in WMH burden and associations between WMH burden and cognition. People with MCI and AD had increased total and regional WMHs compared to NCs. An association between WMHs and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between WMH and global cognition. These findings suggest that the WMH burden is associated with changes in cognition in healthy aging and early cognitive decline.

Increased regional white matter hyperintensity volume in objectively-defined subtle cognitive decline and mild cognitive impairment

White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Less is known about the extent and pattern of WMH in pre-MCI stages, such as among those with objectively-defined subtle cognitive decline (Obj-SCD). Five hundred and fifty-nine Alzheimer's Disease Neuroimaging Initiative participants (170 cognitively unimpaired [CU]; 83 Obj-SCD; 306 MCI) free of clinical dementia or stroke completed neuropsychological testing and MRI exams. ANCOVA models compared cognitive groups on regional WMH adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 frequency. Compared with the CU group, those with Obj-SCD had greater temporal, occipital, and frontal WMH whereas those with MCI had higher WMH volume across all regions (p’s < 0.01). No differences in WMH volume were observed between the Obj-SCD and MCI groups (p’s > 0.05). Findings add to growing evidence of associations between Obj-SCD and imaging biomarkers, providing support for utility of these criteria to capture subtle cognitive changes that are biologically based.

Regional White Matter Hyperintensities and Relation to Cognition in Posterior Cortical Atrophy and Logopenic Progressive Aphasia (P1-1.Virtual)

Regional White Matter Hyperintensities and Relation to Cognition in Posterior Cortical Atrophy and Logopenic Progressive Aphasia (P1-1.Virtual)

Regional associations of white matter hyperintensities and early cortical amyloid pathology.

White matter hyperintensities (WMHs) have a heterogeneous aetiology, associated with both vascular risk factors and amyloidosis due to Alzheimer’s disease. While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored.We included 662 non-demented participants from three Amyloid Imaging to Prevent Alzheimer’s disease (AMYPAD)-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD PreclinAD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early accumulating regions (medial orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection. Global associations between WMH, amyloid, and cardiovascular risk scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language).While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal–precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory.In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology.

Progression of neuroimaging markers of cerebral small vessel disease in older adults: A 6-year follow-up study

We investigated progression and interrelationships of cerebral small vessel disease (cSVD) markers. This population-based cohort study included 325 participants (age ≥ 60 years) who had repeated measures of cSVD markers over 6 years: white-matter hyperintensity (WMH), perivascular spaces (PVS), lacunes, and grey-matter (GM) and ventricular volumes. We found that all cSVD markers, except PVS, progressed faster with increasing age. Regional WMH progressed faster in males and less-educated people (p < 0.05). Each 10-point increment in global WMH score was associated with multi-adjusted hazard ratio of 1.78 (95% CI = 1.50‒2.10) for incident lacunes and multi-adjusted β-coefficients of 0.15 (0.08–0.22), -0.37 (-0.58‒-0.16), and 0.11 (0.03‒0.18) for annual changes of global WMH score, GM volume, and ventricular volume, respectively. The corresponding figures associated with per 10-PVS increment were 1.14 (1.01‒1.28), 0.07 (0.03‒0.11), -0.18 (-0.32‒-0.04), and 0.02 (-0.03‒0.07). Prevalent lacunes were related to multi-adjusted β-coefficients of 0.29 (0.00‒0.58), 0.22 (0.05‒0.38), 0.10 (0.01‒0.18), and -0.93 (-1.83‒-0.03) for annual changes of global, deep, and periventricular WMH scores and GM volume, respectively. These results suggest that cSVD progresses faster in older, male, and less-educated people, and that greater loads of WMH, PVS, and lacunes anticipate faster cSVD progression.

Association between regional white matter hyperintensities classified according to the distance from the ventricular surface and cognitive function in elderly

Association between regional white matter hyperintensities classified according to the distance from the ventricular surface and cognitive function in elderly

The impact of cerebrovascular disease on blood‐based biomarkers of Alzheimer’s disease

AbstractBackgroundThe development of ultrasensitive assays for blood‐based biomarkers may allow for detection of Alzheimer’s disease (AD)‐related pathology in large‐scale community‐based cohorts. We previously showed in the Washington Heights Inwood Columbia Aging Project (WHICAP) an association of plasma biomarker concentrations with clinical and pathological AD diagnosis, and that MRI markers of cerebrovascular disease, particularly parietal lobe white matter hyperintensities (WMH), increase the risk and progression of clinical AD. Here, we test the hypothesis that cerebrovascular disease has a direct impact on AD‐related pathology by examining the association of MRI markers of cerebrovascular disease and plasma biomarker concentrations in WHICAP.MethodAmong 300 WHICAP participants with available structural MRI (mean age 81.87+6.45 years, 67% women, 33.3% non‐Hispanic white, 33.3% African American, 33.3% Hispanic, 42% with cognitive impairment) we used SIMOA and MSD technology to measure plasma concentrations of Aβ42, Aβ40, ptau181, ptau217, total tau, and NfL from banked plasma samples. MRI scans were analyzed for regional WMH, presence of infarct, and presence of microbleeds. We first examined bivariate correlations between MRI cerebrovascular measures and plasma biomarker concentrations. For markers that were associated, we conducted demographically adjusted analyses and examined interactions with cognitive diagnostic status.ResultIncreased parietal lobe WMH, specifically, was associated with higher ptau181 (r=0.21, p=0.008) and ptau217 (r=0.13, p=0.05) concentrations. Increased WMH in frontal, temporal, and parietal regions was associated with increased NfL concentrations (rs=0.21‐0.25, ps&lt;0.001‐0.002). Presence of one or more microbleed was associated with increased NfL (r=0.19, p=0.02). In adjusted models the associations of regional WMH with ptau181 and NfL concentrations were independent of and did not interact with diagnosis.ConclusionMarkers of small vessel cerebrovascular disease, particularly parietal lobe WMH, are associated with AD blood‐based biomarkers of phosphorylated tau pathology and neurodegeneration.

Stroke and cardiovascular disease risk exacerbate brain aging among middle‐age and older Hispanics/Latinos: Preliminary findings from the Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI)

AbstractBackgroundHispanics/Latinos have high prevalence of cardiovascular disease (CVD) risk factors which increases risk for stroke. However, the downstream impacts of CVD risk and stroke on brain structure in aging Hispanics/Latinos remains largely unknown. We compared Hispanic/Latino brain aging by CVD risk and stroke.MethodHispanics/Latinos (nunweighted=1,156, 50‐85 years) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) underwent magnetic resonance imaging (MRI) as part of the Study of Latinos ‐ Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI) ancillary study. Outcomes included global (gray matter, total brain) and regional (lobar cortices, hippocampal) brain, lateral ventricle (log‐transformed), and total white matter hyperintensity (WMH; log‐transformed) volumes residualized for total cranial volume. Ten‐year CVD risk at visit 2 (before MRI) was determined by Framingham Risk Score and recoded into three groups (Low (&lt;10%), Medium (10‐&lt;20%) and High (20+%)). Stroke (yes, no) was based on self‐report of ≥1 strokes or transient ischemic attacks at visit 1 and/or 2. Linear regression models tested 1) whether CVD risk or presence of stroke modified the relationship between age and MRI outcomes, and 2) whether CVD risk or stroke related brain aging differed by sex. All models adjusted for height and Hispanic/Latino background.ResultSample was 64.3± 7.1 years old on average (nunweighted=798 women). High CVD risk was inversely associated with total brain (standardized beta β=–0.26; p&lt;0.001), total gray (β=‐0.23; p=0.006), frontal (β = ‐0.33; p&lt;0.001) and parietal cortical gray (β =‐0.28; p=0.002) matter volumes and positively associated with (log) lateral ventricle (β log=0.23; p=0.006) and (log) WMH (βlog =0.42; p&lt;0.001) volumes. Stroke/TIA (nunweighted=48) showed a similar profile of associations but only the associations with (log) lateral ventricle (βlog=0.27; p=0.049) and (log) WMH (βlog=0.44; p=0.001) reached significance. Accelerated brain aging (age slope modification) through CVD risk and stroke was evident for total brain volume but less so for other MRI outcomes, and equivalently so across sexes.ConclusionAmong Hispanics/Latinos, CVD risk and stroke are associated with poorer brain health across brain MRI indicators. Additionally, CVD risk and stroke may accelerate overall brain aging for both Hispanic/Latino men and women as determined by total brain volumes.

Diversity considerations of white matter hyperintensities and connectivity in normal aging and MCI

AbstractBackgroundAlzheimer’s disease (AD) is twice as likely to occur in African Americans than in Non‐Hispanic Whites. However, current neuroimaging models of AD do not accurately overlay onto the African American profile of this disease. One variable that could contribute to more accurate modeling is the inclusion of vascular factors into models of AD, as African Americans are more likely to have vascular as well as AD. Functional MRI is a widely used method to measure brain activity in individuals with AD. Connectivity in the form of correlated between regions can be used to determine neurological dysfunction. Fronto‐striatal connectivity, while understudied in AD, has shown to be affected by AD and vascular disease. This study attempts to determine if there are connectivity measures that relate to vascular lesions(White Matter Hyperintensities (WMH)) across the disease spectrum, and whether these relationships are uniform across race.MethodWe analyzed data from 88 people (54= NC, 34=MCI). We conducted functional connectivity using DPARSFA toolbox with connectivity calculated between the following fronto‐striatal regions within each hemisphere: anterior putamen, middle frontal gyrus, superior frontal gyrus (putamen output regions), pre‐ and postcentral gyri (putamen input regions). To calculate regional white matter hyperintensity we used in‐house code to overlay a regional atlas onto a WMH mask extracted from a T2 weighted FLAIR image, and assigned a score to each individual representing load (0=no WMH in any regions, 1=WMH in 1 or the other region, 2=present in both regions.ResultAcross race and diagnostic categories, WMH were related negatively to right anterior putamen connectivity to the pre and post central gyri such that as WMH load increased, connectivity also decreased. This relationship continued for connectivity measures between the right anterior putamen and the superior and middle frontal gyri, but only within African Americans.ConclusionFronto‐striatal connectivity did correlate with regional WMH load in a uniform manner across races for cortical input regions to the putamen, and this relationship extended to Africans Americans within cortical output regions. This relationship was identified across diagnostic categories, and could be useful in studies investigating vascular relationships to AD biomarkers.

Increased regional white matter hyperintensity volume in objectively‐defined subtle cognitive decline and mild cognitive impairment

AbstractBackgroundWhite matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, less is known about the extent and pattern of WMH in pre‐MCI stages, such as among those with objectively‐defined subtle cognitive decline (Obj‐SCD). Therefore, we aimed to examine regional WMH volume in Obj‐SCD versus those who were cognitively normal (CN) and MCI.MethodSix hundred twenty‐one Alzheimer’s Disease Neuroimaging Initiative participants (182 CN; 96 Obj‐SCD; 343 MCI) underwent neuropsychological testing and MRI exams. Cerebrospinal fluid (CSF) data were available for ∼50% of the sample. MCI was classified using Jak/Bondi criteria and Obj‐SCD was classified using criteria proposed by Thomas et al. (2018, 2020). ANCOVA models were used to compare cognitive groups on regional WMHs adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 status. We also ran analyses stratified by CSF phosphorylated tau (p‐tau)/amyloid‐β (Aβ) ratio positivity versus negativity.ResultCompared to the CN group, those with Obj‐SCD had greater frontal (p=.036) and temporal WMH (p=.034) with a trend toward greater occipital WMH (p=.052). Those with MCI had greater frontal, temporal, parietal, and occipital WMH (p’s &lt;.01). No significant differences in WMH volume were observed between Obj‐SCD and MCI (p’s &gt;.05). Among p‐tau/Aβ negative individuals, those with Obj‐SCD showed a trend toward greater temporal WMH (p=.053) compared to CN individuals. In addition, the p‐tau/Aβ negative MCI participants showed significantly higher frontal (p=.001), temporal (p=.004), and parietal (p=.027) WMH relative to the CN group. Among p‐tau/Aβ positive individuals, there were no significant group differences in WMH volume.ConclusionRegional WMH vary across cognitive groups. Compared to the CN group, the Obj‐SCD group showed higher temporal and frontal WMH whereas the MCI group showed more widespread WMH increases affecting all lobes, which is in line with their greater cognitive impairment. Notably, these findings do not appear to be driven by p‐tau/Aβ positive individuals. Findings add to growing evidence of associations between Obj‐SCD and imaging biomarkers, providing support for utility of our criteria to capture very subtle cognitive changes.

Relationship between regional white matter hyperintensities and alpha oscillations in older adults

Aging is associated with increased white matter hyperintensities (WMHs) and with alterations of alpha oscillations (7–13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N = 907, 60–80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and long-range temporal correlations. Finally, higher age was associated with elevated alpha power via total WMH volume. We suggest that an elevated alpha power is a consequence of WMHs affecting a spatial organization of alpha sources.

Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults

Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Total and regional WMH volumes. The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized β = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: β = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: β = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: β = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: β = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: β = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: β = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.

Impact of regional white matter hyperintensities on specific gait function in Alzheimer's disease and mild cognitive impairment.

BackgroundGait disturbance and musculoskeletal changes are evident in persons living with Alzheimer's disease (AD). Because complex gait control requires the integration of neural networks, cerebral small vessel disease (SVD), which is highly prevalent in persons with AD, might have an additional impact on gait disturbance. This study investigated whether white matter hyperintensities (WMH) are more predominantly associated with gait disturbance in persons with AD than in individuals with mild cognitive impairment (MCI) and normal cognition (NC) and further identified the regional impact of WMH on specific gait changes.MethodsThis study included 396 subjects (aged 65 to 86 years, 63.9% female) diagnosed with AD (n = 187), MCI (n = 118), or NC (n = 91). WMH, lacunes, perivascular spaces, and cerebral microbleeds were assessed as markers of SVD. The volume of WMH was quantified in each brain lobe (frontal, temporal, occipital, and parietal) and sublobar regions in the basal ganglia and thalamus. Gait function was assessed using an electronic walkway. We investigated the association between regional WMH and gait disturbance in individuals with AD, MCI, and NC, adjusted for classical and musculoskeletal confounders.ResultsAmong markers of SVD, WMH were most associated with gait disturbance. In AD subjects, periventricular WMH in the frontal and parietal lobes were associated with slow gait speed (r s = −0.21, P = 0.007 and r s = −0.18, P = 0.019, respectively). These lesions were also associated with changes in stride time, double‐leg support time, and walking angle (all r s > 0.20, P < 0.01). Lesions in the basal ganglia and thalamus were associated with slow gait speed (r s = −0.16, P = 0.034 and r s = −0.18, P = 0.023, respectively) and greater gait speed variability (r s = 0.16, P = 0.034 and r s = 0.20, P = 0.010, respectively). MCI subjects showed only associations between sublobar lesions and shorter stride length (r s = −0.24, P = 0.016) and increased walking angle (r s = 0.32, P = 0.002). NC subjects did not show associations between WMH and gait parameters. MCI and NC subjects were more affected by muscle weakness than WMH for global gait function (r s = 0.42, P < 0.001 and r s = 0.23, P = 0.046, respectively).ConclusionsPersons with AD showed a predominant association between WMH and gait disturbance compared with MCI and NC subjects, and regional WMH had a detrimental effect on specific gait changes.

Estimated Regional White Matter Hyperintensity Burden, Resting State Functional Connectivity, and Cognitive Functions in Older Adults

White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults. Cross-sectional study. Community. Fifty-eight cognitively-healthy older adults. Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory. The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant. Findings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.