Baseline White Matter Hyperintensities Research Articles

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

BackgroundGrowing evidence suggests that not only cerebrovascular disease but also Alzheimer’s disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach.MethodsTotal 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies.ResultsBaseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female, but not in male.ConclusionsOur findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs.

Cerebral white matter hyperintensities indicate severity and progression of coronary artery calcification

Cerebral white matter hyperintensities (WMH) have been associated with subclinical atherosclerosis including coronary artery calcification (CAC). However, previous studies on this association are limited by only cross-sectional analysis. We aimed to explore the relationship between WMH and CAC in elderly individuals both cross-sectionally and longitudinally. The study population consisted of elderly stroke- and dementia-free participants from the community-based Austrian Stroke Prevention Family Study (ASPFS). WMH volume and CAC levels (via Agatston score) were analyzed at baseline and after a 6-year follow-up period. Of 324 study participants (median age: 68 years), 115 underwent follow-up. Baseline WMH volume (median: 4.1 cm3) positively correlated with baseline CAC levels in multivariable analysis correcting for common vascular risk factors (p = 0.010). While baseline CAC levels were not predictive for WMH progression (p = 0.447), baseline WMH volume was associated CAC progression (median Agatston score progression: 27) in multivariable analysis (ß = 66.3 ± 22.3 [per cm3], p = 0.004). Ten of 11 participants (91%) with severe WMH (Fazekas Scale: 3) at baseline showed significant CAC progression > 100 during follow-up. In this community-based cohort of elderly individuals, WMH were associated with CAC and predictive of its progression over a 6-year follow-up. Screening for coronary artery disease might be considered in people with more severe WMH.

Clinical Markers for Small Vessel Pathology in Alzheimer’s Disease

Background:White matter hyperintensities (WMH) and cerebral microhemorrhages (MH) are common small vessel pathologies that often co-occur with hallmarks of Alzheimer’s Disease (AD) including amyloid-β and tau deposition, neurodegeneration, and decreased cognition. We investigated the relationship among these pathologies to better understand their roles in AD pathogenesis.
 Methods:A sample from the AD Neuroimaging Initiative (ADNI) with baseline WMH volume WMHV), MH counts, and serum lipids measurements using the Nightingale Health metabolomics platform included cognitively normal, mild cognitive impairment, and AD participants. Spearman rank correlations coefficient and rank regression models were generated to assess the relationship between vascular pathology and mean arterial pressure (MAP), history of hypertension, and serum biomarkers. Models were covaried for age, sex, APOE status, BMI, and years of education. Further analysis was conducted by dividing participants based on APOE status. False discovery rate was controlled by the Benjamini-Hochberg method.
 Results:WMHV and MH were weakly positively associated (ρ=0.197, p<1*10-10). MH and MAP were positively correlated (p<.05), but MH was not related to history of hypertension, or serum lipids. WMHV was negatively associated with serum VLDL cholesterol (p<1*10-12), LDL cholesterol (p<.0001), and remnant cholesterol (p<1*10-11). In APOE4 carriers only, WMHV was negatively associated with triglycerides (p<.001) and total fatty acids (p<.001), and positively associated with HDL cholesterol (p<.002). WMHV was not related to MAP or history of hypertension.
 Conclusion:Vascular imaging markers have distinct risk factors with lipid profiles most associated with WMH burden, whereas MAP was predictive of MH. Counterintuitively, lipids associated with higher risk of systemic vascular pathology appeared protective against WMH in the ADNI sample. This phenomenon was particularly notable in APOE4 carriers. Further investigation should be conducted to better understand the relationship between serum lipids and small vessel pathology, and how these contribute to AD pathogenesis.

White Matter Hyperintensities as a Predictor of Aphasia Recovery

ObjectiveTo examine the relation between baseline white matter hyperintensities (WMH) and change in naming, content production, and efficiency after treatment in subacute aphasia. We hypothesized that more severe baseline WMH would result in less improvement with treatment. DesignRetrospective analysis of a cohort from a double-blind randomized controlled trial (RCT). SettingOutpatient clinical setting or participant home. ParticipantsWe retrospectively reviewed imaging and behavioral data for 52 participants with subacute aphasia due to left-hemisphere ischemic stroke enrolled in the RCT. RCT inclusion criteria: English proficiency, normal/corrected-to-normal hearing/vision, and no history of neurologic conditions other than the stroke resulting aphasia. One participant with a chronic right-hemisphere lesion was retained as she presented with no residual deficits on neurologic examination. Individuals with scalp sensitivities or on medications that lower seizure threshold or any N-methyl-D-aspartate (NMDA) antagonists were excluded. Of the 52 participants, for this analysis, 2 were excluded for not having a magnetic resonance imaging, and 7 were excluded for not participating in treatment or pre/post assessment for at least 1 outcome, resulting in final sample of 43 participants (20 women sex, M [SD] age=64.4 [11.9] and M [SD] education=14.9 [3.1] years). InterventionsParticipants received 15 sessions (2-3 times/week) of computerized lexical-semantic (ie, verification) treatment with [sham/active] transcranial direct current stimulation (tDCS). Sessions were approximately 45 minutes each (tDCS for first 20 minutes). Main Outcome MeasuresNaming accuracy, content units (CUs, a measure of semantically accurate production), and efficiency (ie, syllables/CU) on a picture description task. ResultsPeriventricular WMH severity was independently associated with recovery in picture naming for the active tDCS group. Deep WMH severity was associated with recovery for CU production for the sham tDCS group. ConclusionBaseline periventricular and deep WMH, among other factors, may be an important consideration for prognosis and treatment planning, especially when considered in conjunction with tDCS treatment.

Effect of white matter hyperintensities and amyloid on neurodegenerative change and cognitive trajectory in cognitively unimpaired older adults

AbstractBackgroundOverwhelming evidence of association between amyloidosis and neurodegeneration, particularly in the hippocampus, has been reported. However, the recognition of cerebrovascular disease (CVD), the most common comorbidity in elderly patients with dementia2, as a contributor to neurodegeneration process has remained modest. The objective of this study is to investigate the contributions of amyloidosis, as measured by amyloid PET, and CVD, as reflected by white matter hyperintensity (WMH), on neurodegenerative change and how their combination impacts cognitive trajectory in cognitively unimpaired (CU) individuals.Method139 CU participants from the University of California, Davis Alzheimer’s Disease Research Center diversity cohort received at least two cognitive assessments and underwent a PET exam at baseline, and baseline and follow‐up MRI imaging (Table 1). Z‐score measures of DVR19 and SUVR20 values were used as measure of baseline amyloid beta (Aβ) burden. Baseline WMH volume was log‐transformed and regressed against intracranial volume (TCV). Four markers of neurodegeneration were used, including hippocampal volume (regressed against TCV), mean cortical GM thickness and two cognitive‐related signature region of interest (sROI), including episodic memory and executive function. We used structural equation modeling (SEM) analyses (Figure 1) to investigate associations between cognitive performance trajectories (∼6 years), including episodic memory and executive function, and baseline Aβ, baseline WMH and change in the four neurodegeneration markers.ResultSEM analysis revealed significant effects of increased baseline Aβ and greater baseline WMH on accelerated decrease in neurodegeneration marker measures in all models (Figure 2). Increased baseline amyloid and WMH, but not neurodegenerative change measures, were also associated with accelerated decline in episodic memory performance (pvalues<0.05, Figure 2, panels A‐C‐E). Finally, increased baseline Aβ and accelerated decreased in cortical GM and sROI thickness were found to be associated with accelerated decline in executive function (pvalues<0.05, Figure 2, panels B‐D‐F).ConclusionOur findings suggest that both CVD and amyloidosis simultaneously impact neurodegenerative change and that these pathologies are associated with cognitive trajectories, but the dynamics of these trajectory are different for executive and memory, suggesting different early path of vulnerability for these domains and emphasizing the need to thoroughly understand the interaction between amyloidosis, CVD, and neurodegeneration.

Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period

AbstractBackgroundWomen have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.ResultIn main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values>0.20) or longitudinal WMH progression (p‐values>0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values<0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).ConclusionHigher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.FundingIIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082

Examining Complex Relationships among Cerebrovascular, β‐Amyloid, Tau and Cognitive Measures in a Cognitively Unimpaired Late‐Middle Aged Sample

AbstractBackgroundRecent research linking vascular risk with promotion of tau pathology in the inferior temporal cortex (ITC) suggests a potential mechanism connecting cerebrovascular risk to AD pathology and cognitive decline among cognitively unimpaired (CU) individuals (Yau et al, 2022).We used MRI White Matter Hyperintensity (WMH), a neuroimaging marker of chronic cerebral small‐vessel disease/cerebrovascular disease, to further elucidate longitudinal relationships between cerebrovascular risk, PET AD pathological burden, and cognition.MethodWe examined baseline CU late middle‐aged adults from the University of Wisconsin’s Alzheimer’s disease research cohorts. β‐Amyloid burden was measured with 11C‐Pittsburgh compound B (“PiB”; DVR derived from a 0‐70 min dynamic PET scan; PET A+ threshold∼1.16 DVR/∼CL 17). Cerebrovascular risk was quantified using WMH volumes (T2‐FLAIR images; SPM Lesion Segmentation Tool). Tau burden was measured with florquinitau PET (MK6240 SUVR from 70‐90 min post‐injection). Tau outcomes included bilateral volume‐weighted averages for ITC, Medial temporal lobe (MTL) and Meta‐temporal (MTC) composites. Biomarker values were z‐transformed relative to CU/PET A‐ values. Random intercept models examined interactive effects of baseline WMH and Aβ levels on longitudinal tau (covarying baseline tau age, sex, APOE ε4 count). We modeled time two ways: years since baseline PiB (TimePiB1; replicating Yau, et al models); and, in parallel models, amyloid duration (years) at tau scans was substituted for years since PiB1 in the A+ subset (TimePiB1/PiB+). We also used LME to examine Aβ, WMH, and time interactions in longitudinal cognition (PACC3 and Digit Symbol Substitution).ResultThe mean(SD) tau baseline age was 67.9(6.8) years (sample details in Table1). The most parsimonious models using TimePiB1 included WMH*Aβ*Time for ITC and MTC and WMH*Aβ for MTL. Patterns showed a synergistic effect of WMH and Aβ on tau accumulation that was attenuated using TimePiB1/PiB+ where the most parsimonious models included Aβ_status*TimePiB1/PiB+ (ITC, MTC) or WMH*Aβ_status*TimePiB1/PiB+ (MTL; Figure1). AICc model fits were substantially better using TimePiB1/PiB+. Both Aβ and WMH contributed to cognitive trajectories (Figure2).ConclusionAlthough cerebrovascular risk’s apparent contribution to tau accumulation varied depending on how time was modeled, results suggest that cerebrovascular risk may complement imaging biomarkers in assessing risk of tau accumulation and cognitive decline in preclinical Alzheimer disease.

White Matter Hyperintensity Trajectories in Patients With Progressive and Stable Mild Cognitive Impairment.

White matter hyperintensities (WMH) are pathologic brain changes that are associated with increased age and cognitive decline. However, the association of WMH burden with amyloid positivity and conversion to dementia in people with mild cognitive impairment (MCI) is unclear. The aim of this study was to expand on this research by examining whether change in WMH burden over time differs in amyloid-negative (Aβ-) and amyloid-positive (Aβ+) people with MCI who either remain stable or convert to dementia. To examine this question, we compared regional WMH burden in 4 groups: Aβ+ progressor, Aβ- progressor, Aβ+ stable, and Aβ- stable. Participants with MCI from the Alzheimer Disease Neuroimaging Initiative were included if they had APOE ɛ4 status and if amyloid measures were available to determine amyloid status (i.e., Aβ+, or Aβ-). Participants with a baseline diagnosis of MCI and who had APOE ɛ4 information and amyloid measures were included. An average of 5.7 follow-up time points per participant were included, with a total of 5,054 follow-up time points with a maximum follow-up duration of 13 years. Differences in total and regional WMH burden were examined using linear mixed-effects models. A total of 820 participants (55-90 years of age) were included in the study (Aβ+ progressor, n = 239; Aβ- progressor, n = 22; Aβ+ stable, n = 343; Aβ- stable, n = 216). People who were Aβ- stable exhibited reduced baseline WMH compared with Aβ+ progressors and people who were Aβ+ stable at all regions of interest (β belongs to 0.20-0.33, CI belongs to 0.03-0.49, p < 0.02), except deep WMH. When examining longitudinal results, compared with people who were Aβ- stable, all groups had steeper accumulation in WMH burden with Aβ+ progressors (β belongs to -0.03 to 0.06, CI belongs to -0.05 to 0.09, p < 0.01) having the largest increase (i.e., largest increase in WMH accumulation over time). These results indicate that WMH accumulation contributes to conversion to dementia in older adults with MCI who are Aβ+ and Aβ-.

Mediterranean diet and longitudinal change of white matter hyperintensity in cognitively intact young and older adults

AbstractBackgroundA healthy dietary pattern, Mediterranean diet (MeDi), has been reported to be associated with better brain and cognition. White matter hyperintensities (WMHs), seen in brain magnetic resonance imaging, are considered to be due to cerebral small vessel diseases and have been shown to predict faster cognitive decline in older adults. However, current evidence on the association between MeDi and WMH is inconsistent and longitudinal data are scarce. This study aims to examine whether better adherence to MeDi is associated with less accumulation of WMH over time.MethodThis longitudinal study was conducted among 183 cognitively intact adults aged 20‐80 years. MeDi was calculated from dietary data assessed by a self‐reported food frequency questionnaire, ranging from 0‐55, with a higher score indicating better adherence. WMH was assessed by 3T MRI, and log‐transformed prior to analyses. A one‐sample T‐test was used to examine if WMH burden increased from baseline to follow‐up over an average of five years. Multivariable linear regression was used to estimate the effect of MeDi on the change in WMH. Covariates included age, gender, race/ethnicity, education, IQ, follow‐up interval, caloric intake, baseline WMH, baseline total gray matter volume, and baseline mean cortical thickness. Moderation effects by age (young: &lt;43, middle‐aged: 43‐65, and older: ≥65 years), sex, and race/ethnicity (non‐Hispanic White and other, non‐Hispanic Black, and Hispanic) were examined, followed by stratification analyses.ResultAmong all participants, WMH increased from baseline to follow‐up (mean difference [follow‐up‐baseline][standard error(SE)] = 0.31[0.04], p&lt;0.001). A higher MeDi was associated with less increase of WMH (β[SE] = ‐0.014[0.006], p = 0.034), adjusting by all covariates. The association between MeDi and WMH change was moderated by age group (young group as the reference, p‐interaction[middle‐aged*MeDi] = 0.024, p‐interaction[older*MeDi] = 0.017), adjusting by follow‐up interval: the association was observed among the young group (β[SE] = ‐0.038[0.010], p&lt;0.001), but not among the middle‐aged ((β[SE] = ‐0.002[0.013, p = 0.872]) or the older group ((β[SE] = ‐0.002[0.009], p = 0.836). No significant moderation effects by sex or race/ethnicity were found, adjusting by age and follow‐up interval.ConclusionBetter adherence to MeDi was associated with reduced increase of WMH over time. Following a healthy diet, especially at an early age, may help maintain a healthy brain.

The combined effect of β ‐amyloid and white matter hyperintensities on present and future executive function performance in cognitively normal older adults

AbstractBackgroundβ‐amyloid (Aβ) and White matter hyperintensities (WMH) are key drivers of cognitive decline in healthy older adults and both are considered biomarkers of preclinical dementia. Deficit in executive function (EF) linked to WMHs and Aβ burden, have been shown to predict the development of dementia. The present study aimed to explore the interactions of regional and global Aβ with WMH on baseline and longitudinal performance in EF in cognitively normal (CN) older adults.MethodGlobal and regional Standard Uptake Value ratios (SUVr) from Aβ‐PET, WMH volumes from MRI FLAIR images, and composite scores of EF at baseline and after approximately 2 years were analyzed across a sample of 714 clinically‐normal (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2). We used multiple regression models including the interaction tem and main effects for Aβ and WMH to investigate the independent and combined associations of these pathologies with EF. Age, ApoE, education, baseline EF score, and time to follow up EF testing were entered as covariates in the regression models.ResultThe moderation regression analysis showed that additive effects on Aβ burden and WMH in relation to baseline EF with p value for the interaction term between the two pathologies 0.07, and significant interaction effects of global, frontal and cingulate Aβ burden, and WMH in relation to longitudinal EF performance with p values of 0.037, 0.03, and 0.032 respectively. The main effect from regression analysis demonstrated that baseline EF performance was predicted by the combination of Aβ burden and WMH, while Aβ burden was the only predictor for longitudinal EF performance.ConclusionThese data demonstrated that baseline Aβ and WMHs have both independent effects on EF scores at baseline and synergistic effects on longitudinal EF performance. The biological relationships and interplay between Ab and WMH responsible for the synergistic effects seen on longitudinal EF performance warrants further study.

Longitudinal characterization of white matter degeneration in early stages of AD

AbstractBackgroundWhite matter (WM) degeneration in older adults is often characterized unimodally by diffusion tensor imaging (DTI), T1w and T2‐FLAIR MRI. However, approaches integrating multimodal MRI information will be necessary for better understanding WM degeneration in early stages of AD.MethodThis study characterizes the longitudinal changes of WM structure among 66 participants with marked baseline white matter hyperintensity volume (WMHv &gt; 2000 mm3). 42 cognitively normal [CN, 72±7.2y, F = 25] and 24 mild cognitive impairment [MCI, 74±5.7y, F = 14]) adults underwent longitudinal MRI (scan interval: 2.8±0.85 years) within the Wake Forest AD Research Center. DTI metrics were estimated using FMRIB’s Diffusion Toolbox, voxel‐wise volumetric changes of WM (Jacobian Determinant [JD]) were estimated from fractional anisotropy (FA) maps using SPM CAT12, and WMHv were quantified using SPM’s Lesion Segmentation Toolbox. We segmented WM into WMH and normal‐appearing WM (NAWM) to characterize different degeneration patterns by integrating multimodal MRI information. We performed a linear regression analysis of %WMHv change with cognitive status, scan interval, and baseline WMH volume as covariates.ResultDecreased FA and increased mean diffusivity (MD) were observed in WMH regions compared with NAWM. Within WMH, interestingly, volume and FA increased, while MD decreased (p &lt;0.001) during the longitudinal follow‐up (Figs. 1 and 2). Baseline WMHv was not significantly associated with cognitive status, but trended toward higher WMHv in MCI compared to CN (p = 0.07). Adjusted for baseline WMHv, cognitive status was associated with WMHv change (p = 0.036, MCI faster than CN, Fig. 3). While FA (p = 0.99) and MD (p = 0.16) did not change in the NAWM, volumetric change rate (JD) indicated volumetric contraction (p&lt;0.001, Figs. 4 and 5). WMH progresses with time in older adults at risk of AD dementia by occupying neighboring NAWM regions, resulting in relative increases in FA and decreases in MD.ConclusionIn NAWM, WM degeneration can be better characterized by volumetric contraction than white matter microstructural integrity. This observation could implicate that secondary or peripheral WM fibers may reveal more vulnerable tracts in early stages of AD. Further investigation incorporating imaging makers of blood perfusion and metabolism could better explain structural mechanisms of WM degeneration.

Cerebral Small Vessel Disease Progression and the Risk of Dementia: A 14-Year Follow-Up Study.

Cerebral small vessel disease (SVD) is considered the most important vascular contributor to cognitive decline and dementia, although a causal relation between its MRI markers and dementia still needs to be established. The authors investigated the relation between baseline SVD severity as well as SVD progression on MRI markers and incident dementia, by subtype, in individuals with sporadic SVD over a follow-up period of 14 years. The study included 503 participants with sporadic SVD, and without dementia, from the prospective Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, with screening for baseline inclusion conducted in 2006. Follow-ups in 2011, 2015, and 2020 included cognitive assessments and MRI scans. Dementia was diagnosed according to DSM-5 criteria and stratified into Alzheimer's dementia and vascular dementia. Dementia as an endpoint was available for 498 participants (99.0%) and occurred in 108 participants (21.5%) (Alzheimer's dementia, N=38; vascular dementia, N=34; mixed-etiology Alzheimer's dementia/vascular dementia, N=26), with a median follow-up time of 13.2 years (interquartile range, 8.8-13.8). Higher baseline white matter hyperintensity (WMH) volume (hazard ratio=1.31 per 1-SD increase, 95% CI=1.02-1.67), presence of diffusion-weighted-imaging-positive lesions (hazard ratio=2.03, 95% CI=1.01-4.04), and higher peak width of skeletonized mean diffusivity (hazard ratio=1.24 per 1-SD increase, 95% CI=1.02-1.51) were independently associated with all-cause dementia and vascular dementia. WMH progression predicted incident all-cause dementia (hazard ratio=1.76 per 1-SD increase, 95% CI=1.18-2.63). Both baseline SVD severity and SVD progression were independently associated with an increase in risk of all-cause dementia over a follow-up of 14 years. The results suggest that SVD progression precedes dementia and may causally contribute to its development. Slowing SVD progression may delay dementia onset.

Statin Usage Increases White Matter Hyperintensities: A Post Hoc Analysis of SPRINT-MIND.

Progression of white matter hyperintensities (WMHs), a radiographic marker of cerebral small vessel disease, occurs with uncontrolled conventional cerebrovascular risk factors. Less certain, however, is the influence of dyslipidemia and the impact of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) on WMH progression. The goal of this study was to evaluate the influence of statins on the progression of WMH over a 4-year interval. We performed a post hoc analysis of the SPRINT-MIND database on those with serial volumetric WMH data. WMH progression was calculated as the difference in WMH volume between the 2 scans and then segmented into tertiles due to rightward skew. We defined statin usage as no therapy (0% of visits), partial therapy (1% to 99% of visits) or full therapy (100% of visits) as logged during study visits. Analysis of variance and χ2 tests were used for continuous and categorical variables with adjustments made for variables known to influence WMH development. A total of 425 individuals were included in this study: 53% without statins use, 27% partial use, and 20% full use. Demographic characteristics and baseline WMH volumes were similar among the cohort. Those with full statin use were significantly more likely to be in the top tertile of WMH progression (adjusted odds ratio: 2.30, 95% confidence interval: 1.11-4.77, P=0.025), despite improvement in dyslipidemia. SPRINT-MIND participants prescribed a statin were nearly 2.5 times more likely to be within the top tertile of WMH progression over 4 years, despite adjustment for synergistic risk factors and improvement in low-density lipoprotein.

Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR]=1.46 per 1-SD increase, 95% confidence interval [CI]=1.21-1.78), peak width of skeletonized mean diffusivity (HR=1.66 per 1-SD increase, 95% CI=1.34-2.05), and presence of lacunes (HR=1.84, 95% CI=0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR=4.64, 95% CI=1.32-16.32). Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Twenty-four hour blood pressure variability and the prevalence and the progression of cerebral white matter hyperintensities

Blood pressure variability (BPV) is related to cerebral white matter hyperintensities (WMH), but longitudinal studies assessing WMH progression are scarce. Patients with cardiovascular disease and control participants of the Heart-Brain Connection Study underwent 24-hour ambulatory blood pressure monitoring and repeated brain MRI at baseline and after 2 years. Using linear regression, we determined whether different measures of BPV (standard deviation, coefficient of variation, average real variability (ARV), variability independent of the mean) and nocturnal dipping were associated with WMH and whether this association was mediated or moderated by baseline cerebral perfusion. Among 177 participants (mean age: 65.9 ± 8.1 years, 33.9% female), the absence of diastolic nocturnal dipping was associated with higher WMH volume at baseline (β = 0.208, 95%CI: 0.025–0.392), but not with WMH progression among 91 participants with follow-up imaging. None of the BPV measures were associated with baseline WMH. Only 24-hour diastolic ARV was significantly associated with WMH progression (β = 0.144, 95%CI: 0.030–0.258), most profound in participants with low cerebral perfusion at baseline (p-interaction = 0.042). In conclusion, absent diastolic nocturnal dipping and 24-hour diastolic ARV were associated with higher WMH volume. Whilst requiring replication, these findings suggest that blood pressure patterns and variability may be a target for prevention of small vessel disease.

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period

IntroductionFunctional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. MethodsLinear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. ResultsSmaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer’s disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. DiscussionGreater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD.

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia

BackgroundAlzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aβ) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aβ deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies. MethodsTwenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. 11C-PK11195 standard uptake value ratio (SUVR) and 11C-PiB mean cortical binding potential (MCBP) were used to evaluate neuroinflammation and Aβ deposition in-vivo, respectively. Fluid-attenuated inversion recovery MR images were acquired to obtain baseline WMH volume and its progression over 11.5 years. Composite cognitive scores (global, processing speed and memory) were computed at baseline and follow-up over 7.5 years. Multiple linear regression models evaluated the association between PET biomarkers (11C-PK11195 SUVR and 11C-PiB MCBP) and baseline WMH volume and cognitive function. Moreover, linear mixed-effects models evaluated whether PET biomarkers predicted greater WMH progression or cognitive decline over a decade. ResultsFifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated 11C-PK11195 SUVR, but not 11C-PiB MCBP, was associated with greater baseline WMH volume and predicted greater WMH progression. Elevated 11C-PiB MCBP was associated with baseline memory and global cognition. Elevated 11C-PK11195 SUVR and elevated 11C-PiB MCBP independently predicted greater global cognition and processing speed declines. No association was found between 11C-PK11195 SUVR and 11C-PiB MCBP. ConclusionsNeuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression.

Associations of Amyloid, White Matter Hyperintensities, and Hippocampal Volume with Cognitive Trajectories in the Oldest‐Old: The 90+ Study

AbstractBackgroundAmyloid pathology, vascular disease pathology, and hippocampal atrophy are associated with cognitive trajectories in older adults. However, there is almost no prior evidence on how these pathologies influence cognition in the oldest‐old.MethodWe included 216 individuals from The 90+ Study, a longitudinal study of aging and dementia in people aged 90 years and older, who had 18F‐florbetapir PET and MRI imaging. We examined the association of amyloid, white matter hyperintensities (WMH) volume, and hippocampal volume (HV) with baseline cognition and longitudinal cognitive decline. Amyloid burden was measured using the standardized uptake value ratio (SUVR) in the precuneus/posterior cingulate with white matter mask as reference. WMH volume and HV were normalized by intracranial volume (IV) and normalized WMH were log‐transformed. SUVR and HV for each individual were Z‐scored using the sample mean and standard deviation. Global cognitive performance was measured by Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every six months. We defined baseline (time=0) as the visit closest to the PET imaging and included all visits starting from one year before baseline (time=‐1). We used linear mixed‐effects models with a random intercept to estimate the effect of pathologies on cognitive trajectories. All models included baseline age, sex, education, APOE‐ε4, time, time squared, amyloid, WMH, HV, and interactions between linear time and pathology variables.ResultAt baseline, participants were 93.2 years old on average, 65.3% were females, 10.6% were APOE‐ε4 carriers, and 66.2% had normal cognition (Table 1). Higher HV was associated with higher MMSE and 3MS scores at baseline. Both lower amyloid burden and higher HV were associated with slower rate of cognitive decline longitudinally. WMH was not associated with baseline cognition or cognitive trajectory. Parameter estimates are shown in Table 2 and illustrative cognitive trajectories predicted for a 93.2‐year‐old female with APOE‐ε4 alleles and a college degree predicted at varying degrees of amyloid, HV, and WMH are shown in Figure 1.ConclusionAmyloid burden and HV are associated with longitudinal cognitive trajectories, highlighting the utility of amyloid and HV in predicting future cognitive decline for the oldest‐old.

Racial differences in white matter hyperintensity load in aging, MCI, and AD

AbstractBackgroundCerebral small vessel disease (CSVD), often measured using white matter hyperintensities (WMHs) is a pathological change to the brain that increases ones’ risk for both age‐related cognitive decline and dementia. Several studies have noted that there is greater risk of CSVD in African Americans than in Caucasians. However, limited research has examined WMHs as a proxy of CSVD in an ethnically diverse sample. The goal of this research was to determine whether WMH load differs between African Americans and Caucasians.MethodsParticipants for this study were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1, GO, 2, and 3). They were included if they had baseline WMH measurements and a baseline diagnosis. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). A total of 91 African Americans and 1846 Caucasians were included in this analysis. To compare samples, 91 Caucasian participants were randomly matched to African Americans based on age, sex, education, and diagnosis. This random selection was completed 1000 times using bootstrap resampling. A linear mixed effects was completed to examine the influence of race on WMH load: WMH ∼ Race + Age + Sex + Education + Diagnosis. The 95% confidence limits of the t‐statistics distributions for the 1000 samples were examined to determine whether the differences were statistically significant.ResultsThe following figure shows the t‐statistic, 95% confidence intervals, and p‐value distributions of the 1000 bootstrapped samples. The 95% confidence intervals are between t=‐3.06 and t=‐0.89 for total WMH load, indicating significance, as the limits do not include 0.ConclusionsAccounting for age, sex, education, and diagnostic status, racial differences were observed for total WMH load. That is, African Americans had higher total WMH load than Caucasians. Future research should examine whether these findings are observed longitudinally and if they influence cognition in an ethnically diverse sample.

White matter hyperintensities are an early marker for cognitive decline in cognitively healthy older adults

AbstractBackgroundPrevious research suggests that white matter hyperintensities, amyloid, and tau contribute to cognitive decline. It remains unknown as to how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. The goal of this study was to examine the association between these pathologies and their relationship to cognitive decline.MethodsCognitively normal older adult data from the Alzheimer’s Disease Neuroimaging Initiative were examined. Participants were included if they had no subjective cognitive decline, had baseline white matter hyperintensity measurements, CSF Aß42, CSF pTau181, and cognitive scores. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). Of the 230 participants included, only 199 had follow‐up cognitive scores. Linear regressions examined the influence of white matter hyperintensities, amyloid, and tau on baseline and follow‐up cognitive scores. Linear regressions also examined the association of amyloid and tau on white matter hyperintensities and between tau and amyloid.ResultsIncreased baseline WMHs were associated with increased baseline ADAS‐13 scores (t=2.59, p=.01) and lower follow‐up executive functioning (t= ‐2.84, p=.005). Lower baseline Aß42 was associated with lower baseline (t=3.58, p&lt;.004) but not follow‐up executive function. Baseline pTau was not associated with decline in cognition at baseline or follow‐up. At baseline, WMHs were not associated with pTau but were inversely related to lower baseline Aß42 (t=‐4.20, p&lt;.001). Aß42 and pTau were not associated (t=0.51, p=.61).ConclusionWhite matter hyperintensities may be one of the earliest pathologies observed in healthy older adults that contribute to cognitive decline. The inclusion of white matter hyperintensities as an additional marker for early cognitive decline may improve our current understanding of age‐related changes in cognitively healthy older adults.