Baseline White Matter Hyperintensities Volume Research Articles

Baseline and Longitudinal MRI Markers Associated With 16-Year Mortality in Patients With Cerebral Small Vessel Disease.

Information on whether small vessel disease (SVD) reduces life expectancy is limited. Moreover, the excess mortality risk attributed specifically to SVD compared with controls from the general population has not been evaluated. This study aimed to investigate the baseline and progression of MRI markers of SVD associated with mortality in a 16-year follow-up cohort study and to determine the excess long-term mortality risk of patients with SVD. Participants with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (with MRI assessments in 2006, 2011, 2015, and 2020) were followed until their death or December 1, 2021. Adjusted Cox regression analyses and linear mixed-effect regression models were used to investigate the association between MRI markers of SVD and mortality. The excess mortality risk of SVD was calculated by comparing mortality data of the RUN DMC study with the general population matched by sex, age, and calendar year. 200 of 503 (39.9%) participants died during a follow-up period of 15.9 years. Cause of death was available for 182 (91%) participants. Baseline white matter hyperintensity volume (HR 1.3 per 1-SD increase [95% CI 1.1-1.5], p = 0.010), presence of lacunes (1.5 [95% CI 1.1-2.0], p = 0.008), mean diffusivity (HR 1.1 per 1-SD increase [95% CI 1.1-1.2], p = 0.001), and total brain volume (HR 1.5 per 1-SD decrease [95% CI 1.3-1.9], p < 0.001) were associated with all-cause mortality after adjusting for age, sex, and vascular risk factors. Total brain volume decrease over time was associated with all-cause mortality after adjusting for age, sex, and vascular risk factors (HR 1.3 per 1-SD decrease [95% CI 1.1-1.7], p = 0.035), and gray matter volume decrease remained significant after additionally adjusting for its baseline volume (1.3 per 1-SD decrease [1.1-1.6], p = 0.019). Participants with a Fazekas score of 3, presence of lacunes, or lower microstructural integrity had an excess long-term mortality risk (21.8, 15.7, 10.1 per 1,000 person-years, respectively) compared with the general population. Excess long-term mortality risk only exists in patients with severe SVD (Fazekas score of 3, presence of lacunes, or lower microstructural integrity). This could help in assisting clinicians to predict the clinical outcomes of patients with SVD by severity.

Framingham Stroke Risk Profile Score and White Matter Disease Progression.

To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm 3 /year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm 3 (IQR: 3.3-28.4 cm 3 ), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm 3 /year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P <0.001). This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer’s Disease

BackgroundIncreased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer’s disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).Objectives1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial.DesignA multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period.SettingAnti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.ParticipantsA sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers).MeasurementsA linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group.ResultsBaseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH.ConclusionThese results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.

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.&#x0D; 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.&#x0D; Results:WMHV and MH were weakly positively associated (ρ=0.197, p&lt;1*10-10). MH and MAP were positively correlated (p&lt;.05), but MH was not related to history of hypertension, or serum lipids. WMHV was negatively associated with serum VLDL cholesterol (p&lt;1*10-12), LDL cholesterol (p&lt;.0001), and remnant cholesterol (p&lt;1*10-11). In APOE4 carriers only, WMHV was negatively associated with triglycerides (p&lt;.001) and total fatty acids (p&lt;.001), and positively associated with HDL cholesterol (p&lt;.002). WMHV was not related to MAP or history of hypertension.&#x0D; 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.

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&lt;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&lt;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.

Risk architecture for altered hippocampal connectivity in normal aging differ between men and women

AbstractBackgroundFunctional MRI (fMRI) studies have associated impaired memory networks with increase in AD pathology. Recently, cross‐sectional analyses found b‐amyloid (Aβ) deposition associated with different patterns of hippocampal connectivity in a memory task based on sex and white matter hyperintensity volume (WMHV). However, cross‐sectional studies don’t provide insight into the driving mechanisms of network change. In this longitudinal study, we identify risk factors based on sex that are associated with memory network connectivity changes.MethodOur study included 54 cognitively normal older adults (N = 34 female, mean age 74.6 years) with MRI scans on average 2.43 (SD 0.82) years apart. T1w, T2‐FLAIR MRI, and PiB PET were collected to quantify cortical volume, WMHV and Aβ deposition, respectively. Task fMRI was collected while participants performed face‐name associative memory tasks. Left and right hippocampus seeds were used to estimate functional connectivity between hippocampus and voxels in the brain. Second‐level analyses were performed to determine regions of interest (ROI) with significant differences in sex by time interaction (p&lt;0.001). The mean beta values were extracted from the significant ROIs for post‐hoc analysis where we performed multivariate linear regression analyses to find correlations with connectivity change (follow‐up minus baseline).ResultThree ROIs presented significant sex by time interactions: left‐right hippocampus, hippocampus‐anterior cingulate cortex (ACC), and hippocampus‐medial frontal gyrus. The change in left‐right hippocampus connectivity increased for women and decreased for men (Fig.1). For the other ROIs, connectivity increased for men and decreased for women (Fig.2). Left‐right hippocampal connectivity change had a significant sex‐WMHV interaction effect (p&lt;0.01), where only women had a positive association between connectivity change and baseline WMHV. Hippocampus‐ACC connectivity change had a significant sex‐Aβ interaction (p&lt;0.01), with greater baseline Aβ associated with increased connectivity change for men and decreased for women.ConclusionWe observed sex‐differences in risk architecture for altered hippocampal connectivity. In the presence of vascular pathology and Aβ, women appear to experience local hippocampal connectivity and decrease hippocampal‐frontal connectivity. Meanwhile, men experienced hippocampal‐frontal connectivity with increased Aβ burden. Characterizing these sex differences in memory network alterations can help guide the development of sex‐specific prevention and treatment strategies.

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.

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.

Spatial Relation Between White Matter Hyperintensities and Incident Lacunes of Presumed Vascular Origin: A 14-Year Follow-Up Study.

The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6-4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5-6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. The 2 different distribution patterns of lacunes regarding their relation to WMH may suggest distinct underlying mechanisms, one of which may be more closely linked to a similar pathophysiology as that of WMH. The longitudinal relation between WMH and lacunes further supports plausible shared mechanisms between the 2 key markers.

Associations between cerebral blood flow and progression of white matter hyperintensity in community-dwelling adults: a longitudinal cohort study.

BackgroundWhite matter hyperintensity (WMH) is prevalent in elderly populations. Ischemia is characterized by a decline in cerebral blood flow (CBF) and may play a key role in the pathogenesis of WMH. However, the association between CBF reduction and WMH progression remains controversial. This study aimed to investigate the association between CBF and the progression of WMH at a 2-year follow-up of community-based, asymptomatic adults in a longitudinal cohort study across the lifespan.MethodsAsymptomatic adults who participated in a community-based study were recruited and underwent brain structural and perfusion magnetic resonance imaging (MRI) at baseline and at a 2-year follow-up visit. The CBF was measured on pseudo-continuous arterial spin-labeling (pCASL) MRI. The WMH was evaluated on T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images. Tissue segmentation was conducted on T1-weighted (T1W) images to derive binary masks of gray matter and normal-appearing white matter. Linear mixed effect models were conducted to analyze the cross-sectional and longitudinal associations between CBF and WMH.ResultsA total of 229 adults (mean age 57.3±12.6 years; 94 males) were enrolled at baseline, among whom 84 participants (mean age 54.1±11.9 years; 41 males) completed a follow-up visit with a mean time interval of 2.77±0.44 years. At baseline, there was a decreasing trend in gray matter (GM) CBF with an increase of WMH burden (P=0.063), but this association was attenuated after adjusting for age (P=0.362). In the longitudinal analysis, baseline WMH volume was significantly associated with the reduction of perfusion in GM [coefficient =−1.96, 95% confidence interval (CI): −3.25 to −0.67; P=0.004] and normal appearing white matter (coefficient =−0.99, 95% CI: −1.66 to −0.31; P=0.005) during follow-up. On the contrary, neither baseline CBF in GM (P=0.888) nor normal appearing white matter (P=0.850) was associated with WMH progression. In addition, CBF changes within WMH were significantly associated with both baseline (coefficient =−0.014, 95% CI: −0.025 to −0.003; P=0.017) and progression (coefficient =−1.01, 95% CI: −1.81 to −0.20; P=0.015) of WMH volume.ConclusionsA WMH burden was not found to be directly associated with cortex perfusion at baseline due to the effects of age on both CBF and WMH. However, baseline WMH volume could predict the reduction of perfusion.

Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort.

Background and ObjectivesThe goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort.MethodsParticipants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aβ deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years.ResultsThree hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87–mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39–mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016–mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07–mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31–mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014–mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aβ status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aβ.DiscussionAβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

Neuropsychiatric symptoms as a sign of small vessel disease progression in cognitive impairment.

Neuropsychiatric symptoms associate cross-sectionally with cerebral small vessel disease but it is not clear whether these symptoms could act as early clinical markers of small vessel disease progression. We investigated whether longitudinal change in Neuropsychiatric Inventory (NPI) scores associated with white matter hyperintensity (WMH) progression in a memory clinic population. We included participants from the prospective Sunnybrook Dementia Study with Alzheimer's disease and vascular subtypes of mild cognitive impairment and dementia with two MRI and ≥ 1 NPI. We conducted linear mixed-effects analyses, adjusting for age, atrophy, vascular risk factors, cognition, function, and interscan interval. At baseline (n=124), greater atrophy, age, vascular risk factors and total NPI score were associated with higher baseline WMH volume, while longitudinally, all but vascular risk factors were associated. Change in total NPI score was associated with change in WMH volume, χ2=7.18, p=0.007, whereby a one-point change in NPI score from baseline to follow-up was associated with a 0.0017 change in normalized WMH volume [expressed as cube root of (WMH volume cm³ as % intracranial volume)], after adjusting for age, atrophy, vascular risk factors and interscan interval. In memory clinic patients, WMH progression over 1-2 years associated with worsening neuropsychiatric symptoms, while WMH volume remained unchanged in those with stable NPI scores in this population with low background WMH burden.

Longitudinal White Matter Damage Evolution in Parkinson's Disease.

White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society.

The association between white matter hyperintensity volume and cognitive/physical decline in older people with dementia: A one-year longitudinal study

Objectives Understanding the relationship between white matter hyperintensities (WMHs) and cognitive and physical decline in people with dementia will assist in determining potential treatment strategies. Currently there is conflicting evidence describing the association between WMHs and cognitive decline and, WMHs association with declines in objective measures of physical function have not been examined. We examined the relationship between baseline WMH volume and physical/cognitive decline over one-year in older people with dementia. Methods Twenty-six community-dwelling older people with dementia (mean age = 81 ± 8 years; 35% female) were assessed at baseline and follow-up (one-year) using the Addenbrooke’s Cognitive Examination-Revised (including verbal fluency), Trail Making Test A, the Physiological Profile Assessment (PPA), timed-up-and-go (TUG) and gait speed. WMH volumes were quantified using a fully automated segmentation toolbox, UBO Detector. Results In analyses adjusted for baseline performance, higher baseline WMH volume was associated with decline in executive function (verbal fluency), sensorimotor function (PPA) and mobility (TUG). Executive function (semantic/category fluency) was the only domain association that withstood adjustment for age, and additionally hippocampal volume. Conclusions In unadjusted analyses, WMH volume was associated with one-year declines in cognitive and physical function in older people with dementia. The association with executive function decline withstood adjustment for age. More research is needed to confirm these findings and explore whether vascular risk reduction strategies can reduce WMH volume and associated cognitive and physical impairments in this group.

Blood\u2013brain barrier leakage at baseline and cognitive decline in cerebral small vessel disease: a 2-year follow-up study

Blood–brain barrier (BBB) dysfunction is one of the pathophysiological mechanisms in cerebral small vessel disease (SVD). Previously, it was shown that BBB leakage volume is larger in patients with SVD compared with controls. In this study, we investigated the link between BBB leakage and cognitive decline over 2 years in patients with cSVD. At baseline, 51 patients with clinically overt cSVD (lacunar stroke or mild vascular cognitive impairment) received a dynamic contrast-enhanced MRI scan to quantify BBB permeability in the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical grey matter (CGM), and deep grey matter (DGM). Cognitive function in the domain executive function, information processing speed, and memory was measured in all patients at baseline and after 2 years. The association between baseline BBB leakage and cognitive decline over 2 years was determined with multivariable linear regression analysis, corrected for age, sex, educational level, baseline WMH volume, and baseline brain volume. Regression analyses showed that higher baseline leakage volume and rate in the NAWM and CGM were significantly associated with increased overall cognitive decline. Furthermore, higher baseline leakage volume in the NAWM and CGM, and higher baseline leakage rate in the CGM were significantly associated with increased decline in executive function. This longitudinal study showed that higher BBB leakage at baseline is associated with stronger cognitive decline, specifically in executive function, over 2 years of follow-up in patients with cSVD. These results emphasize the key role of BBB disruption in the pathophysiology and clinical progression of cSVD.

Cerebral Microbleeds and White Matter Hyperintensities are Associated with Cognitive Decline in an Asian Memory Clinic Study.

Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

White Matter Hyperintensity and Cardiovascular Disease Outcomes in the SPRINT MIND Trial

BackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal systolic blood pressure (SBP) <120 mm Hg vs. <140 mm Hg. In a subset of participants, the SPRINT MIND ancillary study performed a baseline MRI and measured white matter hyperintensity volume (WMHv). In this secondary analysis, we evaluated the association between baseline WMHv and cardiovascular events during follow-up in the overall sample. MethodsThe primary outcome was the same as SPRINT, a composite of stroke, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, or cardiovascular death. We fit Cox models to the primary outcome and report adjusted hazard ratios (HR) for log-transformed WMHv and quartiles of WMHv. ResultsAmong 717 participants, the median (IQR) baseline WMHv was 1.62 (0.66–3.98) mL. The primary outcome occurred in 51/719 (7.1%). The median WMHv was higher in patients with the primary outcome (3.40 mL versus 1.56 mL, p < 0.001). In adjusted models, WMHv as a log-transformed continuous variable was associated with the primary outcome (HR 1.44, 95% CI 1.15–1.80). The highest quartile of WMHv, compared to the lowest, was also independently associated with the primary outcome (HR 3.21, 95% CI 1.27–8.13). ConclusionsWe found that the baseline volume of WMH was associated with future CVD risk in SPRINT MIND. Prospective clinical trials with larger sample sizes than the current study are needed to determine whether intensive BP lowering can reduce the high cardiovascular risk in patients with WMH.

Lacunar Stroke Lesion Extent and Location and White Matter Hyperintensities Evolution 1 Year Post-lacunar Stroke.

Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [n = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, P = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, P = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, P = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale (n = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ P ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [n = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.