Influence Of White Matter Hyperintensities Research Articles

A composite measure of atrophy using volumetric T1‐weighted and T2‐FLAIR imaging using the Boundary Shift Integral

AbstractBackgroundWhole‐brain volume loss using T1‐weighted imaging is an established measurement of neurodegeneration. The Boundary Shift Integral (BSI) produces reliable metrics of longitudinal volume loss, used in research studies and clinical trials. With the increased acquisition of volumetric T2‐FLAIR imaging in studies, there is opportunity to produce atrophy metrics using a composite atrophy measure (T1‐weighted and T2‐FLAIR) that is more precise than either modality alone.MethodData from Alzheimer’s Disease Neuroimaging Initiative (ADNI3) were used. Volumetric T1 and T2‐FLAIR weighted imaging were obtained (n = 269), for baseline and follow‐up; Table 1. T1‐weighted images were bias corrected and underwent Geodesic Information Flow (GIF), producing probabilistic brain masks. Masks were resampled to T2‐FLAIR space. The BSI was performed on serial T1‐weighted (gBSI), and T2‐FLAIR (fBSI) separately. We tested differences by diagnosis (control (CN), mild cognitive impairment (MCI) and Alzheimer’s disease (AD)) between indirect volume change, gBSI, fBSI, and composite BSI, using linear regression and effect size. We further compared metric differences within diagnosis, using pairwise correlation, paired samples t‐test, and Pitman’s test of variance.ResultDemographic information is reported in Table 1. fBSI showed good Pearson’s correlation (r) with both gBSI (CN 0.7, p < 0.001; MCI 0.8, p < 0.001; AD 0.9, p < 0.001), and indirect change (CN 0.6, p < 0.001; MCI 0.6, < 0.001; AD 0.7, < 0.001). The composite BSI further showed good correlation with indirect change (CN 0.8, p < 0.001; MCI 0.8, p < 0.001; AD 0.8, 0.004). Mean values by diagnosis are shown in figure 1, along with paired samples t and variance tests. Pairwise comparisons reported in table 2, highlight good diagnostic group separation in all BSI metrics, with overall strong effect sizes for fBSI, composite BSI, and gBSI respectively.ConclusionCalculating atrophy using T2‐weighted imaging is possible using fBSI. This can be used in a composite atrophy measure using fBSI and gBSI. Both fBSI and composite BSI perform well with group separation, and with good correlations with classical atrophy metrics. Future work will explore the influence of White Matter Hyperintensities on BSI.

A composite measure of atrophy using volumetric T1‐weighted and T2‐FLAIR imaging using the Boundary Shift Integral

AbstractBackgroundWhole‐brain volume loss using T1‐weighted imaging is an established measurement of neurodegeneration. The Boundary Shift Integral (BSI) produces reliable metrics of longitudinal volume loss, used in research studies and clinical trials. With the increased acquisition of volumetric T2‐FLAIR imaging in studies, there is opportunity to produce atrophy metrics using a composite atrophy measure (T1‐weighted and T2‐FLAIR) that is more precise than either modality alone.MethodData from Alzheimer’s Disease Neuroimaging Initiative (ADNI3) were used. Volumetric T1 and T2‐FLAIR weighted imaging were obtained (n = 269), for baseline and follow‐up; Table 1. T1‐weighted images were bias corrected and underwent Geodesic Information Flow (GIF), producing probabilistic brain masks. Masks were resampled to T2‐FLAIR space. The BSI was performed on serial T1‐weighted (gBSI), and T2‐FLAIR (fBSI) separately. We tested differences by diagnosis (control (CN), mild cognitive impairment (MCI) and Alzheimer’s disease (AD)) between indirect volume change, gBSI, fBSI, and composite BSI, using linear regression and effect size. We further compared metric differences within diagnosis, using pairwise correlation, paired samples t‐test, and Pitman’s test of variance.ResultDemographic information is reported in Table 1. fBSI showed good Pearson’s correlation (r) with both gBSI (CN 0.7, p < 0.001; MCI 0.8, p < 0.001; AD 0.9, p < 0.001), and indirect change (CN 0.6, p < 0.001; MCI 0.6, < 0.001; AD 0.7, < 0.001). The composite BSI further showed good correlation with indirect change (CN 0.8, p < 0.001; MCI 0.8, p < 0.001; AD 0.8, 0.004). Mean values by diagnosis are shown in figure 1, along with paired samples t and variance tests. Pairwise comparisons reported in table 2, highlight good diagnostic group separation in all BSI metrics, with overall strong effect sizes for fBSI, composite BSI, and gBSI respectively.ConclusionCalculating atrophy using T2‐weighted imaging is possible using fBSI. This can be used in a composite atrophy measure using fBSI and gBSI. Both fBSI and composite BSI perform well with group separation, and with good correlations with classical atrophy metrics. Future work will explore the influence of White Matter Hyperintensities on BSI.

Independent and additive contribution of white matter hyperintensities and Alzheimer’s disease pathology to basal forebrain cholinergic system degeneration

ObjectivesDegeneration of the cholinergic basal forebrain nuclei (CBFN) system has been studied extensively in Alzheimer's disease (AD). White matter hyperintensities are a hallmark of aging as well as a common co-morbidity of AD, but their contribution to CBFN degeneration has remained unclear. Therefore, we explored the influence of white matter hyperintensities within cholinergic subcortical-cortical projection pathways on CBFN volumes and regional gray matter volumes in AD and age- and gender-matched controls. MethodsWe analyzed magnetic resonance images (MRI) from 42 patients with AD and 87 age- and gender-matched control subjects. We assessed the white matter hyperintensity burden within the cholinergic projection pathways using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and applied probabilistic anatomical maps for the analysis of CBFN volumes, i.e. the Ch1-3 compartment and the Ch4 cell group (nucleus basalis of Meynert), by diffeomorphic anatomical registration using exponentiated lie algebra analysis of voxel-based morphometry. Using multiple linear regression analyses, we explored correlations between regional gray matter volumes and the extent of white matter hyperintensities or CBFN volumes in both groups. ResultsIn AD, all CBFN volumes were significantly smaller than in controls, and white matter hyperintensity burden within the cholinergic projection pathways was not correlated with CBFN volume. In controls, white matter hyperintensity burden within the cholinergic projection pathways was inversely correlated with CBFN volume when corrected for sex and total intracranial volume, but this correlation was no longer significant after correction for age. Voxel-wise multiple linear regression analyses using threshold-free cluster enhancement revealed that in controls, cholinergic pathway hyperintensities correlated with gray matter loss in perisylvian areas, whereas the were no effects in AD. Moreover, we found that CBFN volumes correlated with distinct regional cortical atrophy patterns in both groups. ConclusionOur results indicate that white matter hyperintensities and AD pathology contribute independently but additively to the degeneration of cholinergic basal forebrain structures. Whereas AD is primarily associated with CBFN volume loss, cholinergic degeneration associated with white matter hyperintensities appears to involve disruption of cholinergic cortical projection fibers with less pronounced effects on CBFN volumes.

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<.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<.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.

Mild Parkinsonian Signs Are Related to Lower Cortico-Striatal Connectivity in Executive Networks

Mild Parkinsonian signs (MPS) affect up to 24% of community-dwelling older adults. We hypothesize that MPS are associated with Parkinson’s-like alterations of functional connectivity (FC) in sensorimotor, executive, and reward cortico-striatal networks. Participants (N=266; mean age=83; 57% female) without Parkinson’s completed resting-state fMRI and Unified Parkinsonian Disease Rating Scale (UPDRS). FC between striatum and cortex was measured within each network. Logistic regression tested associations of each network’s FC with MPS (UPDRS>0), adjusted for MPS risk factors, then including white matter hyperintensities (WMH). MPS was associated with lower cortical-striatal FC in the left executive cortico-striatal network (OR [95%CI]: 0.188 [0.043,0.824]). Association survived adjusting for risk factors (0.162 [0.030,0.874]) but was attenuated after including WMH (0.209 [0.036, 1.200]). In stratified analyses, left executive cortico-striatal FC was associated with MPS only for those with higher WMH (0.077 [0.010,0.599]). Future work should examine whether higher FC protects against the influence of WMH on MPS.

Influence of White Matter Hyperintensities on Baseline and Longitudinal Amyloid-β in Cognitively Normal Individuals.

The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42) pathology have not been well-elucidated. Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. This study included 72 subjects from the Alzheimer's Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between BL WMH/ICV and Aβ1-42 on memory and executive function. Mean age of the subjects (Nmales = 36) = 73.80 years, SD = 6.73; mean education years = 17.1, SD = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p = 0.008) and two-year change in Aβ1-42 (p = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p = 0.003). BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer's disease.

Abstract P323: Stroke Lesion Pattern-Specific Influence of White Matter Hyperintensities on Stroke Severity in Acute Ischemic Stroke

Introduction: MRI-detected white matter hyperintensity (WMH) burden is linked to the overall brain health and incident stroke outcomes. However, data are limited as to whether specific acute stroke lesion patterns purport greater stroke severity in patients with extensive pre-existing WMH. In this analysis, we sought to investigate lesion pattern-specific WMH effects on AIS severity. Methods: We analyzed clinical and lesion data from 621 AIS patients enrolled in the multi-site MRI-GENIE study. The acute NIHSS was modelled via Bayesian hierarchical regression. Using ten stroke lesion patterns, that served as input variables of main interest, we introduced a hierarchical level differentiating between patients with higher and lower than median WMH volume (WMHv). Lesion pattern posterior distributions for higher and lower WMHv patients were subtracted to infer substantial differences. Results: In this AIS cohort [age: 65.3±14.6, 60% male], a higher WMHv was associated with greater stroke severity only when specific left-hemispheric brain regions were infarcted. This “lesion pattern 3” was mainly characterized by left middle and inferior frontal gyrus, insular and opercular cortex, pre- and post-central gyrus, and subcortical basal ganglia regions ( Fig ). Conclusions: Higher WMH burden appears to enhance the detrimental effect of acute stroke lesions involving left-hemispheric brain regions underlying language and motor functions. This effect might be due to an exacerbated disruption of functional network integrity by the combination of WMH and stroke lesions and could be explored further in functional imaging studies that simultaneously considered information from both lesion types.

Epidemiology of MRI-defined vascular depression: A longitudinal, community-based study in Korean elders

BackgroundThere are no cross-sectional or longitudinal epidemiological studies present on MRI-defined vascular depression in community populations. The purpose of this study was to estimate the prevalence rates of both vascular and non-vascular late life depression (LLD) at baseline, to examine the natural course of LLD, and to investigate the influence of White matter hyperintensities (WMHs) on depression after three years. MethodThe baseline study employed a two-stage design, Phase I population survey (n=783) and Phase II diagnostic evaluation (n=122). In the 3-year follow-up study, baseline participants completing the second phase were reassessed with the same methodology. WMHs severity was rated visually by the modified Fazekas scale and WMHs volume was calculated using an automated method. ResultsThe prevalence rates of vascular major depressive disorder (MDD) and vascular non-major depressive disorder (nMDD) were 2.39% (56.2% of MDD) and 4.24% (34.0% of nMDD). Subjects with a score of 2 or more on the modified Fazekas scale in either deep white matter hyperintensities or subcortical gray matter ratings had an 8.1 times greater risk of developing a depressive disorder in the 3-year follow-up study. Greater Log WMHs volume (odds ratio=5.78, 95% CI, 1.04–31.72) at baseline was an independent predictor for depressive disorder in the 3-year assessment. LimitationsResponse rate and follow-up rate were relatively low. ConclusionsVascular depression is common and makes up about a half of MDD in elders. Greater WMHs severity is a crucial factor predicting future depression risk, which supports the previous vascular depression hypothesis.

To Exclude or Not To Exclude: Further Examination of the Influence of White Matter Hyperintensities in Diffusion Tensor Imaging Research

White matter hyperintensities (WMHIs) visible on magnetic resonance imaging (MRI) are common in both healthy adults and in those with medical or psychiatric problems. A practical methodological issue for diffusion tensor imaging (DTI) researchers is whether to include, or exclude, participants from a control group who have WMHIs. The aim of this study was to compare the influence of WMHIs on whole-brain DTI in trauma control subjects. Participants were 48 patients (no-WMHIs, n=36; 2+WMHIs, n=12) prospectively recruited from the Emergency Department of Vancouver General Hospital (British Columbia, Canada). Participants completed an MRI brain scan at 6-8 weeks postinjury (mean, 47.3 days; standard deviation [SD], 6.2; range, 39-66). DTI was used to examine the integrity of white matter (WM) in 50 regions of the brain using measures of fractional anisotropy (FA), and mean (MD), radial (RD), and axial (AD) diffusivity. FA values that were >2 SDs below the mean, and MD, RD, and AD values that were >2 SDs above the mean, were classified as "abnormal scores" indicative of reduced WM integrity. In the entire sample, the 2+WMHI group had a greater number of abnormal FA, MD, and RD scores, compared to the no-WMHI group (p<0.015 and Cohen's d >0.82, indicating large to very large effect sizes, for all comparisons). When controlling for the effects of age using a matched-groups design, the 2+WMHI group still had a significantly greater number of abnormal FA, MD, and RD scores, compared to the no-WMHI group (all p<0.012, all d >0.89, large to very large effect sizes). Researchers should be aware that the inclusion or exclusion of subjects with incidental WMHIs will influence the results of DTI studies.

2649 – White matter hyperintensities are an independent predictor of future depressive disorders: 3-year results from epidemiological study of vascular depression in korean elderly

The purposes of this study were to estimate the prevalence rates of subtypes of late life depression (LLD) including (vascular depression and non-vascular depression) in the baseline study, to examine the natural course of LLD and to investigate influence of white matter hyperintensities (WMH) volume on depression and neurocognitive function in the 3-year follow-up study. WMH was rated by the modified Fazekas scale and the volume of WMH was also calculated by an automated quantification method. Patients were classified as having vascular depression if they suffered from any type of depressive disorders and had a score of 2 or more on either deep white matter hyperintensity or subcortical gray matter ratings. In the 3- year follow-up study, the participants of the in the baseline were follow-uped with the same methodology of the baseline study. The prevalence rates of vascular major depressive disorder (MDD) and vascular non-major depressive disorder (nMDD) were 2.39% (53.6% of MDD) and 4.24% (34.0% of nMDD), respectively, in the baseline study. Among non-depressive group in the baseline study, subjects with WMH(+) had 13.5 times (OR=13.5, 95% CI=1.10-165.97) risk of developing depressive disorder in the 3-year follow-up study, as compared to those without WMH(+). Log WMH volume (OR=5.78, 95 CI=1.04-31.72) in the baseline study was an independent predictor for depressive disorder in the 3-year follow-up study WMH is a crucial predictor for future depressive disorder, which supports the previous vascular depression hypothesis. Vascular depression is a useful construct accounting for clinical characteristics of LLD.

White matter hyperintensities and quality of life in acute lacunar stroke

White matter hyperintensities (WMH) are common in stroke. The influence of WMH on health-related quality of life (HRQoL) following a lacunar stroke is unknown. This study evaluated the impact of WMH on HRQoL in acute lacunar stroke. A cohort of 160 patients with acute lacunar stroke admitted to the stroke unit of a university-affiliated regional hospital in Hong Kong was recruited. Three months after the index stroke, a research assistant administered the Short Form-36 (SF-36) to assess HRQoL. The severity of WMH was evaluated with magnetic resonance imaging (MRI). In univariate analysis, the severity of deep WMH (DWMH) negatively correlated with patients' vitality (VT; p < 0.05), social function (SF; p < 0.001), role-emotional (RE; p < 0.01), mental health (MH; p < 0.01), and mental component summary (MCS; p < 0.001) scores of HRQoL. DWMH was independently associated with all of the above five SF-36 scores (p < 0.05) in linear regression analysis. These findings suggest that DWMH has a significant impact on the HRQoL of stroke survivors. The importance of DWMH in the long-term HRQoL in lacunar stroke warrants further investigation.

White Matter Hyperintensities Are an Independent Predictor of Physical Decline in Community-Dwelling Older People

Background: Ageing is associated with physical disability, but little is known about the influence of white matter hyperintensities (WMHs) on physical function decline in older people. Objective: To investigate the role of WMHs as a predictor of decline in physical function in cognitively intact older people. Methods: 287 community-dwelling people aged 70–90 years underwent the Physiological Profile Assessment (PPA) and assessments of total and regional WMH volumes, cognitive function and comorbidities. Participants underwent reassessment of the PPA 12 months later, and those in the top quartile for increases in PPA scores over the year were regarded as having declined physically. Results: Multivariate logistic regression analyses revealed that people with WMH volumes in the 4th quartile showed greater physical decline (odds ratio 3.02, 95% confidence interval 1.02–8.95) while controlling for age, baseline physical function, general health, physical activity and cognitive function. Subsequent univariate analyses indicated that WMHs in the deep fronto-parietal and periventricular parieto-occipital regions had the strongest associations with physical decline. Conclusions: These findings indicate that WMHs are an independent predictor of decline in physical function and suggest that interventions that focus on preventing the development or progression of white matter lesions may help preserve physical function in older people.

Influence of White Matter Hyperintensities on the Cognition of Patients With Parkinson Disease

White matter hyperintensities (WMH) have been associated with cognitive impairment in elderly persons and in patients with Alzheimer disease. However, the role of WMH in Parkinson disease (PD) dementia remains to be elucidated. The cohort for this study comprised 71 consecutive patients with PD, all of whom completed a clinical assessment, neuropsychologic investigation, and magnetic resonance imaging of brain. WMH were rated using the semiquantitative visual rating system proposed by Scheltens et al. The PD dementia group had significantly more WMH than the PD without dementia group in the evaluated brain regions except for the infratentorial area. The WMH showed a significant correlation with age, Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, sum of the box of Clinical Dementia Rating, and many of the cognitive domains. The linear regression model showed that the WMH was independently associated with cognitive impairment in patients with PD, regardless of age, sex, duration or severity of PD symptoms, and vascular risk factors. These findings confirm that WMH might be associated with cognitive decline in patients with PD, regardless of age, sex, education status, duration or severity of PD symptoms, and vascular risk factors. This result suggests that other nonvascular factors contribute to the progression of dementia in patients with PD.

Construction of periventricular white matter hyperintensity maps by spatial normalization of the lateral ventricles

Subcortical and periventricular white matter hyperintensities (WMHs) may have different associations with cognition and pathophysiology. The aim of the present study is to develop an automated method for construction of periventricular WMH maps that enables the analysis of between-group differences in WMH location and characteristics in the periventricular region without the requirement of prior boundary definition. To avoid influence of WMHs on spatial normalization, a reference image of the lateral ventricles was constructed based on images of 24 subjects. Construction was not biased to a single subject. WMHs were segmented by k-nearest neighbor-based classification of magnetic resonance inversion recovery and fluid attenuated inversion recovery images. Cerebrospinal fluid segmentations of individual subjects were nonrigidly mapped to the reference image of the lateral ventricles. The subject's WMHs were transformed to the reference space accordingly. Spatial normalization accuracy was validated using measures of overlap and of displacement relative to the boundary of the lateral ventricles. After spatial normalization, the boundaries of the lateral ventricles closely matched the reference image and in an area of approximately 1 cm around the lateral ventricles the relative displacement was less than 1 mm. To illustrate the method, it was applied to 61 patients with Type 2 diabetes and 26 control subjects, whereupon periventricular WMH maps were constructed and compared. The proposed method is particularly suited to analyze WMH distribution differences at the level of the lateral ventricles between large groups of patients.

Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear. Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression. 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance. PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

The influence of white matter hyperintensities on the clinical features of Parkinson's disease.

This study was designed to investigate the influence of white matter hyperintensities (WMH) on clinical features of Parkinson's disease (PD) patients. The study subjects were 44 patients with PD who took a brain MRI. The severity of Parkinsonian symptoms was assessed in both 'on' and 'off' states, using the UPDRS-motor score. Thirteen patients (30%) showed WMH. The patients with WMH were significantly older than those without WMH (67 +/- 5.7 vs 60 +/- 6.4 years). In both 'off' and 'on' states, the gait scores were significantly higher in patients with WMH than in those without WMH (1.6 +/- 0.18 vs 1.1 +/- 0.12, P < 0.05), but other motor symptom (tremor, bradykinesia, rigidity) scores between the two patient groups were not statistically different. After taking a single dose of oral levodopa/benserazide (200mg/50mg), the patients with WMH showed significantly less improvement in bradykinesia score than those without WMH (25 +/- 4.1% vs 40 +/- 4.0%, P < 0.05), but the improvements in other symptoms were comparable between the two groups. These results suggest that WMH on MRI may influence Parkinsonian motor symptoms, particularly gait symptom and levodopa-responsiveness to bradykinesia symptom.