Total White Matter Hyperintensities Volume Research Articles

White Matter Hyperintensity Burden Is Associated With Hippocampal Subfield Volume in Stroke.

White matter hyperintensities of presumed vascular origin (WMH) are a prevalent form of cerebral small-vessel disease and an important risk factor for post-stroke cognitive dysfunction. Despite this prevalence, it is not well understood how WMH contributes to post-stroke cognitive dysfunction. Preliminary findings suggest that increasing WMH volume is associated with total hippocampal volume in chronic stroke patients. The hippocampus, however, is a complex structure with distinct subfields that have varying roles in the function of the hippocampal circuitry and unique anatomical projections to different brain regions. For these reasons, an investigation into the relationship between WMH and hippocampal subfield volume may further delineate how WMH predispose to post-stroke cognitive dysfunction. In a prospective study of acute ischemic stroke patients with moderate/severe WMH burden, we assessed the relationship between quantitative WMH burden and hippocampal subfield volumes. Patients underwent a 3T MRI brain within 2–5 days of stroke onset. Total WMH volume was calculated in a semi-automated manner. Mean cortical thickness and hippocampal volumes were measured in the contralesional hemisphere. Total and subfield hippocampal volumes were measured using an automated, high-resolution, ex vivo computational atlas. Linear regression analyses were performed for predictors of total and subfield hippocampal volumes. Forty patients with acute ischemic stroke and moderate/severe white matter hyperintensity burden were included in this analysis. Median WMH volume was 9.0 cm3. Adjusting for intracranial volume and stroke laterality, age (β = −3.7, P < 0.001), hypertension (β = −44.7, P = 0.04), WMH volume (β = −0.89, P = 0.049), and mean cortical thickness (β = 286.2, P = 0.006) were associated with total hippocampal volume. In multivariable analysis, age (β = −3.3, P < 0.001) and cortical thickness (β = 205.2, P = 0.028) remained independently associated with total hippocampal volume. In linear regression for predictors of hippocampal subfield volume, increasing WMH volume was associated with decreased hippocampal-amygdala transition area volume (β = −0.04, P = 0.001). These finding suggest that in ischemic stroke patients, increased WMH burden is associated with selective hippocampal subfield degeneration in the hippocampal-amygdala transition area.

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions—a neuroimaging marker of ICAS—and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden—defined as the number of vessel wall lesions—was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12–2.43), lacunes (RR = 1.45; 95% CI: 1.14–1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13–1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02–0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.

The Impact of Strategic White Matter Hyperintensity Lesion Location on Language

The impact of white matter hyperintensities (WMH) on language possibly depends on lesion location through disturbance of strategic white matter tracts. We examined the impact of WMH location on language in elderly Asians. Cross-sectional. Population-based. Eight-hundred nineteen residents of Singapore, ages (≥65 years). Clinical, cognitive and 3T magnetic resonance imaging assessments were performed on all participants. Language was assessed using the Modified Boston Naming Test (MBNT) and Verbal Fluency (VF). Hypothesis-free region-of-interest-based (ROI) analyses based on major white matter tracts were used to determine the association between WMH location and language. Conditional dependencies between the regional WMH volumes and language were examined using Bayesian-network analysis. ROI-based analyses showed that WMH located within the anterior thalamic radiation (mean difference: -0.12, 95% confidence interval [CI]: -0.22; -0.02, p = 0.019) and uncinate fasciculus (mean difference: -0.09, 95% CI: -0.18; -0.01, p = 0.022) in the left hemisphere were significantly associated with worse VF but did not survive multiple testing. Conversely, WMH volume in the left cingulum of cingulate gyrus was significantly associated with MBNT performance (mean difference: -0.09, 95% CI: -0.17; -0.02, p = 0.016). Bayesian-network analyses confirmed the left cingulum of cingulate gyrus as a direct determinant of MBNT performance. Our findings identify the left cingulum of cingulate gyrus as a strategic white matter tract for MBNT, suggesting that language - is sensitive to subcortical ischemic damage. Future studies on the role of sporadic ischemic lesions and vascular cognitive impairment should not only focus on total WMH volume but should also take WMH lesion location into account when addressing language.

High white matter hyperintensity burden in strategic white matter tracts relates to worse global cognitive performance in community-dwelling individuals

BackgroundWhite matter hyperintensities (WMH) are associated with cognitive impairment. The impact of WMH on cognitive domains (e.g. processing speed, executive functioning) depends on location. We determined whether the relevance of WMH location also applies to global cognitive functioning by testing if WMH in strategic white matter tracts are associated with global cognitive functioning independent of total WMH burden. MethodsWe included 830 community-dwelling individuals. WMH volume within two a priori specified strategic white matter tracts (forceps minor and anterior thalamic radiation) were entered in a linear regression model with the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) as outcome variables and corrected for total WMH volume and other MRI markers for vascular injury and neurodegenerations (i.e. brain parenchymal fraction, and the presence of lacunes and microbleeds). ResultsWMH in the forceps minor and left anterior thalamic radiation inversely correlated with MoCA, and WMH in the forceps minor inversely correlated with MMSE, independent of total WMH volume and other MRI markers. ConclusionThe impact of WMH on global cognitive functioning depends on location. Whether this reflects accumulated impairment in isolated cognitive domains or disruption of a network that is crucially involved in global cognitive performance remains to be determined.

Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease.

Small vessel cerebrovascular dysfunction that manifests on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH) is linked to increased risk and progression of Alzheimer's disease (AD), but there is considerable debate about whether it represents a core feature of the disease. Parental history of dementia is a risk factor for AD, suggesting a strong heritable component; the examination of the extent to which parental history of dementia is associated with cerebrovascular disease could provide insight into the aggregation of AD and cerebrovascular disease. This study included 481 community-dwelling older adults (mean age = 74.07 ± 5.81; 56% women) with available MRI scans. Participants were classified as having a parental history of dementia or having no parental history based on self-report. Total WMH values were calculated and compared between the two groups with general linear models, adjusting for relevant covariates. We also compared WMH volume between those with a reported sibling history of dementia and those without. One hundred twelve participants reported having a parental history of dementia and 369 reported no parental history. Those with parental history had greater total WMH volume than those without (F = 4.17, p = .042, partial η 2 = 0.009). Results were strongest for those with maternal versus paternal history (F = 2.43, p = .089, partial η 2 = 0.010 vs <0.001) and among Hispanic (F = 5.57, p = .020, partial η 2 = 0.038) and non-Hispanic White participants (F = 4.17, p = .042, partial η 2 = 0.009). Those with reported sibling history of dementia did not differ from those without. Older adults with parental, particularly maternal, history of dementia have increased WMH. The results highlight the possibility that cerebrovascular changes are a core feature of AD, as WMH severity and parental history aggregate together.

Periodicity of cerebral flow velocity during sleep and its association with white-matter hyperintensity volume

Impaired sleep-related activation of the cerebral waste-clearance system might be related with the brain aging process. We hypothesized that cerebral blood-flow pattern changes during sleep might reflect the activation of the cerebral waste-clearance system and investigated its association with the cerebral white-matter hyperintensity (WMH) volume. Fifty healthy volunteers were prospectively recruited. In addition to the baseline transcranial Doppler parameters, the mean flow velocity (MFV) of the middle cerebral artery was monitored during waking and short-term non-REM sleep. Spectral density analysis was performed to analyze the periodic MFV variation patterns. For the aged subgroup (>50 years, n = 25), the WMH volumes in the total, subcortical, and periventricular regions were measured. The MFV periodic pattern during sleep was substantially augmented over that in the waking status. Spectral density analysis of MFV showed a noticeable peak in the very-low–frequency (VLF) band during sleep status (sleep/waking ratio 2.87 ± 2.71, P < 0.001). In linear regression analysis in the aged subgroup, the sleep/waking ratio of the VLF peak was inversely associated with total (P = 0.013) and subcortical (P = 0.020) WMH volumes. Sleep-related amplification of the cerebral flow-velocity periodicity might reflect the activation of cerebral waste clearance system during sleep, and be related to the pathogenesis of cerebral WMH.

APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia.

ObjectiveTo determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).MethodsA total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.ResultsA significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only.ConclusionAPOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.

Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume.

White matter hyperintensities on T2-weighted MR imaging are typical in older adults and have been linked to several poor health outcomes, including cognitive impairment and Alzheimer disease. The presence and severity of white matter hyperintensities have traditionally been attributed to occlusive arteriopathy, but recent evidence also implicates deep medullary venule collagenosis and associated vasogenic edema. Historically, postmortem analyses have been the sole way to analyze cerebral veins, but SWI can be now used to examine cortical veins in vivo. The aim of the current study was to determine whether there is an association between the diameters of the large draining cerebral veins/sinuses and white matter hyperintensity volume. T2-weighted FLAIR and SWI were performed in 682 older adults without dementia (mean age, 73.9 ± 5.9 years; 59.1% women). Total and regional white matter hyperintensity volume was derived. We measured the diameters of 5 regions of the cerebral venous draining system: internal cerebral veins, basal veins of Rosenthal, superior sagittal sinus, vein of Galen, and straight sinus terminus. Increased diameter of the internal cerebral veins was associated with greater total white matter hyperintensity volume (β = 0.09, P = .02) and regionally in the parietal (β = 0.10, P = .006), frontal (β = 0.09, P = .02), and temporal (β = 0.09, P = .02) lobes. Increased diameter of the basal veins of Rosenthal was associated with greater total (β = 0.10, P = .01), frontal (β = 0.11, P = .003), and temporal (β = 0.09, P = .02) white matter hyperintensity volume. Our results suggest that the caliber of the internal cerebral veins and of the basal veins of Rosenthal relates to regional white matter disease.

Contribution of acute infarcts to cerebral small vessel disease progression.

ObjectiveTo determine the contribution of acute infarcts, evidenced by diffusion‐weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.MethodsWe performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high‐resolution multishell DWI, and 3‐dimensional fluid‐attenuated inversion recovery, T1, and susceptibility‐weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.ResultsWe identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow‐up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow‐up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005–0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow‐up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.InterpretationDWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one‐third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582–592

P2‐410: A RISK FACTOR PROFILE OF INCREASED WHITE MATTER HYPERINTENSITY BURDEN IN THE ABERDEEN CHILDREN OF THE NINETEEN FIFTIES COHORT

The Aberdeen Children of the Nineteen Fifties (ACONF) is a well-characterised cohort of healthy, community-dwelling individuals, born in Aberdeen, Scotland (UK) between 1950 and 1956. This rich source of data allows us to investigate early- and mid-life risk factors for poor health in later life. Recently, subgroup of this cohort underwent brain magnetic resonance imaging (MRI), as well as health and neuropsychological assessments. Here, we aimed to utilise these life-course data to identify risk-factors for increased brain white matter hyperintensity (WMH) burden: a common MRI finding in older adults, associated with cognitive decline, dementia, stroke and death. We calculated the relative risk (RR) of certain factors on increased global WMH burden in 277 cognitively healthy ACONF participants (mean age = 62.3). Global WMH burden was measured as total WMH volume (ml) using an automated WMH segmentation algorithm. We investigated potential risk factors within the domains of demographics, early-life, medical history, socioeconomic circumstance, late-life objective health, and late-life cognition. We identified elevated risk factors for increased global WMH burden among each domain mentioned above. The most significant risk factors for increased WMH burden in this cohort included medical histories of stroke (RR = 2.642, 95% CI = 1.59 – 4.39), heart disease (RR = 1.864, 95% CI = 1.098 – 3.165), diabetes (RR = 1.903, 95% CI = 1.194 – 3.032), and high cholesterol (RR = 1.566, 95% CI = 1.077 – 2.277). Notable early- and mid-life risk factors approaching significance included birth weight of less than 5.5lbs (RR = 1.697, 95% CI = .913 – 3.153) and working in lower-income occupations (RR = 1.049, 95% CI = .715 – 1.538). We were able to confirm age and cardiometabolic risk factors for increased WMH burden in a relatively young cohort of older adults, and add contributions of emerging early and mid-life risk factors. Many of these cardiometabolic risk factors have their origins in early life and are greatest in those with the least resilience. Future work will involve developing a robust model of risk- and protective determinants of WMH burden.

Impact of white matter hyperintensity location on depressive symptoms in memory-clinic patients: a lesion–symptom mapping study

We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion–symptom mapping. We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumptionfree voxel-based lesion–symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis. Voxel-based lesion–symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (β = 0.26, p < 0.05), but not in mild cognitive impairment or dementia. We observed a lack of convergence of findings between voxel-based lesion–symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts. This lesion–symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity.

Magnetic Resonance Imaging of Cerebral Small Vessel Disease in Men Living with HIV and HIV-Negative Men Aged 50 and Above.

We assessed whether HIV status was associated with white matter hyperintensities (WMH), a neuroimaging correlate of cerebral small vessel disease (CSVD), in men aged ≥50 years. A cross-sectional substudy was nested within a larger cohort study. Virologically suppressed men living with HIV (MLWH) and demographically matched HIV-negative men aged ≥50 underwent magnetic resonance imaging (MRI) at 3 Tesla. Sequences included volumetric three-dimensional (3D) T1-weighted, fluid-attenuated inversion recovery and pseudocontinuous arterial spin labeling. Regional segmentation by automated image processing algorithms was used to extract WMH volume (WMHV) and resting cerebral blood flow (CBF). The association between HIV status and WMHV as a proportion of intracranial volume (ICV; log-transformed) was estimated using a multivariable linear regression model. Thirty-eight MLWH [median age 59 years (interquartile range, IQR 55-64)] and 37 HIV-negative [median 58 years (54-63)] men were analyzed. MLWH had median CD4+ count 570 (470-700) cells/μL and a median time since diagnosis of 20 (14-24) years. Framingham 10-year risk of cardiovascular disease was 6.5% in MLWH and 7.4% in controls. Two (5%) MLWH reported a history of stroke or transient ischemic attack and five (13%) reported coronary heart disease compared with none of the controls. The total WMHV in MLWH was 1,696 μL (IQR 1,229-3,268 μL) or 0.10% of ICV compared with 1,627 μL (IQR 1,032-3,077 μL), also 0.10% of ICV in the HIV-negative group (p = .43). In the multivariable model, WMHV/ICV was not associated with HIV status (p = .86). There was an age-dependent decline in cortical CBF [-3.9 mL/100 mL/min per decade of life (95% confidence interval 1.1-6.7 mL)] but no association between CBF and HIV status (p > .2 in all brain regions analyzed). In conclusion, we found no quantitative MRI evidence of an increased burden of CSVD in MLWH aged 50 years and older.

Abstract 49: White Matter Hyperintensity Spatial Pattern Variations reflect distinct Cerebral Small Vessel Disease Pathologies

Introduction: Cerebral small vessel disease (SVD) comprise of heterogeneous pathologies affecting small cerebral vessels. A novel phenotyping approach using etiology-based SVD imaging markers may improve discovery of SVD-related mechanisms. Topographical patterns seen in common SVD subtypes (hypertension-related (HTN) and cerebral amyloid angiopathy (CAA)) suggest that spatial location may reflect regionally different SVD pathology. We propose a machine-learning method leveraging spatial location information to partition WMH (a representative SVD imaging marker) into patterns that can discriminate underlying SVD pathology. Method: We selected subjects with WMH on FLAIR MRI from the Alzheimer’s Disease Neuroimaging Initiative database and created WMH segmentation maps using a custom deep learning algorithm. We performed voxel-based spectral clustering analysis on aligned WMH maps to group image voxels into clusters, maximizing within-group and minimizing between-group similarities. HTN-SVD risk was scored using serial blood pressure measurements and medication history. We quantified CAA risk using the Boston criteria. We used multivariable regression to evaluate extent to which different WMH clusters influenced CAA and HTN-SVD risks. Demographics and total WMH volume were included as covariates. Results: We analyzed 878 subjects; 39% were hypertensive, 4.4% had probable CAA. We observed partitioning of WMH into five distinct clusters, which demonstrate recognizable spatial distributions that suggest biological relevance (deep, periventricular, subcortical, anterior horns of lateral ventricles, posterior predominant). Multivariable regression models revealed independent associations of WMH clusters with CAA (posterior predominant WM; p=0.02; ß=0.63), and HTN-SVD (deep WM; p=0.01; ß=0.20). Conclusion: WMH occur in unique spatial patterns that reflect different underlying SVD pathology. WMH spatial pattern variations may serve as etiology-based SVD imaging markers, providing a critical new tool in efforts to resolve homogeneous disease mechanisms among heterogeneous disease presentations. Such strategy enhances genomic studies, allowing more comprehensive modelling of genetic effects on SVD pathogenesis.

Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease.

BackgroundWhite matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease.MethodsThe Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart. Both cross-sectional and longitudinal comparisons were made between composite scores in the domains of executive function, memory, and language, and Unified Parkinson's Disease Rating Scale (UPDRS) scores.ResultsWe found no difference between disease and control groups in total WMH volume or progression during the study. Greater regional and global WMH at baseline was more strongly associated with lower executive function in PD subjects than in controls. Increased regional WMH was also more strongly associated with impaired memory performance in PD relative to controls. Longitudinally, no associations between cognitive change and total or regional WMH progression were detected in either group. A positive relationship between baseline regional WMH and total UPDRS scores was present in the control group, but not PD. However, greater WMH increase was associated with a greater increase in UPDRS motor sub-scores in PD.ConclusionsThese findings suggest that although PD patients do not experience greater mean WMH load than normal aged adults, comorbid WMH do exacerbate cognitive and motor symptoms in PD.

Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment.

The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease.

To examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOEε2 allele. We included 36 β-amyloid-positive (by CSF or PET) APOEε2 carriers (all ε2/ε3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOEε3 homozygotes and APOEε4 carriers (70% ε3/ε4 and 30% ε4/ε4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between ε2 carriers, ε3 homozygotes, and ε4 carriers were assessed using analysis of variance analyses, and Pearson χ2 tests were used to examine differences in prevalence of microbleeds. We found that ε2 carriers performed worse on nonmemory domains compared to both ε3 homozygotes and ε4 carriers but better on memory compared to ε4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial-temporal structures in ε2 carriers compared to ε4 carriers. Finally, ε2 carriers had larger total white matter hyperintensity volumes compared to ε4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to ε3 homozygotes (37.5% vs 18.3%). APOEε2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.

The association between lacunes and white matter hyperintensity features on MRI: The SMART-MR study

Lacunes and white matter hyperintensities (WMHs) are features of cerebral small vessel disease (CSVD) that are associated with poor functional outcomes. However, how the two are related remains unclear. In this study, we examined the association between lacunes and several WMH features in patients with a history of vascular disease. A total of 999 patients (mean age 59 ± 10 years) with a 1.5 T brain magnetic resonance imaging (MRI) scan were included from the SMART-MR study. Lacunes were scored visually and WMH features (volume, subtype and shape) were automatically determined. Analyses consisted of linear and Poisson regression adjusted for age, sex, and total intracranial volume (ICV). Patients with lacunes (n = 188; 19%) had greater total (B = 1.03, 95% CI: 0.86 to 1.21), periventricular/confluent (B = 1.08, 95% CI: 0.89 to 1.27), and deep (B = 0.71, 95% CI: 0.44 to 0.97) natural log-transformed WMH volumes than patients without lacunes. Patients with lacunes had an increased risk of confluent type WMHs (RR = 2.41, 95% CI: 1.98 to 2.92) and deep WMHs (RR = 1.41, 95% CI: 1.22 to 1.62) and had a more irregular shape of confluent WMHs than patients without lacunes, independent of total WMH volume. In conclusion, we found that lacunes on MRI were associated with WMH features that correspond to more severe small vessel changes, mortality, and poor functional outcomes.

White matter hyperintensities are associated with falls in older people with dementia.

White Matter Hyperintensities (WMHs) are associated with impaired gait, balance and cognition and increased fall risk in cognitively healthy older people. However, few studies have examined such relationships in older people with dementia. Understanding the role of WMHs in falls may assist in developing effective fall prevention strategies. We investigated the relationship between baseline WMHs, cognitive and sensorimotor function and prospective falls in older people with dementia. Twenty-eight community-dwelling older people with mild-moderate dementia (MMSE 11-23; ACE-R < 83) underwent magnetic resonance imaging and assessment of sensorimotor and cognitive (global and processing speed) function at baseline. WMHs, were quantified using a fully automated segmentation toolbox, UBO Detector ( https://cheba.unsw.edu.au/group/neuroimaging-pipeline ). Falls were ascertained prospectively for 12-months using monthly calendars with the assistance of carers. The median age of the participants was 83years (IQR 77-86); 36% were female; 21 (75%) fell during follow-up. Using Generalized Linear Models, larger volumes of total WMHs were found to be significantly associated with poorer global cognitive and sensorimotor function. Using modified Poisson regression, total, periventricular and deep WMHs were each associated with future falls while controlling for age, sex, intracranial volume and vascular risk. Each standard deviation increase in total and periventricular WMH volume resulted in a 33% (RR 1.33 95%CI 1.07-1.66) and 30% (RR 1.30 95%CI 1.06-1.60) increased risk of falling, respectively. When the deep WMH volume z-scores were dichotomized at the median, individuals with greater deep WMH volumes had an 81% (RR 1.81 95% CI 1.02-3.21) increased risk of falling. WMHs were associated with poorer sensorimotor and cognitive function in people with dementia and total, periventricular and deep WMHs were associated with falls. Further research is needed to confirm these preliminary findings and explore the impact of vascular risk reduction strategies on WMHs, functional performance and falls.

Longitudinal changes in neuroimaging and neuropsychiatric status of post-deployment veterans: a CENC pilot study

ABSTRACTPrimary objective: The purpose of this study was to evaluate preliminary data on longitudinal changes in psychiatric, neurobehavioural, and neuroimaging findings in Iraq and Afghanistan combat veterans following blast exposure.Research design: Longitudinal observational analysis.Methods and procedures: Participants were invited to participate in two research projects approximately 7 years apart. For each project, veterans completed the Structured Clinical Interview for DSM-IV Disorders and/or the Clinician-Administered PTSD Scale, Neurobehavioral Symptom Inventory, and magnetic resonance imaging (MRI).Main outcomes and results: Chi-squared tests indicated no significant changes in current psychiatric diagnoses, traumatic brain injury (TBI) history, or blast exposure history between assessment visits. Wilcoxon signed-rank tests indicated significant increases in median neurobehavioural symptoms, total number of white matter hyperintensities (WMH), and total WMH volume between assessment visits. Spearman rank correlations indicated no significant associations between change in psychiatric diagnoses, TBI history, blast exposure history, or neurobehavioural symptoms and change in WMH.Conclusion: MRI WMH changes were not associated with changes in psychiatric diagnoses or symptom burden, but were associated with severity of blast exposure. Future, larger studies might further evaluate presence and aetiology of long-term neuropsychiatric symptoms and MRI findings in blast-exposed populations.

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology.

White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility. This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04). This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.