Brain atrophy and white matter hyperintensities in early Parkinson's disease

The purpose of this research was to examine the extent of global brain atrophy and white matter hyperintensities (WMH) in early Parkinson's disease (PD) compared to normal controls (NC), to explore the relationship between the MRI variables and cognition in PD. In this multicenter study we included 155 PD patients (age 65.6 ± 9.1 years, disease duration 26.7 ± 19.9 months) and 101 age‐matched NC. On 3D‐T1‐WI, we calculated normalized brain volumes using SIENAX software. WMH volumes were assessed semiautomatically. In PD patients, correlation and regression analyses investigated the association between atrophy and WMH outcomes and global, attention‐executive, visuospatial, and memory cognitive functions. Regression analysis was controlled for age, education, depression score, motor severity, cerebrovascular risk, and sex. No significant MRI variable volume group differences were found. The models did not retain any of the imaging variables as significant predictors of cognitive impairment. There was no evidence of brain atrophy or higher WMH volume in PD compared to NC, and MRI volumetric measurements were not significant predictors of cognitive functions in PD patients. We conclude that global structural brain changes are not a major feature in patients with incident PD. © 2009 Movement Disorder Society     

Linking cortical atrophy to white matter hyperintensities of presumed vascular origin

We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46–76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness (p = 0.009) after controlling for covariates. This association was found for periventricular WMH (p = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.     

Beware of white matter hyperintensities causing systematic errors in FreeSurfer gray matter segmentations!

Volumetric estimates of subcortical and cortical structures, extracted from T1‐weighted MRIs, are widely used in many clinical and research applications. Here, we investigate the impact of the presence of white matter hyperintensities (WMHs) on FreeSurfer gray matter (GM) structure volumes and its possible bias on functional relationships. T1‐weighted images from 1,077 participants (4,321 timepoints) from the Alzheimer''s Disease Neuroimaging Initiative were processed with FreeSurfer version 6.0.0. WMHs were segmented using a previously validated algorithm on either T2‐weighted or Fluid‐attenuated inversion recovery images. Mixed‐effects models were used to assess the relationships between overlapping WMHs and GM structure volumes and overall WMH burden, as well as to investigate whether such overlaps impact associations with age, diagnosis, and cognitive performance. Participants with higher WMH volumes had higher overlaps with GM volumes of bilateral caudate, cerebral cortex, putamen, thalamus, pallidum, and accumbens areas (p < .0001). When not corrected for WMHs, caudate volumes increased with age (p < .0001) and were not different between cognitively healthy individuals and age‐matched probable Alzheimer''s disease patients. After correcting for WMHs, caudate volumes decreased with age (p < .0001), and Alzheimer''s disease patients had lower caudate volumes than cognitively healthy individuals (p < .01). Uncorrected caudate volume was not associated with ADAS13 scores, whereas corrected lower caudate volumes were significantly associated with poorer cognitive performance (p < .0001). Presence of WMHs leads to systematic inaccuracies in GM segmentations, particularly for the caudate, which can also change clinical associations. While specifically measured for the Freesurfer toolkit, this problem likely affects other algorithms.     

Lesion probability maps of white matter hyperintensities in elderly individuals

Objective White matter hyperintensities (WMH) are common on brain MRI of the elderly. Their size ranges from punctate to early confluent to confluent lesions. While this increase in extension is frequently seen as evidence for a continuum of changes, histological data and clinical follow-up suggest differences in underlying pathology and their progression. Methods We tested this hypothesis by exploring the distributions of punctuate and confluent lesions using lesion probability maps (LPM) generated from MRI scans of 189 participants (mean age 60.8+/−6.2 years) in the Austrian Stroke Prevention Study. We dichotomised WMH according to the classification by Fazekas et al. [punctate (n=143) vs. early confluent and confluent (n=33)] to run voxel-based t-tests using permutation-based nonparametric inference. To test alternative hypotheses, we created similar LPM for age and arterial hypertension. Results We observed significant differences in the spatial distribution of lesions for the two WMH groups (p<0.01). Punctate lesions were more diffusely distributed throughout the cerebral white matter (peak probability ∼5%) relative to confluent lesions (peak probability 45%). Confluent lesions had greatest likelihood of being found in perfusion “watershed” regions. These differences in distribution could not be explained by differences in age or hypertension only, as both greater age and the diagnosis of hypertension were associated with WMH abutting the occipital horns. Conclusions Punctate and early confluent to confluent WMH show distinguishable differences in their spatial distribution within a normal elderly population. The pattern of punctate WMH is probably a consequence of mixed etiologies. Preferential localization of the more confluent WMH with arterial watershed areas implies a stronger ischemic component in their development. Received in revised form: 31 October 2005     

Brain perfusion correlates of medial temporal lobe atrophy and white matter hyperintensities in mild cognitive impairment

Abstract Objective To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI). Methods 56 MCI patients (age = 69.3 ± 7.0, 32 females) underwent brain MR scan and ^99mTc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates. Results MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus. Conclusions MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.     

White matter hyperintensities and chronicity of depression

OBJECTIVE: White matter hyperintensities (WMHs) on T(2)-weighted magnetic resonance imaging (MRI) of the brain are associated with advanced age and late-life depression. Most investigations predominantly found these lesions in frontal lobe and basal ganglia supporting the hypothesis of a fronto-striatal dysfunction in depression. A prospective study was undertaken to investigate the association between extent of WMHs and clinical outcome in elderly depressed patients. METHODS: Thirty-one non-demented depressed subjects underwent a 1.5 T cranial MRI scan. The MRI scans were analysed in consensus by two experienced radiologists. Each MRI scan was assessed for presence and extent of WMHs, which are differentiated in periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs). A total of 21 patients of the original cohort of 31 patients were re-assessed 5 years after baseline assessment. We ascertained the severity of depressive symptoms, the longitudinal course of depression, the cognitive decline and the global assessment of functioning at follow-up visit. RESULTS: (1) Subjects with greater extent of WMHs had a significant higher Hamilton Depression Rating Scale (HAM-D) score, (2) had more severe longitudinal courses of depression (3) and had a lower Mini-Mental State Examination (MMSE) score. CONCLUSIONS: WMHs on MRI are associated with poorer outcome in elderly depressed subjects. Further studies are needed to evaluate WHMs as prognostic factor for an appropriate treatment decision-making.     

Longitudinal increase in the volume of white matter hyperintensities in late-onset depression

BACKGROUND: Cerebrovascular disease is thought to play a role in the pathogenesis of geriatric major depression. One finding supporting such a "vascular depression" is the increased neuropathology in the form of white matter hyperintensities (WMH) found in patients diagnosed with a late-onset depression. However, at present there is little evidence that a longitudinal increase in WMH burden within an individual is associated with the onset of a late-life depression. METHODS: This study examined three-year longitudinal change in WMH volume and in cognition in: (a) an older man who developed his first episode of major depression during the study period, and (b) a comparison group of twelve older individuals who remained depression free. All subjects received at baseline and three years later a structural magnetic resonance imaging (MRI) using fast-FLAIR technology. The images were analyzed with semi-automated computerized software to obtain WMH volumes. Subjects also received at both time points the Mini Mental State Exam (MMSE) as well a series of cognitive tasks assessing executive abilities (verbal fluency, Trail Making Test and Stroop test) since executive dysfunction is thought to be characteristic of a vascular depression. RESULTS: The individual who became depressed during the followup showed an increase in WMH volume that exceeded the 95% Confidence Intervals (CI) for change in the comparison group. This individual also showed a similar decline on the measures of executive function but not on the MMSE. CONCLUSIONS: These results are consistent with cerebrovascular disease being a factor in the pathogenesis of late-onset depression (i.e. "vascular depression").     

High prevalence of white matter hyperintensities in normal aging: relation to blood pressure and cognition

The occurrence of cerebral white matter hyperintensities (WMHs), and their associations with blood pressure, episodic memory, and other cognitive tasks, were examined in a population-based sample of 123 individuals between 64 and 74 years old. Magnetic Resonance Imaging (MRI) detected subcortical and periventricular hyperintensities in 90% and 67% of the cases, respectively. Subcortical WMHs were related to elevated diastolic blood pressure measured ten years earlier, and periventricular WMHs were related to elevated diastolic blood pressure measured five and ten years earlier. Subcortical hyperintensities were weakly associated with impaired motor speed, but this association was not significant. Periventricular WMHs had a negative effect on episodic memory, although the relation was not linear. Collectively, the notion that white matter hyperintensities impair cognitive function got weak support in this Swedish sample.     

SIENA‐XL for improving the assessment of gray and white matter volume changes on brain MRI

In this article, SIENA‐XL, a new segmentation‐based longitudinal pipeline is introduced, for: (i) increasing the precision of longitudinal volume change estimation for white (WM) and gray (GM) matter separately, compared with cross‐sectional segmentation methods such as SIENAX; and (ii) avoiding potential biases in registration‐based methods when Jacobians are used, with a smoothing extent larger than spatial scale between tissue‐interfaces, which is where atrophy usually occurs. SIENA‐XL implements a new brain extraction procedure and a multi‐time‐point intensity equalization step before performing the final segmentation that also includes separate segmentation of deep GM structures by using FMRIB's Integrated Registration and Segmentation Tool. The detection of GM and WM volume changes with SIENA‐XL was evaluated using different healthy control (HC) and multiple sclerosis (MS) MRI datasets and compared with the traditional SIENAX and two Jacobian‐based approaches, SPM12 and SIENAX‐JI (a version of SIENAX including Jacobian integration ‐ JI). In scan‐rescan data from HCs, SIENA‐XL showed: (i) a significant decrease in error, of 50–70% when compared with SIENAX; (ii) no significant differences in error when compared with SIENAX‐JI and SPM12 in a scan‐rescan HC dataset that included repositioning. When tested in a HC dataset with scan‐rescan both at baseline and after 1 year of follow‐up, SIENA‐XL showed: (i) significantly higher precision (P < 0.01) than SIENAX; (ii) no significant differences to SIENAX‐JI and SPM12. Finally, in a dataset of 79 MS patients with a 2 years follow‐up, SIENA‐XL showed a substantial reduction of sample size, by comparison with SIENAX, SIENAX‐JI, and SPM12, for detecting treatment effects of 25, 30, and 50%. Hum Brain Mapp 39:1063–1077, 2018. © 2017 Wiley Periodicals, Inc.     

Semisupervised white matter hyperintensities segmentation on MRI

This study proposed a semisupervised loss function named level‐set loss (LSLoss) for cerebral white matter hyperintensities (WMHs) segmentation on fluid‐attenuated inversion recovery images. The training procedure did not require manually labeled WMH masks. Our image preprocessing steps included biased field correction, skull stripping, and white matter segmentation. With the proposed LSLoss, we trained a V‐Net using the MRI images from both local and public databases. Local databases were the small vessel disease cohort (HKU‐SVD, n = 360) and the multiple sclerosis cohort (HKU‐MS, n = 20) from our institutional imaging center. Public databases were the Medical Image Computing Computer‐assisted Intervention (MICCAI) WMH challenge database (MICCAI‐WMH, n = 60) and the normal control cohort of the Alzheimer''s Disease Neuroimaging Initiative database (ADNI‐CN, n = 15). We achieved an overall dice similarity coefficient (DSC) of 0.81 on the HKU‐SVD testing set (n = 20), DSC = 0.77 on the HKU‐MS testing set (n = 5), and DSC = 0.78 on MICCAI‐WMH testing set (n = 30). The segmentation results obtained by our semisupervised V‐Net were comparable with the supervised methods and outperformed the unsupervised methods in the literature.     

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population

OBJECTIVE: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. METHODS: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. RESULTS: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. CONCLUSION: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.     

White matter integrity mediates the associations between white matter hyperintensities and cognitive function in patients with silent cerebrovascular diseases

ObjectiveTo evaluate the relationships between cognitive function and white matter hyperintensity volume (WMHV) in patients with silent cerebrovascular disease and to investigate whether white matter integrity or brain atrophy play a role in this association.MethodsAutomated Fiber Quantification and Voxel‐ based morphometry were used to track and identify the integrity of 20 well‐defined white matter tracts and to measure the gray matter volume (GMV). A linear regression model was applied for examining the associations between cognitive function and WMHV and mediation analysis was used to identify the roles of white matter integrity or GMV in the influence of WMHV on cognitive function.ResultsTwo hundred and thirty‐six individuals were included for analysis. Executive function was linearly associated with fractional anisotropy (FA) of the right interior frontal occipital fasciculus (IFOF) (β = 0.193; 95% CI, 0.126 to 1.218) and with WMHV (β = −0.188; 95% CI, −0.372 to −0.037). Information processing speed was linearly associated with WMHV (β = −0.357; 95% CI, −0.643 to −0.245), FA of the right anterior thalamic radiation (ATR) (β = 0.207; 95% CI, 0.116 to 0.920), and FA of the left superior longitudinal fasciculus (SLF) (β = 0.177; 95% CI, 0.103 to 1.315). The relationship between WMHV and executive function was mediated by FA of the right IFOF (effect size = −0.045, 95% CI, −0.015 to −0.092). Parallel mediation analysis showed that the association between WMHV and information processing speed was mediated by FA of the right ATR (effect size = −0.099, 95% CI, −0.198 to −0.038) and FA of the left SLF (effect size = −0.038, 95% CI, −0.080 to −0.003).ConclusionThese findings suggest a mechanism by which WMH affects executive function and information processing speed by impairing white matter integrity. This may be helpful in providing a theoretical basis for rehabilitation strategies of cognitive function in patients with silent cerebrovascular diseases.     

The efficiency of the brain connectome is associated with cerebrovascular reactivity in persons with white matter hyperintensities

The purpose of this study was to determine the relationship between the organization of the brain connectome and cerebrovascular reactivity (CVR) in persons with white matter hyperintensities. Diffusion tensor and CVR mapping 3T MRI scans were acquired in 31 participants with white matter hyperintensities. In each participant, the connectome was assessed by reconstructing all white matter tracts with tractography and segmenting the whole brain into multiple regions. Graph theory analysis was performed to quantify how effectively tracts connected brain regions by measuring the global and local efficiency of the connectome. CVR in white matter and gray matter was correlated with the global and local efficiency of the connectome, while adjusting for age, gender, and gray matter volume. For comparison, white matter hyperintensity volume was also correlated with global and local efficiency. White matter CVR was positively correlated with the global efficiency (coefficient: 23.3, p = .005) and local efficiency (coefficient: 2850, p = .004) of the connectome. Gray matter CVR was positively correlated with the global efficiency (coefficient: 21.3, p < .001) and local efficiency (coefficient: 2670, p < .001) of the connectome. White matter hyperintensity volume was negatively correlated with global efficiency (coefficient: ?0.0002, p = .003) and local efficiency (coefficient: ?0.024, p = .003) of the connectome. The association between CVR and the brain connectome suggests that impaired cerebrovascular function may be part of the pathophysiology of the disruption of the brain connectome in persons with white matter hyperintensities.     

Gray matter atrophy and white matter lesions burden in delayed cognitive decline following carbon monoxide poisoning

Gray matter (GM) atrophy and white matter (WM) lesions may contribute to cognitive decline in patients with delayed neurological sequelae (DNS) after carbon monoxide (CO) poisoning. However, there is currently a lack of evidence supporting this relationship. This study aimed to investigate the volume of GM, cortical thickness, and burden of WM lesions in 33 DNS patients with dementia, 24 DNS patients with mild cognitive impairment, and 51 healthy controls. Various methods, including voxel-based, deformation-based, surface-based, and atlas-based analyses, were used to examine GM structures. Furthermore, we explored the connection between GM volume changes, WM lesions burden, and cognitive decline. Compared to the healthy controls, both patient groups exhibited widespread GM atrophy in the cerebral cortices (for volume and cortical thickness), subcortical nuclei (for volume), and cerebellum (for volume) (p < .05 corrected for false discovery rate [FDR]). The total volume of GM atrophy in 31 subregions, which included the default mode network (DMN), visual network (VN), and cerebellar network (CN) (p < .05, FDR-corrected), independently contributed to the severity of cognitive impairment (p < .05). Additionally, WM lesions impacted cognitive decline through both direct and indirect effects, with the latter mediated by volume reduction in 16 subregions of cognitive networks (p < .05). These preliminary findings suggested that both GM atrophy and WM lesions were involved in cognitive decline in DNS patients following CO poisoning. Moreover, the reduction in the volume of DMN, VN, and posterior CN nodes mediated the WM lesions-induced cognitive decline.     

Deep white matter hyperintensities in patients with bipolar depression,unipolar depression and age-matched control subjects

Objective:  Hyperintensities in the white matter of the brain (DWH) and in the periventricular area (PVH) seen on magnetic resonance imaging (MRI) have been reported to be more frequent in patients with bipolar disorder (BP) than in normal subjects. To examine this further we compared MRI of patients with BP with age-matched patients with major depressive disorder (unipolar depression, UP) and healthy control subjects.
Methods:  T2 weighted axial and coronal brain MRI scans were obtained from 13 patients in the depressive phase of BP, 11 with current UP and 19 age-matched control subjects. The degree of DWH and PVH present in each scan was determined using a standardized scoring method.
Results:  The PVH ratings were similar in the three groups of subjects. However, proportionately more BP patients had higher DWH scores than either UP patients or controls. Although this difference did attain statistical significant, a main effect of age was noted. Further, subjects over the age of 50 were under-represented in the UP group.
Conclusions:  Notwithstanding the small total sample size and relative lack of older subjects in the UP group, the fact that almost twice as many BP patients showed more severe DWH suggests that patients with BP may be more vulnerable to develop these changes than UP patients and healthy controls.     

Increased rates of white matter hyperintensities in late-onset bipolar disorder

Objectives: Magnetic resonance imaging (MRI) studies have reported an increased frequency of white matter hyperintensities (WMH) in association with late-onset (LO) depression, and this has supported the notion that vascular-related mechanisms may be implicated in the pathophysiology of LO mood disorders. Recent clinical studies have also suggested a link between LO bipolar disorder (LO-BD) and cerebrovascular risk factors, but this has been little investigated with neuroimaging techniques. In order to ascertain whether there could be a specific association between WMH and LO-BD, we directly compared WMH rates between LO-BD subjects (illness onset ≥ 60 years), early-onset BD subjects (EO-BD, illness onset <60 years), and elderly healthy volunteers. Methods: T2-weighted MRI data were acquired in LO-BD subjects (n = 10, age = 73.60 ± 4.09), EO-BD patients (n = 49, age = 67.78 ± 4.44), and healthy subjects (n = 24, age = 69.00 ± 7.22). WMH rates were assessed using the Scheltens scale. Results: There was a greater prevalence of WMH in LO-BD patients relative to the two other groups in the deep parietal region (p = 0.018) and basal ganglia (p < 0.045). When between-group comparisons of mean WMH scores were conducted taking account of age differences (ANCOVA), there were more severe scores in LO-BD patients relative to the two other groups in deep frontal and parietal regions, as well as in the putamen (p < 0.05). Conclusions: Our results provide empirical support to the proposed link between vascular risk factors and LO-BD. If extended in future studies with larger samples, these findings may help to clarify the pathophysiological distinctions between bipolar disorder emerging at early and late stages of life.     

Higher severity of frontal periventricular white matter and basal ganglia hyperintensities in first-ever lacunar stroke with multiple silent lacunes

Background and purpose:  We investigated whether patients with a lacunar infarct (LI) syndrome exhibiting unique LI or multiple LI on magnetic resonance imaging (MRI) examinations differed in terms of topography and severity of white matter hyperintensities (WMH) ratings.
Methods:  Forty consecutive patients with a first-ever acute LI, who presented a lacunar syndrome according to Miller–Fisher's classification were recruited and were classified into a group presenting isolated LI on MRI ( n  = 17) or multiple LI ( n  = 23).
Results:  Despite equivalent demographic, clinical and cognitive characteristics, patients with multiple LI had increased ratings of WMH in frontal, occipital and subcortical regions. No significant correlations could be evidenced between the number of LI and WMH ratings.
Conclusions:  Present findings provide support to previous hypothesis considering single and multiple LI MRI presentations of lacunar infarct patients as distinct entities.     

Extracting and summarizing white matter hyperintensities using supervised segmentation methods in Alzheimer's disease risk and aging studies

Precise detection and quantification of white matter hyperintensities (WMH) observed in T2‐weighted Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) is of substantial interest in aging, and age‐related neurological disorders such as Alzheimer's disease (AD). This is mainly because WMH may reflect co‐morbid neural injury or cerebral vascular disease burden. WMH in the older population may be small, diffuse, and irregular in shape, and sufficiently heterogeneous within and across subjects. Here, we pose hyperintensity detection as a supervised inference problem and adapt two learning models, specifically, Support Vector Machines and Random Forests, for this task. Using texture features engineered by texton filter banks, we provide a suite of effective segmentation methods for this problem. Through extensive evaluations on healthy middle‐aged and older adults who vary in AD risk, we show that our methods are reliable and robust in segmenting hyperintense regions. A measure of hyperintensity accumulation, referred to as normalized effective WMH volume, is shown to be associated with dementia in older adults and parental family history in cognitively normal subjects. We provide an open source library for hyperintensity detection and accumulation (interfaced with existing neuroimaging tools), that can be adapted for segmentation problems in other neuroimaging studies. Hum Brain Mapp 35:4219–4235, 2014. © 2014 Wiley Periodicals, Inc .