Broad white matter impairment in multiple system atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of α‐synuclein (α‐syn). MSA differs from other synucleinopathies such as Parkinson''s disease (PD) in that α‐syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p < .001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini‐Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of α‐syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.     

NODDI,diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis

Journal of Neurology - Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS). Using diffusion tensor...     

Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease leading to gray matter atrophy and brain network reconfiguration as a response to increasing tissue damage. We evaluated whether white matter network reconfiguration appears subsequently to gray matter damage, or whether the gray matter degenerates following alterations in white matter networks. MRI data from 83 patients with clinically isolated syndrome and early relapsing–remitting MS were acquired at two time points with a follow‐up after 1 year. White matter network integrity was assessed based on probabilistic tractography performed on diffusion‐weighted data using graph theoretical analyses. We evaluated gray matter integrity by computing cortical thickness and deep gray matter volume in 94 regions at both time points. The thickness of middle temporal cortex and the volume of deep gray matter regions including thalamus, caudate, putamen, and brain stem showed significant atrophy between baseline and follow‐up. White matter network dynamics, as defined by modularity and distance measure changes over time, were predicted by deep gray matter volume of the atrophying anatomical structures. Initial white matter network properties, on the other hand, did not predict atrophy. Furthermore, gray matter integrity at baseline significantly predicted physical disability at 1‐year follow‐up. In a sub‐analysis, deep gray matter volume was significantly related to cognitive performance at baseline. Hence, we postulate that atrophy of deep gray matter structures drives the adaptation of white matter networks. Moreover, deep gray matter volumes are highly predictive for disability progression and cognitive performance.     

Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis

We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age-matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and high-resolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Between-group differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel-based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c-MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal–temporal–parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS.     

Gray and normal-appearing white matter in multiple sclerosis: an MRI perspective

Besides focal white matter lesions, multiple sclerosis brain tissue also displays abnormalities in the gray matter and the normal-appearing white matter. Recent advances in magnetic resonance imaging studies of both types of tissue are discussed. Herein, normal-appearing white matter abnormalities are being found in quantitative magnetic resonance investigations, consistent with a limited degree of axonal damage and/or demyelination, and an increase of glial cells, but the specific nature of the histopathological changes underlying the quantitative magnetic resonance abnormalities remains unclear. Gray matter studies have demonstrated that much of the disease process remains undetected by conventional magnetic resonance imaging. Although newly developed techniques, such as 3D double-inversion recovery, may greatly improve detection of cortical pathology, it remains important to investigate the resultant effects on the cortical tissue alongside this, by studying integrity of normal-appearing cortical tissue through quantitative magnetic resonance studies, as well as the net neurodegenerative effect through measurements of cortical thickness and cortical atrophy (rates). To improve our understanding of normal-appearing white and gray matter changes, their mutual relations, and their relations to clinical changes, further in vivo magnetic resonance imaging studies are required. Specifically, it is proposed that more spatially specific investigations, ideally utilizing subject-specific anatomical information from, for example, diffusion fiber-tracking techniques, could be used to gain more insight into the relations between normal-appearing white matter changes, cortical changes, magnetic resonance visible focal-lesions, and physical and cognitive deficits.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews application of transcranial brain sonography (TCS) in MS patients and TCS findings related to neuropsychological dysfunction. TCS is a new neuroimaging method displaying tissue echogenicity of the brain through the intact skull. Whereas the cortex can not be discriminated from the subcortical white matter with TCS, subcortical brain structures such as ventricles and basal ganglia can be adequately displayed. Even though TCS proved sensitive and reliable in measuring widths of third and lateral ventricles in a number of neurodegenerative diseases, relatively few TCS studies on MS patients have been reported. Data of these studies suggest a good correlation of cognitive dysfunction and width of third ventricle which can be measured reliably with TCS. Moreover, abnormal TCS findings of basal ganglia were associated with cognitive impairment. However, TCS findings of midbrain structures, basal ganglia and ventricles did not correlate with fatigue or depression in MS patients. TCS has the advantages of low costs, short investigation times and unlimited repeatability. The use of third-ventricle and basalganglia TCS for predicting and monitoring neuropsychological impairment in MS patients, however, needs to be elucidated in further studies.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Journal of Neurology - Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews...     

Gray matter involvement in multiple sclerosis

Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression. It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.     

Gray matter pathology and multiple sclerosis

Gray matter demyelination is frequent and extensive in most patients with multiple sclerosis (MS) and has recently received much attention in neuropathologic and imaging studies. Gray matter lesions show distinct pathologic features that make their detection difficult with conventional imaging techniques. Thus, despite their high prevalence, their impact on clinical symptoms has not been defined well so far. This review focuses on recent information from pathologic and imaging studies and summarizes our current knowledge on cortical pathology derived from human and experimental studies.     

Spinal cord atrophy in multiple sclerosis caused by white matter volume loss

OBJECTIVE: To assess the relative contributions of white matter (WM) and gray matter (GM) volume loss to spinal cord atrophy in multiple sclerosis (MS). DESIGN: Postmortem study of transverse sections obtained from 5 levels of the spinal cord, with measurement of the cross-sectional GM and WM areas. SETTING: Department of Neuropathology, University of Nottingham, Nottingham, England. PATIENTS: Fifty-five MS cases and 33 controls. MAIN OUTCOME MEASURES: Size of the WM and GM areas. RESULTS: The WM area was significantly reduced in MS cases in the upper but not the lower cord levels. The GM area was not significantly different between MS and control cases. CONCLUSION: Spinal cord atrophy in MS is due to WM rather than GM volume loss.     

Reliable screening for neuropsychological impairment in multiple sclerosis

In an earlier study, we developed the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) to assist in the screening for neuropsychological (NP) impairments. Self-report MSNQ scores correlated significantly with measures of depression, whereas informant-report MSNQ scores correlated with cognitive performance, but not depression. This study was criticized for use of a small sample and lack of data regarding normal performance and test-retest reliability. The present study was designed to replicate the earlier work with a larger sample of patients and normal controls obtained from multiple sites. We also evaluated the test-retest reliability and predictive validity of the MSNQ. The sample included 85 multiple sclerosis (MS) patients and 40 normal controls, matched on demographic variables. All participants completed the MSNQ and underwent NP testing. Thirty-four patients were re-examined at one week. Pearson and ANOVA techniques were utilized for univariate comparisons. Bayesian statistics were calculated to assess predictive validity. Patient self- and informant-report MSNQ scores differed from normal and test retest reliability indices were high. Both self- and informant-reports were correlated with cognitive dysfunction and depression scales. Self-report MSNQ scores correlated more strongly with depression than cognitive performance, whereas the opposite pattern was observed with informant-report scores. Bayesian statistics showed that informant-report MSNQ scores predict cognitive impairment and patient self-report scores identify patients with cognitive impairment or depression. It is concluded that the MSNQ is useful, although patient self-reports may be exaggerated in depressed patients or reduced in patients with severe cognitive impairment.     

Gray matter atrophy patterns of mild cognitive impairment subtypes

Mild cognitive impairment (MCI) is a heterogeneous neurocognitive disorder that can be classified into various subtypes. The present study aims to examine the gray matter (GM) atrophy patterns of MCI subtypes in comparison with a cognitively healthy group. Participants, including 135 MCI subjects and 120 cognitively healthy controls, were drawn from the Sydney Memory and Ageing Study. The MCI subjects were first categorized into amnestic (aMCI) and non-amnestic (naMCI) subtypes, which were then divided into single-domain (aMCI-SD and naMCI-SD) and multiple-domain subtypes (aMCI-MD and naMCI-MD). Furthermore, naMCI-SD was divided into three subgroups (language, processing speed, and executive function) according to individual cognitive impairment. Voxel-wise GM volumes were then compared between MCI subtypes and controls. The aMCI group had significantly lower GM volumes in the bilateral hippocampi and temporal cortices than the controls. This was mainly due to GM reduction of aMCI-MD but not aMCI-SD, as the latter did not show any significant GM reduction. GM reduction of naMCI and its two subdivisions was shown in widespread brain regions compared to controls. GM volumes of the multiple-domain subtypes (aMCI-MD and naMCI-MD) were lower than their single-domain counterparts (aMCI-SD and naMCI-SD) in the frontal and temporal lobes, respectively. Moreover, the language subgroup of naMCI-SD showed GM reduction in the frontal and temporal lobes compared to controls. MCI subtypes displayed specific patterns of GM atrophy that appear to be related to their various clinical presentations, which implies that underlying mechanisms of MCI subtypes are different.     

Gray matter atrophy pattern in elderly with subjective memory impairment

BackgroundIndividuals with subjective memory impairment (SMI) report worsening of memory without impairment in cognitive tests. Despite normal cognitive performance, they may be at higher risk of cognitive decline compared with individuals without SMI.MethodsWe used a discriminative function (a support vector machine) trained on an independent data set of 226 healthy control subjects and 191 patients with probable Alzheimer's disease (AD) dementia to characterize the baseline gray matter patterns of 24 individuals with SMI and 53 control subjects. We tested for associations of these gray matter patterns with SMI presence, cognitive performance at baseline, and cognitive decline at follow-up.ResultsIndividuals with SMI showed greater similarity to an AD gray matter pattern compared with control subjects without SMI. In addition, episodic memory decline was associated with an AD gray matter pattern in the SMI group.ConclusionsOur results indicate a link between the gray matter atrophy pattern of patients with AD and the presence of SMI. Furthermore, multivariate pattern recognition approaches seem to be a sensitive method for identifying subtle brain changes that correspond to future memory decline in SMI.     

Steroids and brain atrophy in multiple sclerosis

In this review, we focus on different pathogenetic mechanisms of corticosteroids that induce short- and long-term brain volume fluctuations in a variety of systemic conditions and disorders, as well as on corticosteroid-induced immunomodulatory, immunosuppressive and anti-inflammatory mechanisms that contribute to the slowdown of brain atrophy progression in patients with multiple sclerosis (MS). It appears that chronic low-dose treatment with corticosteroids may contribute to irreversible loss of brain tissue in a variety of autoimmune diseases. This side effect of steroid therapy is probably mediated by steroid-induced protein catabolism mechanism. Evidence is mounting that high-dose corticosteroids may induce reversible short-term brain volume changes due to loss of intracellular water and reduction of abnormal vascular permeability, without there having been axonal loss. Other apoptotic and selective inhibiting mechanisms have been proposed to explain the nature of corticosteroid-induced brain volume fluctuations. It has been shown that chronic use of high dose intravenous methylprednisolone (IVMP) in patients with MS may limit brain atrophy progression over the long-term via different immunological mechanisms, including downregulation of adhesion molecule expression on endothelial cells, decreased cytokine and matrix metalloproteinase secretion, decreased autoreactive T-cell-mediated inflammation and T-cell apoptosis induction, blood-brain barrier closure, demyelination inhibition and, possibly, remyelination promotion. Studies in nonhuman primates have confirmed that short-term brain volume fluctuations may be induced by corticosteroid treatment, but that they are inconsistent, potentially reversible and probably dependent upon individual susceptibility to the effects of corticosteroids. Further longitudinal studies are needed to elucidate pathogenetic mechanisms contributing to brain volume fluctuations in autoimmune diseases and multiple sclerosis.     

Changes in the cell population in brain white matter in multiple system atrophy

Background: M ultiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder with adult onset and unknown etiology. Clinically it is characterized by autonomic failure, cerebellar ataxia, parkinsonism, and corticospinal dysfunction in any combination and with varying severity. Objectives and Methods: T o establish the extent of involvement of the white matter in the disease, we have used stereology to quantify the total number of neurons and glial cells (oligodendrocytes, astrocytes, and microglia) in the brains from 10 MSA patients and 11 controls. Results: T he mean total number of white matter interstitial neurons in the patient brains was 0.5 × 10⁹ (coefficient of variation = standard deviation/mean = 0.37), which was significantly lower than the 1.1 × 10⁹ (0.41) in the control brains (P = .001) and equal to a reduction by ～50%. The patient brains had a significantly higher number of white matter microglia, 1.5 × 10⁹ (0.47) versus 0.7 × 10⁹ (0.39) microglia in the control subjects (P = .003) and equal to an increase by ～ 100%. There was no significant difference in mean total numbers of white matter oligodendrocytes and astrocytes between the groups. Conclusions: We found widespread microgliosis without concomitant astrogliosis in brain white matter in MSA patients and demonstrated an absence of significant oligodendrocyte degeneration. The exact role of oligodendrocytes in MSA pathogenesis, including neurodegeneration, remains to be elucidated. © 2017 International Parkinson and Movement Disorder Society     

Cognitive impairment and diffuse white matter atrophy in alcoholics.

OBJECTIVE: Diffuse brain white matter atrophy is often seen in chronic alcoholics, but its relation with cognitive impairment remains to be solved. In order to address this issue, in alcoholics with cognitive impairment at different levels, we studied relations of the central sensory conduction time (CSCT) or brain magnetic resonance imaging (MRI) findings with the cognitive function. METHODS: Subjects were 35 alcoholics with mild cognitive impairment (mini-mental state examination score, MMSE, >/=24; mean+/-SD, 27.7+/-1.9), 12 with moderate to severe cognitive impairment (MMSE<24; 20.3+/-2.7), 15 with Alzheimer's disease (AD) (MMSE, 18.9+/-4.3) (disease control) and 20 healthy volunteers (MMSE, 28.5+/-1.6) (normal control). Median nerve SEPs were recorded in the all subjects, and the latencies and amplitudes of their N9, N11, P13/14, N20 and P25 components were measured. The ventriculocranial ratio (VCR) and the width of cortical sulci were measured on MRIs. These physiological parameters and MRI findings were compared between the 4 groups of the subject, and correlations between those all features were also analyzed. RESULTS: CSCT and VCR were significantly greater in alcoholics with moderate to severe cognitive impairment than those in the other 3 groups. Pearson's product-moment correlation analyses of the alcoholics disclosed that both the CSCT and VCR had significant negative correlations with the MMSE score. Moreover, the CSCT and VCR were positively correlated. CONCLUSIONS: Both physiological and morphological estimates of the white matter function (CSCT and VCR) had a significant correlation with the cognitive dysfunction. SIGNIFICANCE: The diffuse white matter atrophy may be one of the factors causing cognitive impairment in chronic alcoholics.