Information processing deficits in multiple sclerosis: a matter of complexity.

This study examined the relationship between processing speed (PS) and working memory (WM), as measured by performance on an n-back task, in relapsing-remitting multiple sclerosis (RRMS) patients. Simple PS was defined as reaction time (RT) on the 0-back task and complex PS was defined as RT on both the 1-back and 2-back tasks. Participants were administered all three n-back tasks (0-, 1-, and 2-back). Total correct responses, total dyads, and RTs were recorded. As expected, RT for all participants slowed as WM load increased. MS patients had slower RTs than controls across all tasks, and the difference between groups for RT was greatest during the 2-back task. When RT for simple PS (0-back) was parsed from the 1- and 2-back tasks, MS patients still showed impaired complex PS compared to controls. MS patients also made significantly fewer total correct responses and had fewer dyads than controls only on the 2-back task. These findings suggest that both WM and PS deficits are present in RRMS, and that as WM demand increases (from 1- to 2-back) both PS and WM deficits become more prominent.     

Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis

Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing‐remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions—as frequently claimed—or is the atrophy stronger correlated to “silent” (nonlesional) microstructural thalamic alterations? One‐hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic volume (RTV) and thalamic FA were significantly reduced in patients with CIS and RRMS relative to healthy controls. Both measures were also correlated. The age, gender, WM lesion load, thalamic FA, and gray matter volume‐corrected RTV were reduced even in the absence of thalamic and extensive white matter lesions—also in patients with short disease duration (≤24 months). A voxel‐based correlation analysis revealed that the RTV reduction had a significant effect on local WM FA—in areas next to the thalamus and basal ganglia. These WM alterations could not be explained by WM lesions, which had a differing spatial distribution. Early thalamic atrophy is mainly driven by silent microstructural thalamic alterations. Lesions do not disclose the early damage of thalamocortical circuits, which seem to be much more affected in CIS and RRMS than expected. Thalamocortical damage can be detected by DTI in normal appearing brain tissue. Hum Brain Mapp 37:1866–1879, 2016. © 2016 Wiley Periodicals, Inc .     

Structural MRI correlates of cognitive impairment in patients with multiple sclerosis

In a multicenter setting, we applied voxel‐based methods to different structural MR imaging modalities to define the relative contributions of focal lesions, normal‐appearing white matter (NAWM), and gray matter (GM) damage and their regional distribution to cognitive deficits as well as impairment of specific cognitive domains in multiple sclerosis (MS) patients. Approval of the institutional review boards was obtained, together with written informed consent from all participants. Standardized neuropsychological assessment and conventional, diffusion tensor and volumetric brain MRI sequences were collected from 61 relapsing‐remitting MS patients and 61 healthy controls (HC) from seven centers. Patients with ≥2 abnormal tests were considered cognitively impaired (CI). The distribution of focal lesions, GM and WM atrophy, and microstructural WM damage were assessed using voxel‐wise approaches. A random forest analysis identified the best imaging predictors of global cognitive impairment and deficits of specific cognitive domains. Twenty‐three (38%) MS patients were CI. Compared with cognitively preserved (CP), CI MS patients had GM atrophy of the left thalamus, right hippocampus and parietal regions. They also showed atrophy of several WM tracts, mainly located in posterior brain regions and widespread WM diffusivity abnormalities. WM diffusivity abnormalities in cognitive‐relevant WM tracts followed by atrophy of cognitive‐relevant GM regions explained global cognitive impairment. Variable patterns of NAWM and GM damage were associated with deficits in selected cognitive domains. Structural, multiparametric, voxel‐wise MRI approaches are feasible in a multicenter setting. The combination of different imaging modalities is needed to assess and monitor cognitive impairment in MS. Hum Brain Mapp 37:1627‐1644, 2016. © 2016 Wiley Periodicals, Inc.     

The effect of hypointense white matter lesions on automated gray matter segmentation in multiple sclerosis

Previous imaging studies assessing the relationship between white matter (WM) damage and matter (GM) atrophy have raised the concern that Multiple Sclerosis (MS) WM lesions may affect measures of GM volume by inducing voxel misclassification during intensity‐based tissue segmentation. Here, we quantified this misclassification error in simulated and real MS brains using a lesion‐filling method. Using this method, we also corrected GM measures in patients before comparing them with controls in order to assess the impact of this lesion‐induced misclassification error in clinical studies. We found that higher WM lesion volumes artificially reduced total GM volumes. In patients, this effect was about 72% of that predicted by simulation. Misclassified voxels were located at the GM/WM border and could be distant from lesions. Volume of individual deep gray matter (DGM) structures generally decreased with higher lesion volumes, consistent with results from total GM. While preserving differences in GM volumes between patients and controls, lesion‐filling correction revealed more lateralised DGM shape changes in patients, which were not evident with the original images. Our results confirm that WM lesions can influence MRI measures of GM volume and shape in MS patients through their effect on intensity‐based GM segmentation. The greater effect of lesions at increasing levels of damage supports the use of lesion‐filling to correct for this problem and improve the interpretability of the results. Volumetric or morphometric imaging studies, where lesion amount and characteristics may vary between groups of patients or change over time, may especially benefit from this correction. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

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.     

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability

BACKGROUND: Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated. OBJECTIVE: To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability. METHODS: We studied 222 relapsing remitting MS patients with low disability (scores or=5; n=197) and low-fatigue groups (FSS相似文献   

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.     

Normal-appearing white and grey matter damage in MS

Abstract The aims of this study were to improve, using a 3.0 Tesla (T) scanner and diffusion tensor (DT) magnetic resonance imaging (MRI) with sensitivity encoding, our understanding of: 1) the possible pathological substrates of normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis (MS) and 2) the factors associated to WM and GM atrophy in this condition. Conventional and DT MRI of the brain were acquired from 32 relapsing-remitting (RR) MS patients and 16 controls. Lesion load, WM (WMV), overall GM (GMV), and neocortical GM (NCV) volumes were measured. NAWM mean diffusivity (MD) and fractional anisotropy (FA), and GM MD were calculated. GMV and NCV were lower (p ≤ 0.001) in MS patients than controls, whereas WMV did not differ significantly. MS patients had higher NAWM and GM average MD and lower NAWM average FA (p ≤ 0.001) than controls. Moderate correlations were found between intrinsic lesion and tissue damage with both GM volumetric and diffusivity changes ()0.41 ≤ r ≤ 0.42, p ≤ 0.04). DT MRI and volumetry measurements at 3.0 T confirm the presence of NAWM and GM abnormalities in RRMS patients. Although histopathology was not available, axonal and neuronal damage and consequent reactive glial proliferation are the most likely substrates of the changes observed.     

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient‐control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp 36:3793–3804, 2015. © 2015 Wiley Periodicals, Inc.     

A comparison of gray and white matter density in patients with Parkinson's disease dementia and dementia with Lewy bodies using voxel‐based morphometry

Despite clinical and neuropsychological similarities between Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. We used voxel‐based morphometry using a 3‐T MRI scanner to compare gray and white matter densities in 20 patients with probable PDD and 18 patients with probable DLB, who had similar overall severity of dementia and similar demographic characteristics. The gray matter density was significantly decreased in the left occipital, parietal, and striatal areas in patients with DLB compared with patients with PDD. The white matter density was significantly decreased in bilateral occipital and left occipito‐parietal areas in patients with DLB compared with those with PDD. The degree of white and gray matter atrophy was similar in patients with DLB; in contrast, there was markedly less atrophy in the white matter than in the gray matter in patients with PDD. On analyzing the change of WM density relative to that of GM density in patients with DLB compared to those with PDD, the area of WM atrophy in the occipital areas was more extensive than that of GM atrophy. Our data demonstrate that atrophy of both gray and white matter was more severe in patients with DLB and that white matter atrophy relative to gray matter atrophy was less severe in patients with PDD. These data may reflect a difference in the underlying nature of PDD and DLB. © 2009 Movement Disorder Society     

Functional neuroanatomy of visuo-spatial working memory in Turner syndrome

Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.     

Improved prediction of Alzheimer's disease with longitudinal white matter/gray matter contrast changes

Brain morphometry measures derived from magnetic resonance imaging (MRI) are important biomarkers for Alzheimer's disease (AD). The objective of the present study was to test whether we could improve morphometry‐based detection and prediction of disease state by use of white matter/gray matter (WM/GM) signal intensity contrast obtained from conventional MRI scans. We hypothesized that including WM/GM contrast change along with measures of atrophy in the entorhinal cortex and the hippocampi would yield better classification of AD patients, and more accurate prediction of early disease progression. T₁‐weighted MRI scans from two sessions approximately 2 years apart from 78 participants with AD (Clinical Dementia Rating (CDR) = 0.5–2) and 71 age‐matched controls were used to calculate annual change rates. Results showed that WM/GM contrast decay was larger in AD compared with controls in the medial temporal lobes. For the discrimination between AD and controls, entorhinal WM/GM contrast decay contributed significantly when included together with decrease in entorhinal cortical thickness and hippocampal volume, and increased the area under the curve to 0.79 compared with 0.75 when using the two morphometric variables only. Independent effects of WM/GM contrast decay and improved classification were also observed for the CDR‐based subgroups, including participants converting from either a non‐AD status to very mild AD, or from very mild to mild AD. Thus, WM/GM contrast decay increased diagnostic accuracy beyond what was obtained by well‐validated morphometric measures alone. The findings suggest that signal intensity properties constitute a sensitive biomarker for cerebral degenration in AD. Hum Brain Mapp 34:2775–2785, 2013. © 2012 Wiley Periodicals, Inc.     

Structural brain indices and executive functioning in multiple sclerosis: A review

Multiple sclerosis (MS) is a neurological disease characterized by lesion-induced white matter deterioration. Brain atrophy and damage to normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) have also been identified as consequences of MS. Neuroimaging has played an integral role in investigating the effects of white and gray matter damage across the three primary clinical phenotypes of the disease—primary progressive (PPMS), relapsing remitting (RRMS), and secondary progressive (SPMS) MS. Both conventional (e.g., T1-weighted imaged) and nonconventional (e.g., diffusion tensor imaging) neuroimaging methods have yielded important information regarding the structural integrity of the brain during the course of the disease. Moreover, it has provided the opportunity to explore the relationship between structural brain indices and cognitive functioning, such as executive functioning, in MS. In this paper, we provide a brief overview of executive functioning in MS, a general review of how structural damage presents in MS by way of sclerotic lesions, atrophy, and microstructural white matter damage, and, finally, how structural brain damage relates to executive dysfunction.     

MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis

OBJECTIVES: MRI T2 hypointensity in multiple sclerosis (MS) gray matter, suggesting iron deposition, is associated with physical disability, disease course, lesion load, and brain atrophy. Ambulatory dysfunction limits quality of life; however correlation with conventional MRI remains poor. METHODS: Normalized intensity on T2-weighted images was obtained in the basal ganglia, thalamus, red nucleus, and dentate nucleus in 47 MS patients and 15 healthy controls. Brain T1-hypointense and FLAIR-hyperintense lesion volume, third ventricle width, brain parenchymal fraction and timed 25 foot walk (T25FW) were measured in the MS group. RESULTS: T2 hypointensity was present throughout gray matter in MS vs. controls (all p<0.01). Dentate T2 hypointensity was the only MRI variable significantly correlated with T25FW (Pearson r=-0.355, p=0.007) and was also the best MRI correlate of physical disability (EDSS) score in regression modeling (r=-0.463, R(2)=0.223, p=0.004). CONCLUSIONS: T2 hypointensity is present in subcortical gray matter nuclei in patients with MS vs. normal controls. Dentate nucleus T2 hypointensity is independently related to ambulatory impairment and disability, accounting for more variance than conventional lesion and atrophy measures. This study adds more weight to the notion that T2 hypointensity is a clinically relevant marker of tissue damage in MS.     

Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study

Deep gray matter damage may be an important component of the multiple sclerosis (MS) disease process. We tested whether caudate atrophy occurs in MS, and whether it correlates with conventional MRI or clinical markers of disease progression. Caudate nuclei of 24 MS patients and 10 age-matched healthy controls were traced, normalized, reconstructed and visualized from MRI scans. Normalized bicaudate volume was 19% lower in MS controls ( p< 0.001), an effect that persisted after adjusting for whole-brain atrophy ( p< 0.008). Caudate volume did not correlate with disease duration, physical disability score, whole-brain atrophy, or total T2 hyperintense or T1 hypointense lesion load (all p > 0.05). We conclude that selective caudate atrophy is associated with MS and may occur through direct mechanisms.     

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism

ObjectivesTo determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients.DesignForty-three older PD patients (≥65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method.ResultsPatients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum.ConclusionsCortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.     

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia

Abstract

Objectives. Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. Methods. Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. Results. Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. Conclusions. Because 0-back activation reflects verbal attention processes, patients’ persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.     

Comparison of diffusion tensor imaging and voxel-based morphometry to detect white matter damage in Alzheimer's disease

Regional atrophy of gray matter (GM) in Alzheimer's disease (AD) is well known; however, the relationship between macroscopic and microscopic changes of cerebral white matter (WM) is uncertain. The aim of this study was to investigate the pattern of GM, WM atrophy, and microscopic WM changes in the same individuals with AD. All subjects (10AD and 15 healthy controls [HC]) underwent a MRI scanning at 1.5 T, including a 3-dimensional volumetric scan and diffusion tensor imaging (DTI). We performed statistical parametric mapping (SPM) with DTI to evaluate the patterns of the microscopic WM changes, as well as voxel-based morphometry (VBM) for GM and WM volume changes between patients with AD and HC. GM atrophy was detected, mainly in posterior regions, and WM atrophy was similarly distributed, but less involved on VBM analysis. Unlike WM atrophy on VBM analysis, microscopic WM changes were shown in the medial frontal, orbitofrontal, splenium of the corpus callosum, and cingulum on DTI analysis with SPM. We demonstrated that the pattern of macroscopic WM atrophy was similar to GM atrophy, while microscopic WM changes had a different pattern and distribution. Our findings suggest that WM atrophy may preferentially reflect the secondary changes of GM atrophy, while microscopic WM changes start earlier in frontal areas before GM and WM atrophy can be detected macroscopically.     

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

MRI measures of tissue atrophy within the central nervous system may reflect the neurodegenerative process which underpins the progressive phase of multiple sclerosis (MS). There has been limited longitudinal investigation of MRI-detected atrophy in secondary progressive MS. This study includes 56 subjects with secondary progressive MS. Subjects were followed up for 2 years and MRI analysis was conducted at 12 month intervals using the following measures: (1) whole brain (WB) volume change; (2) grey and white matter (WM) volumes; (3) central brain volume; (4) upper cervical spinal cord (SC) area; (5) T2 lesion volumes. Clinical measures included the Expanded Disability Status Scale and the MS Functional Composite. All volumetric MRI measures were assessed for sensitivity, responsiveness, reliability and correlation with disability. The mean annual atrophy rate of WB was 0.59% per year and this was the most responsive atrophy measure assessed. Grey matter (GM) atrophy (−1.18% per year) was greater and more responsive than WM atrophy (0.12% per year). The SC demonstrated the highest atrophy rate at 1.63% per year. WB, GM and SC atrophy all correlated with change in the Multiple Sclerosis Functional Composite z score (r = 0.35, 0.42, 0.34), and GM atrophy was the only correlate of change in the 9 Hole Peg Test and Paced Auditory Serial Addition Test performance. None of the MRI measures correlated with Expanded Disability Status Score progression. Measures of WB, GM and SC atrophy all have attributes for use as surrogate markers in secondary progressive MS trials and improvement in the reliability of the GM and SC volume measurements may enhance these further.     

Working memory deficits in multiple sclerosis: comparison between the n-back task and the Paced Auditory Serial Addition Test.

Working memory (WM) deficits are common in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) is used frequently to measure WM in clinical settings. The n-back paradigm is used often in experimental studies of WM. One unique component of the n-back task is that it provides a measure of reaction time (RT), an additional behavioral index of processing speed and task difficulty. Despite the use of both tasks to measure WM, their common variance has not been documented. We tested 32 MS patients and 20 controls; performance measures were obtained for both tasks. Compared with controls, MS patients generally had poorer performance on both the PASAT and n-back task. MS patients also had slower RTs on the n-back than controls and showed more slowing than controls as a function of WM load. Correlational analyses showed a high correspondence between performance measures on the PASAT and n-back. Principal components analysis pointed to a common feature of the PASAT, n-back, and specific other neuropsychological measures, that is, processing speed. Although the PASAT and n-back were shown to have a significant amount of shared variance, each test has specific advantages and disadvantages for use in clinical populations.