Widespread White Matter Involvement Research Articles

S139. PROGRESSIVE DETERIORATION OF WHITE MATTER TRACTS IN SCHIZOPHRENIA: A DIFFUSION MRI STUDY ON A LARGE SINGLE COHORT USING NORMATIVE MODELS

BackgroundCurrent diffusion MRI studies of schizophrenia are limited by methodology and sample size. With normative models and the largest single-site cohort, we aimed to delineate a comprehensive profile of tract alteration in unaffected siblings, first-episode schizophrenia (FES), and chronic schizophrenia.MethodsA total of 277 patients with schizophrenia, 81 unaffected siblings, and 1023 healthy people underwent diffusion-weighted imaging on the same 3T scanner. Generalized fractional anisotropy (GFA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were sampled along 45 major neural tracts. A normative model was built from the images of 1023 healthy people; Z scores represented the normalized deviation of the index value from that of the age- and sex-matched healthy population.ResultsWidespread involvement of neural tracts was found in patients with FES, and the tracts connecting the prefrontal lobe were the most severely affected. In patients with chronic schizophrenia, virtually all neural tracts were altered, with the tracts connecting the sensorimotor cortex the least affected. A significant negative correlation was observed between GFA alterations and the duration of illness. In unaffected siblings, scattered tracts were involved in GFA, but not in MD or RD.DiscussionThe study revealed widespread white matter involvement in the early stages of schizophrenia. The alteration continues to progress from the neural tracts connecting the prefrontal lobe to the entire brain. Compared to a large sample of normal controls, the attenuated peak and rapid decline of white matter GFA across the lifespan suggest that schizophrenia is associated with neurodevelopmental and neurodegenerative abnormalities of white matter.

Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis.

ObjectiveTo understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI.MethodsWe assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls.ResultsPatients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72-negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate.ConclusionsHeterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration.

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Structural and functional brain signatures of C9orf72 in motor neuron disease

This study investigated structural and functional magnetic resonance imaging abnormalities in hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) motor neuron disease (MND) relative to disease severity-matched sporadic MND cases. We enrolled 19 C9orf72 and 67 disease severity-matched sporadic MND patients, and 22 controls. Sporadic cases were grouped in patients with: no cognitive/behavioral deficits (sporadic-motor); same patterns of cognitive/behavioral impairment as C9orf72 cases (sporadic-cognitive); shorter disease duration versus other sporadic groups (sporadic-early). C9orf72 patients showed cerebellar and thalamic atrophy versus all sporadic cases. All MND patients showed motor, frontal, and temporoparietal cortical thinning and motor and extramotor white matter damage versus controls, independent of genotype and presence of cognitive impairment. Compared with sporadic-early, C9orf72 patients revealed an occipital cortical thinning. C9orf72 patients had enhanced visual network functional connectivity versus sporadic-motor and sporadic-early cases. Structural cerebellar and thalamic damage and posterior cortical alterations are the brain magnetic resonance imaging signatures of C9orf72 MND. Frontotemporal cortical and widespread white matter involvement are likely to be an effect of the disease evolution rather than a C9orf72 marker.

Brain Involvement in Myotonic Dystrophy Type 1: A Morphometric and Diffusion Tensor Imaging Study with Neuropsychological Correlation.

Myotonic dystrophy type 1 (DM1), the most prevalent inherited neuromuscular disease in adults, is a genetic multisystem disorder with a well-established but not well-characterized cerebral involvement. The aim of this study was to evaluate the presence of white matter and gray matter abnormalities in DM1 patients and to investigate their relationship with neurocognitive dysfunction. A total of 42 DM1 patients and 42 healthy controls were included in the study. Clinical, cognitive, and magnetic resonance imaging evaluations, including the use of structural and diffusion tensor imaging (DTI) techniques, were performed. White matter lesion (WML) load, volumetric analysis, and diffusivity changes were assessed and correlated with clinical and neuropsychological test findings. WMLs were significantly more frequent in DM1 patients (p < .001), and anterior temporal lobe lesions were only found in the patient group. Global and regional cortical volume loss and corpus callosum atrophy were found. Diffuse white matter DTI abnormalities, including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were observed with sparing of the internal capsule. Subcortical structures showed volume loss and increased median diffusivity. Neuropsychological evaluation showed significant impairment in several cognitive functions, but only visuospatial impairment was correlated with white matter abnormalities and cortical atrophy. Daytime sleepiness was associated with WML and ventral diencephalon and pallidum volume loss. DM1 produces a widespread involvement of white matter and gray matter, including cortical and subcortical structures. These structural abnormalities are involved in the progressive neuropsychological functional impairment in these patients.

Inflammation Inducing Central Nervous System Damage in HTLV-1 Infection

Human T-cell lymphotropic virus type 1 (HTLV-1) is involved with two well-described clinical conditions: HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia. The neurological disease affects predominantly the spinal cord. Although unusual, the brain as well as other organs may be involved by inflammatory reaction associated with HTLV-1 infection. This condition was recently described in our report “Temporal lesions and widespread involvement of white matter associated with multi-organ inflammatory disease in human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)”. The development of HTLV-1-associated diseases seems to be regulated by viral, host and environmental determinants. High proviral load (PVL) is the best predictor of HAM/TSP. Proviral integration into transcriptionally active units in host genomes and genotypes HLA-B*5401 and HLA-DRB1*0101 are associated with high PVL and consequently linked to HAM/TSP. The increased proliferation and migration of HTLV-1 infected lymphocytes to central nervous system and a resulting strong pro-inflammatory reaction play a crucial role in the neuropathogenesis of the disease. In general, increasing in HTLV-1 PVL in both peripheral blood mononuclear cells and in cerebrospinal fluid (CSF) cells coincides with the exacerbation of neurological symptoms. Analysis of CSF in HAM/TSP shows an inflammatory response characterized by lymphocytic pleocytosis, raised protein content, intrathecal synthesis of oligoclonal IgG bands and of specific IgG, and increased concentration of pro-inflammatory markers. Here, it will be discussed the pathogenesis and the inflammatory mechanisms leading to injury of the central nervous system in HTLV-1 infection.

Tract-based spatial statistics of diffusion tensor imaging in hereditary spastic paraplegia with thin corpus callosum reveals widespread white matter changes

We aimed to investigate white matter diffusivity abnormalities in hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) patients in relation with electrophysiological findings. Brain magnetic resonance imaging (MRI) and diffusion tensor imaging were performed on four HSP-TCC patients and 15 age-matched healthy subjects. Voxel-wise statistical analysis of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity maps were carried out using tract-based spatial statistics, and significantly affected voxels were labeled using a human white matter atlas. Conventional nerve conduction studies, cortical and spinal-root motor evoked potentials, and somatosensory evoked potentials were examined in three patients. On MRI, all patients had a thin corpus callosum with mild T2 hyperintensity in the periventricular white matter. Compared to control subjects, we detected widespread significant decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity in structures including in the corpus callosum, motor, and non-motor white matter tracts in HSP-TCC patients. Several different regions showed significant reduction in axial diffusivity. Electrophysiological studies revealed prolonged central motor conduction times and reduced cortical motor evoked potentials and somatosensory evoked potentials amplitudes in all patients. One patient had low sural sensory nerve action potential suggestive of axonal neuropathy. Tract-based spatial statistics of diffusion tensor imaging revealed a more widespread involvement of white matter in HSP-TCC patients than has previously been detected by conventional MRI. This may explain the broad spectrum of electrophysiological and neurological abnormalities that complicate hereditary spastic paraplegia in these patients.

Multiple white matter tract abnormalities underlie cognitive impairment in RRMS

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p<0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease.

Pathological Assessment of Brain White Matter in Relapsing-Remitting MS Patients using Quantitative Magnetization Transfer Imaging

Introduction: Multiple sclerosis (MS) is characterized by lesions in the white matter (WM) of the central nervous system. Magnetic resonance imaging is the most specific and sensitive method for diagnosis of multiple sclerosis. However, the ability of conventional MRI to show histopathologic heterogeneity of MS lesions is insufficient. Quantitative magnetization transfer imaging (qMTI) is a relatively new method to investigate pathologic processes of the brain tissue occurring in MS patients. Material and Methods: Voxel-based analyses allow regional comparisons between groups to be made for the whole brain in a single analysis. This is done by coregistering data from all individual subjects to a reference brain, generally referred to as the standard space, and then comparing them on a voxel-by-voxel basis. This study aimed to analyze whole-brain quantitative T1 maps, not to find global changes or changes in selected regions, but specifically to investigate the spatial distribution throughout the brain of T1 increases in MS WM with respect to control WM. In this study, 11 healthy controls, 10 relapsing-remitting (RR) MS patients and 13 CIS patients were studied using MT-MRI imaging. MT parameters, including magnetization transfer ratio (MTR), magnetization transfer rate between free protons and restricted macromolecular protons, Ksat and longitudinal relaxation times (with and without MT saturation pulse), T1sat and T1free values were evaluated. Results: The results showed that, at a group level, there is widespread involvement of WM throughout the brain in CIS MS and especially in RRMS, where a significant T1 increase was found in 15.58% of WM voxels (normals < RR). Discussion and Conclusion: This study demonstrates that WM in large parts of the brain is susceptible to disease processes in RR and CIS MS

Correlation between pyramidal tract degeneration and widespread white matter involvement in amyotrophic lateral sclerosis: A study with tractography and diffusion-tensor imaging

Our aim was to evaluate the location and extent of white matter involvement in patients with amyotrophic lateral sclerosis (ALS) using diffusion-tensor magnetic resonance imaging (DTI). We obtained fractional anisotropy (FA) values from the internal capsule and various white matter regions of 46 patients with sporadic ALS and 19 control subjects. In ALS patients, FA values in the internal capsule, frontal white matter, genu and splenium of the corpus callosum (p<0.001), parietal and temporal lobe white matter, and posterior cingulum (p<0.05) were significantly lower than in controls. FA values in frontal white matter were lower than in parietal white matter (p<0.001). Decreased FA values in frontal, parietal, and temporal white matter, and the genu of the corpus callosum, correlated significantly with those in the internal capsule (r=0.66 and p<0.001, r=0.47 and p=0.001, r=0.33 and p=0.021, r=0.41 and p=0.005, respectively). No such correlations were found for FA values in other white matter areas or in controls. Patient FA values generally were not correlated with disease duration. DTI demonstrated more widespread involvement of the cerebral white matter in ALS patients than previously believed. The severity of involvement in the frontal, temporal and parietal white matter correlated with severity in the pyramidal tract.

Correlation between pyramidal tract degeneration and widespread white matter involvement in amyotrophic lateral sclerosis: A study with tractography and diffusion-tensor imaging

Correlation between pyramidal tract degeneration and widespread white matter involvement in amyotrophic lateral sclerosis: A study with tractography and diffusion-tensor imaging

Notes on the pathogenesis of subacute sclerosing panencephalitis

In the original description by van Bogaert and De Busscher of subacute sclerosing leukoencephalitis (SSLE), great emphasis was placed upon the involvement of the white matter, a feature that, in addition to the absence of inclusion bodies, differentiated it from subacute inclusion body encephalitis (SIBE) of Dawson. Subsequently, the common features, primarily clinical, electroencephalographic and immunological led to the consolidation of both into the entity known as subacute sclerosing panencephalitis (SSPE). The white matter lesions of SSLE are identical to those that are seen in progressive rubella encephalitis, subacute AIDS encephalomyelitis, tropical spinal paraparesis due to HTLV-1, and visna of Icelandic sheep, but, more importantly, are characterized by the perivascular edema, inflammation and demyelination known in acute, immune-mediated post-infectious and post-vaccinal acute disseminated encephalomyelitis (ADEM). Furthermore, in SSLE and in the other conditions resulting from a persistent viral infection, deposits of immune complexes can be demonstrated in the walls of small cerebral blood vessels. There is therefore strong evidence to suggest that in SSLE as well as in the other persistent viral infections, in addition to the actual invasion by the virus, there is a contemporaneous immune-mediated response to this virus which is responsible for most, perhaps even all of the disseminated, extensive demyelination observed in these conditions. It is also suggested that SSLE and SIBE, sharing a common etiology, may represent two different phenotypic expressions of the same process. In the former, recognition of the early stage of cognitive deficit and deterioration of scholastic performance, coupled with evidence of widespread white matter involvement by magnetic resonance imaging should lead to considering treatment with corticosteroids (or ACTH) as anti-inflammatory agents, or even with immunosuppressive agents.