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Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43.

ABSTRACT: Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in amyotrophic lateral sclerosis cross-sectionally and longitudinally and to compare the findings with a recently proposed disease-staging model of amyotrophic lateral sclerosis pathology. Deformation-based morphometry was used to identify the patterns of brain atrophy associated with amyotrophic lateral sclerosis and to assess their relationship with clinical symptoms. Longitudinal T₁-weighted MRI data and clinical measures were acquired at baseline, 4?months and 8?months, from 66 patients and 43 age-matched controls who participated in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. Whole brain voxel-wise mixed-effects modelling analysis showed extensive atrophy patterns differentiating patients from the normal controls. Cerebral atrophy was present in the motor cortex and corticospinal tract, involving both grey matter and white matter, and to a lesser extent in non-motor regions. More specifically, the results showed significant bilateral atrophy in the motor cortex and corticospinal tract (including the internal capsule and brainstem) and ventricular enlargement, along with significant longitudinal atrophy in precentral gyrus, frontal and parietal white matter, accompanied by ventricular and sulcal enlargement. Atrophy in the precentral gyrus was significantly associated with greater disability as quantified with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (P?

SUBMITTER: Dadar M

PROVIDER: S-EPMC7846188 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43.

Dadar Mahsa M Manera Ana Laura AL Zinman Lorne L Korngut Lawrence L Genge Angela A Graham Simon J SJ Frayne Richard R Collins D Louis DL Kalra Sanjay S

Brain communications 20200515 2

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in amyotrophic lateral sclerosis cross-sectionally and longitudinally and to compare the findings with a recently proposed disease-staging model of amyotr ...[more]

PMID: 33543125

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Project description:Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.

Dataset Information

Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43.

Publications

Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43.

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