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An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.

ABSTRACT: Recent studies have suggested overlapping pathological features among motor neuron, cognitive and neurodegenerative diseases.Secondary analysis of 46 amyotrophic lateral sclerosis (ALS) patient autopsies was performed to independently assess pathological feature prevalence (e.g. percent of patients with any positive finding), degree of severity (e.g. mild, moderate, severe), and 2,200+ potential clinical/neuropathological correlations. The possible impact of gender, onset age, onset type (limb vs. bulbar), riluzole treatment, and severe TDP-43 pathology was assessed within patient subgroups.Assessed features (prevalence, severity) include: lateral corticospinal tract degeneration (89%, moderate); Purkinje cell loss (85%, mild); localized neuronal loss (83%, mild to moderate); TDP-43 inclusions (80%, moderate); Betz cell loss (76%, mild); neurofibrillary tangles (78%, severe); anterior corticospinal tract degeneration (72%, moderate); spinal ventral root atrophy (65%, moderate); atherosclerosis (35%, mild); ?-amyloid (35%, mild); tauopathy/tau inclusions (17%, mild); ventricular dilation (13%, mild); Lewy body formation (11%, mild); microinfarcts (7%, mild); and ?-synuclein (4%, mild). Twenty-two percent of patients met criteria for Alzheimer's disease (AD) and 26% for frontotemporal lobar degeneration. Substantial differences were identified in the AD group and in the different onset age groups.Our findings support the hypothesis that ALS and its variants could comprise a larger neuropathological continuum.

SUBMITTER: Coan G

PROVIDER: S-EPMC4560965 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.

Coan Grant G Mitchell Cassie S CS

Neuro-degenerative diseases 20150716 5

<h4>Background</h4>Recent studies have suggested overlapping pathological features among motor neuron, cognitive and neurodegenerative diseases.<h4>Aims/methods</h4>Secondary analysis of 46 amyotrophic lateral sclerosis (ALS) patient autopsies was performed to independently assess pathological feature prevalence (e.g. percent of patients with any positive finding), degree of severity (e.g. mild, moderate, severe), and 2,200+ potential clinical/neuropathological correlations. The possible impact ...[more]

PMID: 26183171

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Project description:Rationale: The anatomical substrate of skeletal muscle autonomic innervation has remained underappreciated since it was described many decades ago. As such, the structural and functional features of muscle sympathetic innervation are largely undetermined in both physiology and pathology, mainly due to methodological limitations in the histopathological analysis of small neuronal fibers in tissue samples. Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease which mainly targets motor neurons, and despite autonomic symptoms occurring in a significant fraction of patients, peripheral sympathetic neurons (SNs) are generally considered unaffected and, as such, poorly studied. Purpose: In this research, we compared sympathetic innervation of normal and ALS muscles, through structural analysis of the sympathetic network in human and murine tissue samples. Methods and Results: We first refined tissue processing to circumvent methodological limitations interfering with the detection of muscle sympathetic innervation. The optimized "Neuro Detection Protocol" (NDP) was validated in human muscle biopsies, demonstrating that SNs innervate, at high density, both blood vessels and skeletal myofibers, independent of the fiber metabolic type. Subsequently, NDP was exploited to analyze sympathetic innervation in muscles of SOD1G93A mice, a preclinical ALS model. Our data show that ALS murine muscles display SN denervation, which has already initiated at the early disease stage and worsened during aging. SN degeneration was also observed in muscles of MLC/SOD1G93A mice, with muscle specific expression of the SOD1G93A mutant gene. Notably, similar alterations in SNs were observed in muscle biopsies from an ALS patient, carrying the SOD1G93A mutation. Conclusion: We set up a protocol for the analysis of murine and, more importantly, human muscle sympathetic innervation. Our results indicate that SNs are additional cell types compromised in ALS and suggest that dysfunctional SOD1G93A muscles affect their sympathetic innervation.

Dataset Information

An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.

Publications

An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.

Similar Datasets

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