Dataset Information

Spreading in ALS: The relative impact of upper and lower motor neuron involvement.

ABSTRACT: OBJECTIVE:To investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement. METHODS:We assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, and thoracic regions Non-linear regression analysis was applied to fit the data to a model that described the relation between two random variables, graphically represented by an inverse exponential curve. We analyzed the probability, rate of spread, and both combined (area under the curve). RESULTS:We found that progression was more likely and quicker to or from the region of onset to close spinal regions. When the disease had a limb onset, bulbar motor neurons were more resistant. Furthermore, in the same time frame more patients progressed from bulbar to lower limbs than vice-versa, whether predominantly UMN or LMN involvement. Patients with initial thoracic involvement had a higher probability for rapid change. The presence of predominant UMN signs was associated with a faster caudal progression. INTERPRETATION:Contiguous progression was leading pattern, and predominant UMN involvement is important in shortening the time for cranial-caudal spread. Our results can best be fitted to a model of independent LMN and UMN degeneration, with regional progression of LMN degeneration mostly by contiguity. UMN lesion causes an acceleration of rostral-caudal LMN loss.

SUBMITTER: Gromicho M

PROVIDER: S-EPMC7359118 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Spreading in ALS: The relative impact of upper and lower motor neuron involvement.

Gromicho Marta M Figueiral Manuel M Uysal Hilmi H Grosskreutz Julian J Kuzma-Kozakiewicz Magdalena M Pinto Susana S Petri Susanne S Madeira Sara S Swash Michael M de Carvalho Mamede M

Annals of clinical and translational neurology 20200618 7

<h4>Objective</h4>To investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement.<h4>Methods</h4>We assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, ...[more]

PMID: 32558369

Similar Datasets

Project description:Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis.Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B.We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.

Dataset Information

Spreading in ALS: The relative impact of upper and lower motor neuron involvement.

Publications

Spreading in ALS: The relative impact of upper and lower motor neuron involvement.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets