Primary lateral sclerosis:more than just an upper motor neuron disease

Advances in clinical care and recent research achievements:Primary lateral sclerosis(PLS)has traditionally been regarded as a pure upper motor neuron condition,a view perpetuated by most medical textbooks.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Degenerative and regenerative processes in amyotrophic lateral sclerosis:motor reserve,adaptation and putative compensatory changes

Advances in amyotrophic lateral sclerosis(ALS)research:Research in ALS has gained unprecedented momentum in recent years fueled by important conceptual developments,establishment of international consortia,breakthrough genetic discoveries and relentless technological advances.The first genotypespecific pharmaceutical trials signal the paradigm shift from the notion of‘one-drug-for-all’to precision,individualized therapies.The once arcane presymptomatic phase of the disease is gradually unraveled by seminal studies of asymptomatic mutation carriers(Geevasinga et al.,2015;Querin et al.,2019).