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ObjectiveCerebellar disease burden and cerebro-cerebellar connectivity alterations are poorly characterised in amyotrophic lateral sclerosis (ALS) despite the likely contribution of cerebellar pathology to the clinical heterogeneity of the condition.MethodsA prospective imaging study has been undertaken with 271 participants to systematically evaluate cerebellar grey and white matter alterations, cerebellar peduncle integrity and cerebro-cerebellar connectivity in ALS. Participants were stratified into four groups: (1) patients testing positive for GGGGCC repeat expansions in C9orf72, (2) patients carrying an intermediate-length repeat expansion in ATXN2, (3) patients without established ALS-associated mutations and (4) healthy controls. Additionally, the cerebellar profile of a single patient with ALS who had an ATXN2 allele length of 62 was evaluated. Cortical thickness, grey matter and white matter volumes were calculated in each cerebellar lobule complemented by morphometric analyses to characterise genotype-associated atrophy patterns. A Bayesian segmentation algorithm was used for superior cerebellar peduncle volumetry. White matter diffusivity parameters were appraised both within the cerebellum and in the cerebellar peduncles. Cerebro-cerebellar connectivity was assessed using deterministic tractography.ResultsCerebellar pathology was confined to lobules I–V of the anterior lobe in patients with sporadic ALS in contrast to the considerable posterior lobe and vermis disease burden identified in C9orf72 mutation carriers. Patients with intermediate ATXN2 expansions did not exhibit significant cerebellar pathology.ConclusionsFocal rather than global cerebellar degeneration characterises ALS. Pathognomonic ALS symptoms which are typically attributed to other anatomical regions, such as dysarthria, dysphagia, pseudobulbar affect, eye movement abnormalities and cognitive deficits, may be modulated, exacerbated or partially driven by cerebellar changes in ALS.

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Amyotrophic lateral sclerosis (ALS) encompasses a heterogeneous group of phenotypes with different progression rates, varying degree of extra-motor involvement and divergent progression patterns. The natural history of ALS is increasingly evaluated by large, multi-time point longitudinal studies, many of which now incorporate presymptomatic and post-mortem assessments. These studies not only have the potential to characterize patterns of anatomical propagation, molecular mechanisms of disease spread, but also to identify pragmatic monitoring markers. Sensitive markers of progressive neurodegenerative change are indispensable for clinical trials and individualized patient care. Biofluid markers, neuroimaging indices, electrophysiological markers, rating scales, questionnaires, and other disease-specific instruments have divergent sensitivity profiles. The discussion of candidate monitoring markers in ALS has a dual academic and clinical relevance, and is particularly timely given the increasing number of pharmacological trials. The objective of this paper is to provide a comprehensive and critical review of longitudinal studies in ALS, focusing on the sensitivity profile of established and emerging monitoring markers.

Post-polio syndrome (PPS) is a neurological condition that affects polio survivors decades after their initial infection. Despite its high prevalence, the etiology of PPS remains elusive, mechanisms of progression are poorly understood, and the condition is notoriously under-researched. While motor dysfunction is a hallmark feature of the condition, generalized fatigue, sleep disturbance, decreased endurance, neuropsychological deficits, sensory symptoms, and chronic pain are also often reported and have considerable quality of life implications in PPS. The non-motor aspects of PPS are particularly challenging to evaluate, quantify, and treat. Generalized fatigue is one of the most distressing symptoms of PPS and is likely to be multifactorial due to weight-gain, respiratory compromise, poor sleep, and polypharmacy. No validated diagnostic, monitoring, or prognostic markers have been developed in PPS to date and the mainstay of therapy centers on symptomatic relief and individualized rehabilitation strategies such as energy conservation and muscle strengthening exercise regimes. Despite a number of large clinical trials in PPS, no effective disease-modifying pharmacological treatments are currently available.

HighlightsComputational neuroimaging captures focal brainstem pathology in motor neuron diseases in contrast to both healthy- and disease controls.ALS patients exhibit progressive medulla oblongata, pontine and mesencephalic volume loss over time.Brainstem atrophy in ALS and PLS is dominated by medulla oblongata volume reductions.Vertex analyses of ALS patients reveal flattening of the medullary pyramids bilaterally.Morphometric analyses in ALS detect density reductions in the mesencephalic crura consistent with corticospinal tract degeneration.

Pathological crying and laughing (PCL) has significant quality-of-life implications in amyotrophic lateral sclerosis (ALS); it can provoke restrictive life-style modifications and lead to social isolation. Despite its high prevalence and quality of life implications, it remains surprisingly understudied. Divergent pathophysiological models have been proposed, centered on corticobulbar tract degeneration, prefrontal cortex pathology, sensory deafferentation, and impaired cerebellar gate-control mechanisms. Quantitative MRI techniques and symptom-specific clinical instruments offer unprecedented opportunities to elucidate the anatomical underpinnings of PCL pathogenesis. Emerging neuroimaging studies of ALS support the role of cortico–pontine–cerebellar network dysfunction in context-inappropriate emotional responses. The characterization of PCL-associated pathophysiological processes is indispensable for the development of effective pharmacological therapies.