The cerebellum in ALS: friend or foe?

Bede et al present an intriguing study of cerebellar degeneration in amyotrophic lateral sclerosis (ALS). The authors revisit a contentious facet of ALS to present novel insights into cerebellar pathology. ALS is primarily associated with motor cortex and pyramidal tract degeneration, but accompanying frontotemporal involvement is also commonly observed. Extrapyramidal and cerebellar involvement is less well characterised, despite compelling radiological and postmortem evidence. 3 Positron emission tomography studies often detect hypermetabolic changes in the cerebellum, but the molecular underpinnings of these changes are not entirely clear and a variety of conflicting explanations have been offered. It has been repeatedly suggested the cerebellum may assume a compensatory role as the primary motor cortex degenerates and this notion is accepted and perpetuated by many. Compensatory processes however have been predominantly postulated based on lowresolution functional MRI studies, and never explicitly demonstrated by structural or postmortem studies. While the debate is ongoing, the study by Bede et al demonstrates the importance of performing robust, highresolution structural studies in large cohorts to challenge prevailing concepts. The recognition that intermediatelength CAG trinucleotide repeat expansions in ATXN2 confer a risk for ALS adds further relevance to this paper. Subtle cerebellar manifestations are very difficult to detect clinically in this patient cohort against the backdrop of widespread UMN and LMN degeneration. Bede et al present imaging, genetics and clinical data from 161 patients with ALS stratified for C9orf72 and ATXN2 to describe focal cerebellar changes preferentially affecting specific lobules. They describe vermis and posterior lobe predominant pathology in those carrying hexanucleotide repeat expansions in C9orf72 and symmetric bilateral anterior lobe pathology in sporadic patients who tested negative for established genetic variants associated with ALS. The authors also evaluate the imaging profile of a group of patients with intermediate CAG expansions in ATXN2 and find relatively limited cerebellar pathology. The nuanced characterisation of cerebellar involvement in ALS is hugely important as cerebellar pathology is likely to contribute to motor disability, bulbar dysfunction, respiratory compromise and cognitive problems. The role of the cerebellum in exacerbating these cardinal clinical manifestations is often overlooked as these symptoms are primarily linked to motor cortex, brainstem and frontotemporal pathology. Compared with the evaluation of supratentorial structures, imaging the cerebellum is challenging and requires structurespecific analysis pipelines. Bede et al describe both patterns of intracerebellar changes, as well as cerebrocerebellar connectivity alterations. They evaluate cerebrocerebellar disconnection using tractography and the targeted assessment of the cerebellar peduncles. Their findings across a multitude of methodologies are remarkably consistent, lending credence to the focal degenerative changes identified. In our clinics, cerebellar pathology should be considered when evaluating falls, dysarthria, dysphagia and neuropsychological changes in ALS. From a research perspective, cerebellar changes in ALS merit further investigation, especially in association with other repeat expansions such as those in ATXN1.