Brainstem and cerebellar radiological findings in progressive supranuclear palsy

Progressive supranuclear palsy is a sporadic neurodegenerative 4-repeat tauopathy associated with significant morbidity. Heterogeneity of symptom expression among this group is increasingly recognized, reflecting variable tau spread and neurodegeneration. Clinical manifestations consist of debilitating and rapidly progressive motor, oculomotor, speech, cognitive and affective impairments. Core pathological changes are noted with a predominance in the midbrain and basal ganglia; however, spread to the more caudal brainstem and cerebellar regions is reported at various stages. Accordingly, whilst midbrain atrophy is the best recognized supportive imaging finding, quantitative neuroimaging studies using MRI and PET approaches have revealed a wider profile of brain abnormalities in cohorts of individuals with progressive supranuclear palsy. This expanded neurobiological scope of disease may account for individual heterogeneity and may highlight additional biological markers that are relevant to diagnosing and tracking the illness. Additionally, there is increasing understanding of the diverse cognitive, affective and speech functions of the cerebellum, which may be implicated in progressive supranuclear palsy beyond current recognition. In this review, we undertake a systematic literature search and summary of in vivo structural and functional neuroimaging findings in the brainstem and cerebellum in progressive supranuclear palsy to date. Novel and multimodal imaging techniques have emerged over recent years, which reveal several infratentorial alterations beyond midbrain atrophy in progressive supranuclear palsy. Most saliently, there is evidence for volume loss and microstructural damage in the pons, middle cerebellar peduncles and cerebellar cortex and deep nuclei, reported alongside recognized midbrain and superior cerebellar peduncle changes. Whilst the literature supporting the presence of these features is not unanimous, the evidence base is compelling, including correlations with disease progression, severity or variant differences. A smaller number of studies report on abnormalities in MRI measures of iron deposition, neuromelanin, viscoelasticity and the glymphatic system involving the infratentorial regions. Molecular imaging studies have also shown increased uptake of tau tracer in the midbrain and cerebellar dentate nucleus, although concern remains regarding possible off-target binding. Imaging of other molecular targets has been sparse, but reports of neurotransmitter, inflammatory and synaptic density alterations in cerebellar and brainstem regions are available. Taken together, there is an established evidence base of in vivo imaging alterations in the brainstem and cerebellum which highlights that midbrain atrophy is often accompanied by other infratentorial alterations in people with progressive supranuclear palsy. Further research examining the contribution of these features to clinical morbidity and inter-individual variability in symptom expression is warranted.