Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies

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Parkinson disease (PD) and dementia with Lewy bodies (DLB) belong to the human alpha‐synucleinopathies, which are characterized by neurodegeneration and widespread aggregation of the alpha‐synuclein protein.1 They were originally described as different diseases, but are more recently considered to represent different clinical patterns within the same clinicopathological spectrum.4
The disease symptoms of PD include rigidity, bradykinesia, gait and postural instability, resting tremor, impaired balance and postural reflexes, and a pronounced L‐dopa responsiveness of the cardinal motor symptoms, as well as the manifestation of nonmotor symptoms including autonomic, sleep, sensory, gastrointestinal, oculomotor, and mood disturbances.6 In the advanced disease stages 25 to 40% of all PD patients display a dementing syndrome, usually referred to as PD with dementia (PDD).7 Most PD cases are idiopathic, although there are familial forms, several of which are monogenic and have a brain neuropathology more or less identical to that of idiopathic PD, for example, the alanine to proline (A30P) mutation of the alpha‐synuclein protein.6
DLB represents the second most common dementing neurodegenerative disorder.3 The clinical manifestations include cardinal symptoms, that is, progressive and fluctuating dementia, recurrent visual hallucinations, and Parkinson‐like motor manifestations and secondary symptoms (ie, autonomic, sleep, dysphagia, and oculomotor symptoms, depression, and executive dysfunction).3 As with PD, DLB cases are usually idiopathic, although several familial forms including monogenic causes are known.10
In the brains of PD and DLB patients, the following alpha‐synuclein–immunopositive, insoluble aggregates occur: (1) Lewy bodies (LB) in the neuronal perikarya; (2) Lewy neurites (LN) in neuronal processes; (3) coiled bodies (CB) in oligodendrocytes.3 The PD‐related brain pathology presumably propagates along neuronal interconnectivities in a prionlike manner and spreads in highly stereotypical temporal and topographical sequences, which were compiled into a neuropathological staging system by Braak et al.2 Because DLB patients exhibit similar brain distribution patterns of aggregation pathology as PD patients, it is tempting to suggest that analogous mechanisms of propagation are at work.12
Several of the motor symptoms of PD and DLB patients (ie, resting tremor, disturbed balance, gait and postural reflexes), do not respond well to the widely used L‐dopa treatment but can be associated with pathological changes in pre‐ or postcerebellar circuits or the cerebellum itself, which was considered to be unaffected by the aggregation pathology in PD and DLB.2 Additionally, recent systematic studies demonstrated cerebellar pathology in a monogenic PD patient with the A30P mutation as well as alpha‐synuclein aggregates in precerebellar brainstem structures in idiopathic PD and DLB patients.8 This implies a distinct possibility that the cerebellum is affected by the aggregation pathology in idiopathic PD and DLB. Thus, we performed a systematic investigation of the neuropathology of the cerebella of PD and DLB patients and a reinvestigation of the cerebellum of a patient with the A30P mutation.

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