A clinico-pathological investigation of the human basal ganglia and brainstem in clinical subtypes of Parkinson’s disease

Abstract

Introduction: Parkinson’s disease (PD) is a progressive, neurodegenerative disorder with different motor subtypes (tremor-dominant (TD), akinetic-rigid (AR) or mixed) based on variation in the presence and severity of the four main motor signs – tremor, rigidity, akinesia and postural instability/gait difficulty. The exact pathology underlying these presentations is unclear, but responses to dopaminergic and non-dopaminergic medications vary, suggesting that multiple neurotransmitter systems are involved. AR motor subtype appears to have prognostic capacity for predicting cognitive impairment. However, this not well-characterised, and it is unknown whether the relationship between gait and cognition reflects a shared underlying pathophysiology. In this thesis, I set out to delineate this relationship to identify prognostic trends, and to identify the pathology underpinning motor subtype and the decline to cognitive impairment in PD. Methods: 13 controls, 40 TD, 40 Mixed and 40 AR cases were obtained from the Parkinson’s UK Tissue Bank, based on retrospective clinical note evaluation. Tissue sections containing the substantia nigra (SN), locus coeruleus (LC) and striatum were immunostained for tyrosine hydroxylase (TH) to stain for monoaminergic neurons and choline acetyltransferase (ChAT) for cholinergic interneurons (ChIs) in the striatum. Questionnaires from Tissue Bank cases and longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI) cohort were used to assess clinical correlations between AR features and cognitive decline in PD. Results: Loss of TH cell populations and proteinopathy in the SN and LC occurred to the same extent in all motor subtypes compared to controls. In contrast, striatal ChIs showed reduced primary and secondary arborisation and increased tau deposition in AR cases compared to TD and Mixed cases. Tau deposition in the striatum correlated significantly with branching of ChIs. AR features, gait disturbance particularly, were found to be a harbinger of cognitive decline within 3 years. PPMI data showed that this was most significantly associated with measures of attention, verbal learning, visuospatial and executive dysfunction. Conclusions: The PD motor syndrome in general arises from degeneration of monoaminergic cell populations, but variations in the presence and severity of motor and cognitive symptoms may arise from non-dopaminergic systems such as the cholinergic system. This may explain the differential response of PD motor subtypes to cholinergic medication. Failure of cholinergic neurotransmission, and proteinopathy in regions such as the striatum and the cerebral cortex, may underlie the temporal interaction between gait disturbance and cognitive impairment, with dysfunction of synaptic plasticity playing an important role.