A clinicopathological investigation of brainstem nuclei in Lewy body dementia

Abstract

Introduction: Lewy Body Dementias (LBD) - Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) - are clinical diagnoses based on the one-year rule and varied symptom onset. Previously, degeneration of the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in LBD has been well established. However, the precise relationship between underlying neuropathology and clinical presentation remains to be determined. Methods: Immunohistochemical and image analysis techniques have been performed to examine neuronal loss and protein pathologies in the noradrenergic and serotonergic systems of 20 PD, 20 PD-MCI, 20 PDD, 20 DLB cases and 20 controls. RNAscope technology was used to decipher the role of cell-surface receptors in LBD pathophysiology. Possible associations between administration of pharmacological agents with LBD pathology and disease duration was also examined. Results: The hippocampus, thalamus and cingulate cortex - crucial components of the Papez circuit - were most affected by the proteinopathies, particularly deposition that correlated with the onset of some DLB symptomatology and non-motor symptoms. LC noradrenergic neurons were reduced in LBD compared to PD. The 5-HT2A receptor seemed to be more abundant than the α2A-adrenergic receptor (AR) and serotonin transporter (SERT) in the frontal cortex of a PD patient than a PDD or DLB patient. Conclusion: LBD phenotypes may be differentiated through their limbic involvement in the Papez circuit, where α-syn accumulation may contribute to non-motor symptoms. The behaviour of each protein type may be extremely heterogenous within each region of the noradrenergic and serotonergic systems, such that it correlates with the onset of different symptoms. There may be lower expression of receptors in LBD than PD patients, perhaps due to end-stage disease and more widespread degeneration. Hence, this study may have provided further insights into LBD pathophysiology and possibly assist clinical trials in future therapeutic interventions.