Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder

Aims: Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with alpha-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). Methods: This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and alpha-synuclein pathology was measured in the same regions with immunohistochemistry. Results: Both the LC and PPN/LDT were vulnerable to alpha-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of alpha-synuclein pathology in LBD with and without RBD. Conclusions: Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to alpha-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective alpha-synuclein-mediated neuronal loss in these nuclei remains to be determined.