P4‐018: Biochemical correlates of clinical symptoms in dementia with Lewy bodies and Parkinson's disease dementia

Abstract

Dementia with Lewy bodies (DLB) and Parkinson's Disease Dementia (PDD) are common causes of dementia. The biochemical basis of cognitive and psychiatric symptoms of these conditions remains poorly understood. Synaptic dysfunction is hypothesised to be a major correlate of cognitive dysfunction and to contribute to specific psychiatric symptoms, therefore alterations in key synaptic proteins have been investigated. A cohort of 98 PDD and DLB brains, significantly larger than most previous studies, with 28 control brains and a depth of supporting clinical data was available for study. Semi-quantitative Western blotting was used to investigate the levels of key synaptic proteins: zinc transporter (ZnT3, implicated in mouse models to be involved in age-dependent memory loss), PSD95 (an important regulator of post-synaptic neurotransmitter receptors), beta-III-tubulin (a cytoskeletal neuronal marker) and specific markers of vesicle release and recycling such as synaptophysin (SPP, presynaptic vesicle protein), syntaxin1 (transmembrane SNARE protein), Munc18 (vesicle docking regulator) and dynamin1 (vesicle endocytosis regulator) in two cortical regions. Measurements made in the prefrontal cortex (BA9) of PDD and control cases indicate decreases in the levels of the following synaptic proteins in PDD cases; ZnT3 (-57%), PSD-95 (-54%), synaptophysin (-34%), Munc18 (-34%), Dynamin1 (-41%), and beta-III-tubulin (-18%). PSD95 and ZnT3 were decreased in DLB compared to control (both -47%). All changes were statistically significant (ANOVA P<0.05, DLB n = 22-50, PDD n = 25-32, control n = 10-24). No significant changes were found in BA24, except for Munc18 expression decreased in PDD group compared to DLB group (-23%). Furthermore, a negative correlation was found between SPP levels in BA9 and depression and agitation/aggression (NPI) scores; Munc18 levels in BA9 and BA24 positively correlate with hallucinations scores. Our data suggest a greater synaptic dysfunction in processes of vesicle docking, neurotransmitter release and reuptake in BA9 of PDD cases. The similarities in prefrontal ZnT3 and PSD95 levels could be related to a common underlying cause or that zinc released synaptically has an influence the post-synaptic density. It would appear that some of the behavioural symptoms associated with DLB/PDD may be linked to synaptic dysfunction in the prefrontal cortex and may suggest novel treatment strategies.