AbstractDementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are, combined, the second most common type of dementia in the elderly but remain both poorly understood and researched. Diagnosis is based upon clinical symptoms yet there is considerable overlap between DLB, PDD and Alzheimer’s disease (AD), in terms of clinical presentation and pathology. Synapses are critical for neuronal communication and form the basis of memory and behaviour. The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline (based upon work in ZnT3- knockout mice), an observation corroborated by reports of reduced cortical zinc and ZnT3 in the brains of individuals with AD.
This project utilised a cohort of AD, PDD, DLB and control brains with cognitive data and semi-quantitative scores for key behavioural symptoms (depression, agitation, hallucinations, persecution) and the principal pathologies (amyloid-beta, tau and alpha-synuclein). Semi- quantitative Western blotting was used to investigate key synaptic proteins; zinc transporter 3, PSD95, beta-III-tubulin and synaptophysin in three cortical regions.
The major findings of this project were the occurrence of a loss of regulation of synaptic zinc, which predicted cognitive decline, depression and severity of amyloid-beta, tau and alpha-synuclein pathology in different cortical areas. Differences were also demonstrated in synaptic biochemistry between DLB and PDD cases, with PDD cases having a greater synaptic dysfunction.
Important outcomes of this study include the potential for zinc modulation as a new target for the treatment of depression and cognitive decline in LBD, possibly through a modification of pathology, and the potential for synaptic proteins to be utilised as biomarkers for the differentiation of DLB and PDD.
|Date of Award||2014|
|Supervisor||Paul Francis (Supervisor), Tibor Hortobagyi (Supervisor) & Dag Aarsland (Supervisor)|