Parkinson’s disease is the second most common neurodegenerative disease in the world. The initial motor symptoms are well controlled with replacement therapy with levodopa. Slowly over time the patients run into problems both due to the inexorable progression of the disease and also due to complications of the drugs itself. The two most common disabling complications that are difficult to treat are levodopa-induced-dyskinesias and dementia. Although there have been extensive research, the pathophysiology of both these conditions are still unclear. Unsurprisingly treatment options are limited for both these conditions.
From the dyskinesia research, studies with animal models of Parkinsonism have shown abnormalities in glutamate neurotransmission but the role of glutamate in causing dyskinesias in PD patients in still unclear. Using a novel PET tracer [11C]CNS-5161 we demonstrated in vivo an increased activity of NMDA-glutamate receptors specifically in the motor areas when levodopa was administered to dyskinetic PD patients. On the other hand non-dyskinetic PD patients had the opposite effect i.e. reduction of glutamate channel opening with levodopa administration. Our study implicates glutamate overactivity to be a major factor in causing LID and supports the use of anti-glutamate agents in PD dyskinesias.
In PD Dementia patients the pathophysiological basis of the disease is still unknown. Concomitant AD type amyloid pathology, cortical Lewy disease , inflammation and biochemical neurotransmitter defects have all been thought to cause the disease. Using specific PET tracers, [11C]-PIB which bind to amyloid , [11C]-PK11195 which bind to activated microglia associated with inflammation and [18F] FDG which measure neuronal dysfunction we showed increased cortical microglial activation and glucose utilisation in both PDD and PD patients but more so in PDD patients implying ongoing disease activity with inflammation playing an important role relatively early in the disease. The conspicuous absence of [11C]-PIB uptake in the majority of PD patients makes amyloid pathology quite unlikely in causing the disease. Our study favours treatment strategies to reduce microglial activation relatively early in the disease compared to anti-amyloid therapy in PDD.
Thus this research provides a pathophysiological basis for both PD dyskinesias and dementia and does open up avenues for further treatment strategies.