Pathophysiology of Parkinson's disease

Parkinson's disease (PD) has classically been considered a disease of motor dysfunction, but it also includes psychiatric symptoms. To better understa nd the symptoms and signs that accompany PD, the interrelationships of deep brain structures and cortical areas involved with this neurodegenerative d isease must be investigated. Current models of basal ganglia/cortical physi ology attempt to integrate motor and nonmotor physiology and describe the p athophysiology attributable to PD. The cortical areas comprising basal gang lia/cortical loops include frontal structures involved in motor program as well as more prefrontal structures likely subserving non-motor functions su ch as cognition. The etiology of PD is not clear, but studies have implicat ed oxidative stress from exogenous stressors or endogenous neurotoxins. A l arge number of PD patients have been found to exhibit mitochondrial dysfunc tion. Lewy bodies are seen within dopaminergic and other neuronal populatio ns affected in PD, and they stain positive for ubiquitin and alpha-synuclei n. The small percentage of familial PD has often been found to coincide wit h dominantly inherited mutations in the gene for alpha-synuclein, or with t he recessive gene mutation for parkin, which is involved in the ubiquitinat ion pathway. Selected neuronal populations are affected in PD, and the neur odegeneration may include dopaminergic neurons outside the substantia nigra pars compacta, as well and non-dopaminergic neurons. The loss of these neu ronal populations within the basal ganglia-frontal circuits can have a prof ound effect upon the motor and neurobehavioral symptoms in PD. L-dopa remai ns the most effective pharmacologic therapy for PD, however as the disease progresses, the drug loses its efficacy and troublesome side-effects often occur. The renewal of surgical interventions for PD has increased the insig ht into the pathophysiology of PD, and surgical lesions have shown that mot or and cognitive fronto-subcortical circuits are seemingly segregated in pa tients with PD. Investigation into these circuits helps provides models und erlying motor and cognitive pathophysiology of PD.