P. O. FERNAGUT - Preclinical Insights into Individual Vulnerability to Cognitive Dysfunction and Dopamine Therapy Side Effects in Parkinson's Disease

Parkinson's disease (PD) is a highly heterogenous disorder that does not confine to the cardinal motor symptoms. Non-motor features of PD and non-motor side effects of dopamine replacement therapy are important factors contributing to the decreased quality of life of patients. Within the large spectrum of non-motor symptoms, subtle deficits in executive function (attentional, memory deficits, decreased cognitive flexibility and inhibitory control) can be detected in one third of patients early in the course of the disease.
In some patients, these cognitive impairments may increase the susceptibility to develop neuropsychiatric side-effects of dopamine replacement therapy. Using a rat model of PD with progressive nigrostriatal degeneration, we have shown that both nigrostriatal degeneration and dopamine replacement therapy impair frontostriatal circuits. However, despite homogenous motor impairments, dopaminergic neurodegeneration leads to unequal impairments in behavioral flexibility. Likewise, the deleterious Dopamine replacement therapy on executive function are not uniform between flexible and inflexible rats. Altogether, these predinical studies suggest that the propensity to develop cognitive impairment and neuropsychiatric side-effects could be linked to premorbid interindividual differences.