Preclinical trial for dysarthria treatment in Parkinson disease

项目总结

PROJECT SUMMARY Parkinson disease (PD) is devastating to communication, which is also impacted by concurrent cognitive and affective impairments. The hallmark pathology, loss of dopamine, has guided therapy for decades; however, dopamine-centered treatments do not improve vocal communication, cognition, or affect. In fact, prior to classic dopamine loss, there is significant degeneration in the locus coeruleus, a norepinephrine-rich brainstem region that is vital to communicative and cognitive behaviors. Here, we propose to study three different therapeutic approaches that modulate norepinephrine (exercise, drugs, socialization) based on the rationale that modulating noradrenergic brain systems will improve PD-related communication deficits, as well as cognition and affect. We hypothesize that the benefit of these therapies will be improved communication, cognition, and affect as well as neuroprotection (i.e. sparing of neurons, increased neurotrophins). However, as with any treatment, there may be unwanted side effects such as anxiety, increased motor errors, or enhanced neuroprogression (loss of neurons) due to neurotoxicity of drugs. For superior experimental control and to study underlying neural mechanisms with increased scientific rigor, we will use a well-established translational rat model. The Pink1-/- rat is based on a genetic form of early and progressive PD (PARK6) that is nearly identical to idiopathic PD. We have shown communication, motor, cognitive, and affective deficits and neural abnormalities that are analogous to humans, including early loss of norepinephrine in brain regions important to communication. Aim 1 will analyze the benefits and side effects of intervention on communication, cognition, and affect. Pink1-/- rats will be treated with either: (1) cardiovascular exercise, (2) targeted vocal exercise, (3) methylphenidate, (4) propranolol, (5) social enrichment, or (6) control conditions at 10 months of age, which is equivalent to human age at time of diagnosed and treatment initiation. Vocalization, attention, accuracy, memory, anhedonia, and anxiety will be assayed, and effect sizes of each treatment will be calculated to determine the impact of treatment on all outcomes. Aim 2 will quantify changes to the brain with these interventions. Rats from Aim 1 will undergo in vivo microPET scanning to determine how interventions modulate norepinephrine. Ex vivo, brain tissues will be analyzed for neurotransmitter content, cell numbers, and changes to neurotrophins/receptors in regions associated with vocalization, cognition, and affect using high pressure liquid chromatography and immunohistochemistry. We hypothesize that interventions will result in either neuroprotection (e.g., increases in neurotrophic factors) or neurodegeneration (e.g., cell death/loss of neurotransmitter). This work is innovative because it is the first controlled study to robustly assess behavioral responses to noradrenergically-based interventions and concurrently measures in vivo modulation of norepinephrine and other important brain mechanisms as a result of intervention. Findings will be readily translated to directed human clinical trials to combat this devastating human health problem.