R01DC018584

Preclinical Trial for Dysarthria Treatment in Parkinson's Disease - Project Summary

Parkinson's 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 diagnosis 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.

University Of Wisconsin System

TO INVESTIGATE SOLUTIONS TO PROBLEMS DIRECTLY RELEVANT TO INDIVIDUALS WITH DEAFNESS OR DISORDERS OF HUMAN COMMUNICATION IN THE AREAS OF HEARING, BALANCE, SMELL, TASTE, VOICE, SPEECH, AND LANGUAGE. THE NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS (NIDCD) SUPPORTS RESEARCH AND RESEARCH TRAINING, INCLUDING INVESTIGATION INTO THE ETIOLOGY, PATHOLOGY, DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, PRIMARILY THROUGH THE SUPPORT OF BASIC AND APPLIED RESEARCH IN ANATOMY, AUDIOLOGY, BIOCHEMISTRY, BIOENGINEERING, EPIDEMIOLOGY, GENETICS, IMMUNOLOGY, MICROBIOLOGY, MOLECULAR BIOLOGY, THE NEUROSCIENCES, OTOLARYNGOLOGY, PSYCHOLOGY, PHARMACOLOGY, PHYSIOLOGY, PSYCHOPHYSICS, SPEECH-LANGUAGE PATHOLOGY, AND OTHER SCIENTIFIC DISCIPLINES. THE NIDCD SUPPORTS: (1) RESEARCH INTO THE EVALUATION OF TECHNIQUES AND DEVICES USED IN DIAGNOSIS, TREATMENT, REHABILITATION, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES, (2) RESEARCH INTO PREVENTION AND EARLY DETECTION AND DIAGNOSIS OF HEARING LOSS AND SPEECH, VOICE, AND LANGUAGE DISORDERS AND RESEARCH INTO PREVENTING THE EFFECTS OF SUCH DISORDERS BY MEANS OF APPROPRIATE REFERRAL AND REHABILITATION, (3) RESEARCH INTO THE DETECTION, TREATMENT, AND PREVENTION OF DISORDERS OF HEARING AND OTHER COMMUNICATION PROCESSES IN THE ELDERLY POPULATION AND ITS REHABILITATION TO ENSURE CONTINUED EFFECTIVE COMMUNICATION SKILLS, AND (4) RESEARCH TO EXPAND KNOWLEDGE OF THE EFFECTS OF ENVIRONMENTAL AGENTS THAT INFLUENCE HEARING OR OTHER COMMUNICATION PROCESSES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.173 - Research Related to Deafness and Communication Disorders

National Institute on Deafness and Other Communication Disorders (NIDCD) [HHS - NIH]

Madison, Wisconsin 53715 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 401% from $652,249 to $3,266,069.