Cerebellar Degeneration Research
Title: Ataxia, Imaging, and Exercise Disease Using MRI and Gait Analysis
Contact: Scott Barbuto, MD, PhD
New York, NY
Individuals with degenerative cerebellar disease (DCD) exhibit gradual loss of coordination, resulting in impaired balance, gait deviations, and severe, progressive disability. With no available disease-modifying medications, balance training is the primary treatment option to improve motor skills and functional performance. There is no evidence, however, that balance training impacts DCD at the tissue level.
Aerobic training, on the other hand, may modify DCD progression, as evident from animal data. Compared to sedentary controls, aerobically trained DCD rats have enhanced lifespan, motor function, and cerebellar Purkinje cell survival. Numerous animal studies also document that aerobic training has a direct, favorable effect on the brain that includes production of neurotrophic hormones, enhancement of neuroplasticity mechanisms, and protection from neurotoxins.
The effects of aerobic training in humans with DCD are relatively unknown, despite these encouraging animal data. A single study to date has evaluated the benefits of aerobic exercise on DCD in humans, and this was a secondary outcome of the study. Although participants performed limited aerobic training during the study, modest functional benefits were still detected.
This project’s main objective will be to compare the benefits of aerobic versus balance training in DCD. We hypothesize that both aerobic and balance training will improve function in DCD subjects but that the mechanisms in which these improvements occur differ. 1) Balance training improves DCD individual’s ability to compensate for their activity limitations but does not impact disease progression. 2) Aerobic exercise improves balance and gait in DCD persons by affecting brain processes and slowing cerebellar atrophy.
Title: Natural History of Spinocerebellar Ataxia Type 7 (SCA7)
Principal investigator: Laryssa A Huryn, MD
National Institutes of Health Clinical Center
Objective: Spinocerebellar Ataxia, type 7 (SCA7), is an autosomal dominant neurodegenerative disease characterized by progressive ataxia, retinal degeneration, and marked genetic anticipation. The objectives of this study are to 1) establish a cohort of participants with molecularly-confirmed SCA7 in anticipation of future clinical trials, 2) create a repository of plasma, DNA, and skin fibroblast samples from the accrued cohort of SCA7 participants, 3) formulate clinical outcome measures for future studies, and 4) acquire and perform preliminary analyses of data that may advance our understanding of the progression of retinal and neurodegeneration associated with molecularly-confirmed SCA7.
Study Population: Twenty-five (25) participants, ages 12 and above, with molecularly-confirmed SCA7 will be accrued for this study.
Design: In this natural history study, participants will be followed for at least five years. Because three years may be required to enroll 25 participants, this study will last up to eight years. All participants will undergo a standardized medical/ophthalmic history and a complete baseline eye examination, including non-invasive electrophysiology (e.g., electroretinography), psychophysiology (e.g., microperimetry, static perimetry), and diagnostic imaging examinations (e.g., optical coherence tomography). In addition, participants will undergo a detailed neurology exam, neuroimaging (MRI, including special sequences), and consult with speech pathology and/or other rehabilitation services, audiology, and neuropsychology.
The participants will undergo two separate detailed eye examinations and a single neurology/neuroimaging examination within a one to two-week period to establish a baseline. Afterward, they will return to the NEI clinic annually until the last-enrolled participant reaches five years of follow-up. Therefore, this study will require a minimum of five study visits. Follow-up visits will consist of a single detailed eye exam and a single detailed neurology/neuroimaging exam, and follow-up with appropriate consultants. Participants may be seen at more frequent intervals at the investigators’ discretion, depending on the clinical and research situation. Participants will be required to submit a blood sample for analysis, and they will have the option to provide a skin biopsy to facilitate research at a cellular level.
Outcome Measures: This study’s primary outcome is a determination of the amplitude and time of photopic and scotopic responses on electroretinogram. Secondary outcomes include changes in visual acuity, microperimetry, peripheral visual field, color vision, macular thickness, and neurologic outcome variables. Exploratory outcomes for this study include: 1) the formulation of clinical outcome measures for future studies and 2) the acquisition and preliminary analysis of data that may advance our understanding of the progression of retinal and neurodegeneration associated with molecularly-confirmed SCA7. Cells from skin biopsies may be grown in the laboratory to understand better SCA7, including evaluating potential treatments.
Title: Genetic Characterization of Movement Disorders and Dementias
Principal Investigator: Bryan J Traynor, MD
National Institute on Aging (NIA)
Objective: The objective of this study is to ascertain individuals with a clinical diagnosis of a movement disorder or dementia, their affected and unaffected family members, and unrelated, healthy individuals (to provide control samples); to characterize their phenotypes, and to identify and further characterize genetic contributions to etiology by collecting blood samples, and/or saliva samples on these individuals for DNA and induced Pluripotent stem (iPs) cell line preparation.
Study population: Up to 10,000 persons diagnosed with a movement disorder or dementia, 1,000 asymptomatic persons who are family members/related to individuals with a diagnosis of movement disorder or dementia, and 1,000 unrelated, healthy control individuals.
Design: This study usually requires one outpatient visit to the NIH Clinical Center. Participant visits may also take place when they are an inpatient at the NIH Clinical Center. Those who cannot travel to NIH may have study procedures performed at a site near their
home, such as hospital facilities, private physician offices, nursing homes, assisted living facilities, local community centers, or participant homes. Participants will undergo medical record review, a physical examination, and biospecimen collection, including blood draw and/or saliva collection at the enrollment visit.
Follow-up visits may be scheduled to collect additional phenotype information or biospecimens.
Outcome measures: The primary outcome measure of this study is the identification of pathogenic genetic variants that are causative for the movement disorder or dementia with which the patient has been diagnosed. These disease-causing variants are often inherited.
This study’s secondary outcome is the identification of genetic variants that alter susceptibility/risk for the movement disorder or dementia that the patient has been diagnosed with. These genetic risk factors are associated with the disease that can be sporadic.