Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in approximately 40% of aging male (andless commonly, female) carriers of premutation expansions (55-200 CGG repeats) of the fragile X mentalretardation 1 (FMR1) gene. The overall goal of this project is to develop and utilize quantitative measures ofCNS dysfunction in premutation carriers as outcome measures for targeted treatment studies of FXTAS.Sixty premutation carriers, ages 30 to 79 yr, both affected and unaffected, and an equal number of age-,sex-, and education-matched controls will be recruited per year for the first 3 years of the project. Following amedical assessment that includes a videotaped neurological examination with quantitative standardizedmeasures, subjects will participate in several quantitative analyses of CNS dysfunction (Aim 1), includingvolumetric MRI studies, event related potentials (ERPs), psychophysiological studies (prepulse inhibition andfear potentiated startle), quantitative motor measures (CATSYS), neuropsychological measures (executivefunction and memory), and nerve conduction studies (NCS). Many of these quantitative measures will alsobe carried out in transgenic mouse models of FXTAS (Project 2), which will then be used as animalcorrelates, to better gauge the neuropathology of FXTAS and its intrinsic reversibility as a model forsuccessful therapeutic intervention. A component of this research will develop, with Project 4, an integratedMRI approach for studying volumetric changes across the lifespan of premutation carriers.Consortium Project 1 described preliminary observations for the neuroprotective effect of lithium in aneural cell model of FXTAS.
Aim 2 of this project will study the neuroprotective effects of lithium carbonate ina controlled trial of aging premutation carriers who have early symptoms of FXTAS (Aim 2). We will use thequantitative measures outlined above as outcome measures for this lithium trial in addition to psychiatricassessments of clinical .improvement, including the Neuropsychiatric Inventory, the Symptom Checklist-90(SCL-90), and the Clinical Global Impressions Scale- Improvement (CGI-I).
In Aim 3, we will also offer anopen trial, to patients who are ineligible or unwilling to participate in the lithium trial, to assess the benefit ofthe NMDA antagonist, memantine. Studies in Project 1 and 2, related to involvement of glutamate toxicity inFXTAS, will better inform this treatment trial.
Showing the most recent 10 out of 95 publications
