Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in approximately 40% of aging male (and less commonly, female) carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The overall goal of this project is to develop and utilize quantitative measures of CNS 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 a medical assessment that includes a videotaped neurological examination with quantitative standardized measures, subjects will participate in several quantitative analyses of CNS dysfunction (Aim 1), including volumetric MRI studies, event related potentials (ERPs), psychophysiological studies (prepulse inhibition and fear potentiated startle), quantitative motor measures (CATSYS), neuropsychological measures (executive function and memory), and nerve conduction studies (NCS). Many of these quantitative measures will also be carried out in transgenic mouse models of FXTAS (Project 2), which will then be used as animal correlates, to better gauge the neuropathology of FXTAS and its intrinsic reversibility as a model for successful therapeutic intervention. A component of this research will develop, with Project 4, an integrated MRI approach for studying volumetric changes across the lifespan of premutation carriers. Consortium Project 1 described preliminary observations for the neuroprotective effect of lithium in a neural cell model of FXTAS.
Aim 2 of this project will study the neuroprotective effects of lithium carbonate in a controlled trial of aging premutation carriers who have early symptoms of FXTAS (Aim 2). We will use the quantitative measures outlined above as outcome measures for this lithium trial in addition to psychiatric assessments 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 an open trial, to patients who are ineligible or unwilling to participate in the lithium trial, to assess the benefit of the NMDA antagonist, memantine. Studies in Project 1 and 2, related to involvement of glutamate toxicity in FXTAS, will better inform this treatment trial.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Linked Research project Grant (RL1)
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Special Emphasis Panel (ZRR1-SRC (99))
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Hsiao, John
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University of California Davis
Schools of Medicine
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Seritan, Andreea L; Kim, Kyoungmi; Benjamin, Ian et al. (2016) Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome. J Geriatr Psychiatry Neurol :
Yang, Jin-Chen; Rodriguez, Annette; Royston, Ashley et al. (2016) Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial. Sci Rep 6:21719
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Ram, Suresh; Devapriya, Inoka A; Fenton, Grace et al. (2015) Axonal neuropathy in female carriers of the fragile X premutation with fragile x-associated tremor ataxia syndrome. Muscle Nerve 52:234-9
Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora et al. (2015) Immune mediated disorders in women with a fragile X expansion and FXTAS. Am J Med Genet A 167A:190-7
Muzar, Zukhrofi; Lozano, Reymundo; Schneider, Andrea et al. (2015) Methadone use in a male with the FMRI premutation and FXTAS. Am J Med Genet A 167:1354-9
Careaga, Milo; Rose, Destanie; Tassone, Flora et al. (2014) Immune dysregulation as a cause of autoinflammation in fragile X premutation carriers: link between FMRI CGG repeat number and decreased cytokine responses. PLoS One 9:e94475
Yang, Jin-Chen; Niu, Yu-Qiong; Simon, Christa et al. (2014) Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study. Neuropsychopharmacology 39:2760-8
Hall, Deborah A; Birch, Rachael C; Anheim, Mathieu et al. (2014) Emerging topics in FXTAS. J Neurodev Disord 6:31
Seritan, Andreea L; Nguyen, Danh V; Mu, Yi et al. (2014) Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 75:264-71

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