Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS)

Deborah A Hall, Erin E Robertson, Maureen Leehey, Andrew McAsey, Bichun Ouyang, Elizabeth Berry-Kravis, Joan A O'Keefe, Deborah A Hall, Erin E Robertson, Maureen Leehey, Andrew McAsey, Bichun Ouyang, Elizabeth Berry-Kravis, Joan A O'Keefe

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710.

Trial registration: ClinicalTrials.gov NCT02197104.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Consort flow diagram for recruitment.
Fig 1. Consort flow diagram for recruitment.
Fig 2. Plot of Fragile X-associated tremor/ataxia…
Fig 2. Plot of Fragile X-associated tremor/ataxia syndrome scores.

References

    1. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57: 127–130. 10.1212/wnl.57.1.127
    1. Tassone F, Hagerman R (2012) The fragile X-associated tremor ataxia syndrome. Results Probl Cell Differ 54: 337–357. 10.1007/978-3-642-21649-7_18
    1. Seltzer MM, Baker MW, Hong J, Maenner M, Greenberg J, Mandel D. (2012) Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet 159B: 589–597. 10.1002/ajmg.b.32065
    1. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. (2004) Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291: 460–469. 10.1001/jama.291.4.460
    1. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xuncla M, Badenas C, Kulisevsky J, et al. (2009) Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 17: 1359–1362. 10.1038/ejhg.2009.51
    1. Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, Fernandez-Novoa L, et al. (1999) Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin Pharmacol 21: 633–644.
    1. Qurashi A, Liu H, Ray L, Nelson DL, Duan R, Jin P. (2012) Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila. Hum Mol Genet 21: 2068–2075. 10.1093/hmg/dds024
    1. Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L, et al. (2008) FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 70: 1397–1402. 10.1212/01.wnl.0000281692.98200.f5
    1. Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M, et al. (1999) Total neuropathy score: validation and reliability study. Neurology 53: 1660–1664. 10.1212/wnl.53.8.1660
    1. Seritan AL, Kim K, Benjamin I, Seritan I, Hagerman RJ (2016) Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome. J Geriatr Psychiatry Neurol 29: 328–337. 10.1177/0891988716666379
    1. Grigsby J, Kaye K, Robbins LJ (1992) Reliabilities, norms and factor structure of the Behavioral Dyscontrol Scale. Percept Mot Skills 74: 883–892. 10.2466/pms.1992.74.3.883
    1. Stroop JR (1935) Studies of interference in serial verbal reactions. Journal of Experimental Psychology 18: 643–662.
    1. Wechsler D (1997) Wechsler Adult Intelligence Scale 3rd Edition (WAIS-3®). San Antonio, TX: Harcourt Assessment.
    1. Goodglass H, Kaplan E. (1972) The assessment of aphasia and related disorders. Philadelphia, PA: Lea and Febiger.
    1. Borkowski JG, Benton AL, Spreen O (1967) Word fluency and brain damage. Neuropsychologia 5: 135–140.
    1. Hellmuth J (1968) Learning disorders: Vol. 3. Seattle: Special Child Publications.
    1. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53: 695–699. 10.1111/j.1532-5415.2005.53221.x
    1. Salarian A, Horak FB, Zampieri C, Carlson-Kuhta P, Nutt JG, Aminian K. (2010) iTUG, a sensitive and reliable measure of mobility. IEEE Trans Neural Syst Rehabil Eng 18: 303–310. 10.1109/TNSRE.2010.2047606
    1. Kellor M, Frost J, Silberberg N, Iversen I, Cummings R (1971) Hand strength and dexterity. Am J Occup Ther 25: 77–83.
    1. Powell LE, Myers AM (1995) The Activities-specific Balance Confidence (ABC) Scale. J Gerontol A Biol Sci Med Sci 50A: M28–34. 10.1093/gerona/50a.1.m28
    1. Beck AT, Epstein N, Brown G, Steer RA (1988) An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 56: 893–897. 10.1037//0022-006x.56.6.893
    1. Eaton WW, Smith C, Ybarra M, Muntaner C, Tien A (2004) Center for Epidemiologic Studies Depression Scale: Review and Revision (CESD and CESD-R). The use of psychological testing for treatment planning and outcomes assessment: Instruments for adults, Volume 3, 3rd ed Mahwah, NJ, US: Lawrence Erlbaum Associates Publishers; pp. 363–377.
    1. Hunter JE, Sherman S, Grigsby J, Kogan C, Cornish K (2012) Capturing the fragile X premutation phenotypes: a collaborative effort across multiple cohorts. Neuropsychology
    1. Seritan AL, Nguyen DV, Mu Y, Tassone F, Bourgeois JA, Schneider A, et al. (2014) Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 75: 264–271. 10.4088/JCP.13m08546

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