Neural Substrates of Executive Dysfunction in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): a Brain Potential Study

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 23; no. 11; pp. 2657 - 2666
• Main Authors: Yang, J.-C., Chan, S.-H., Khan, S., Schneider, A., Nanakul, R., Teichholtz, S., Niu, Y.-Q., Seritan, A., Tassone, F., Grigsby, J., Hagerman, P. J., Hagerman, R. J., Olichney, J. M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.11.2013
• Subjects: Acoustic Stimulation; Attention - physiology; Cerebellar Diseases - physiopathology; Cerebral Cortex - physiopathology; Electroencephalography; Evoked Potentials, Auditory; Executive Function - physiology; Female; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Humans; Male; Memory, Short-Term - physiology; Middle Aged; Neuropsychological Tests; attention; working memory; FMR1; P300; executive function
• ISSN: 1047-3211; 1460-2199; 1460-2199
• DOI: 10.1093/cercor/bhs251

Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.