title: Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation.
abstract: Recent evidence indicates that adults with a premutation (PM: 55-199 CGG repeats) expansion in the fragile X mental retardation 1 (FMR1) gene show postural control deficits that may reflect disruption to cerebellar motor regions. Less is known about the influence of reduced cerebellar volume and structural changes, and increase in CGG repeat and FMR1 mRNA levels on the attentional demands of step initiation in PM males. We investigated the effects of a concurrent cognitive task on choice stepping reaction time (CSRT) and explored the associations between CSRT performance, cerebellar volume, CGG size, and FMR1 mRNA levels in blood in PM males. We examined 19 PM males (ages 28-75) and 23 matched controls (CGG <44; ages 26-77), who performed a verbal fluency task during CSRT performance and single-task stepping without a secondary cognitive task. Our results provide preliminary evidence that smaller cerebellar volume (β = -2.73, p = 0.002) and increasing CGG repeat length (β = 1.69, p = 0.003) were associated with greater dual-task step initiation times in PM males, but not in controls. There was evidence of a mediating effect of cerebellar volume on the relationship between FMR1 mRNA levels and single-task CSRT performance in PM males (estimate coefficient = 8.69, standard error = 4.42, p = 0.049). These findings suggest increasing CGG repeat and FMR1 mRNA levels have neurotoxic effects on cerebellar regions underlying anticipatory postural responses during stepping. Cerebellar postural changes may be predictive of the increased risk of falls in older PM males.
authors.affiliation: Developmental Neuromotor and Cognition Lab, School of Psychology and Public Health, La Trobe University, Melbourne, Australia. Electronic address: D.Hocking@latrobe.edu.au.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Hocking
authors.affiliation: Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW Australia, Sydney, Australia.
authors.forename: Rachael C
authors.initials: RC
authors.lastname: Birch
authors.affiliation: Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Victoria, Australia.
authors.forename: Quang M
authors.initials: QM
authors.lastname: Bui
authors.affiliation: Falls and Balance Research Group, Neuroscience Research Australia, Sydney, Australia; School of Public Health, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Jasmine C
authors.initials: JC
authors.lastname: Menant
authors.affiliation: Falls and Balance Research Group, Neuroscience Research Australia, Sydney, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Lord
authors.affiliation: Monash School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
authors.forename: Nellie
authors.initials: N
authors.lastname: Georgiou-Karistianis
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: Godler
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Australia, Sydney, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Newcastle, Australia; School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Newcastle, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW Australia, Sydney, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Australia, Sydney, Australia. Electronic address: j.trollor@unsw.edu.au.
authors.forename: Julian N
authors.initials: JN
authors.lastname: Trollor
mesh_terms: D000328:Adult; D000368:Aged; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000473:pathology*; D003071:Cognition / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D059906:Neuroimaging; D004856:Postural Balance / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D011930:Reaction Time; D018911:Trinucleotide Repeats
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human
keywords: Cerebellar motor networks; Choice stepping reaction time; Cognitive-motor interference; FMR1 premutation carrier; Fragile X mental retardation gene 1 (FMR1); Motor symptoms; Postural balance; Step initiation