title: Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives.
abstract: Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions.
authors.affiliation: 1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA2 National Institute on Drug Abuse, Bethesda MD 20892, USA nvolkow@nida.nih.gov.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.affiliation: 1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA.
authors.forename: Dardo
authors.initials: D
authors.lastname: Tomasi
authors.affiliation: 1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA.
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: 1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Studentsova
authors.affiliation: 3 A-T Children's Project; 5300 W. Hillsboro Blvd, Suite 105, Coconut Creek FL 33073, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Margus
authors.affiliation: 4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
mesh_terms: D000293:Adolescent; D000328:Adult; D001260:Ataxia Telangiectasia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D009154:Mutation / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods; D055815:Young Adult
chemical_list: D019788:Fluorodeoxyglucose F18; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D005947:Glucose
keywords: ATM; ataxia telangiectasia mutated; cerebellum; fusiform gyrus; globus pallidus; hippocampus
references.citation: J Neurosci. 2006 Jul 19;26(29):7767-74
references.pmid: 16855104
references.citation: Lancet Neurol. 2012 May;11(5):429-42
references.pmid: 22516078
references.citation: J Clin Neurosci. 1998 Oct;5(4):471-3
references.pmid: 18639085
references.citation: Mov Disord. 1994 Jul;9(4):455-9
references.pmid: 7969215
references.citation: Neuropathology. 2012 Jun;32(3):234-44
references.pmid: 22017321
references.citation: Brain. 2006 Mar;129(Pt 3):564-83
references.pmid: 16399806
references.citation: Neurologist. 2008 May;14(3):192-5
references.pmid: 18469676
references.citation: J Neurophysiol. 2010 Dec;104(6):3667-76
references.pmid: 20962069
references.citation: Cerebellum. 2012 Mar;11(1):233-45
references.pmid: 21761197
references.citation: Neuropediatrics. 2012 Jun;43(3):119-29
references.pmid: 22614068
references.citation: Minerva Med. 1982 Sep 8;73(34):2183-8
references.pmid: 7110600
references.citation: Hum Mutat. 2012 Mar;33(3):561-71
references.pmid: 22213089
references.citation: Neurology. 2000 Apr 11;54(7):1505-9
references.pmid: 10751267
references.citation: Lancet Neurol. 2009 Aug;8(8):709-17
references.pmid: 19576854
references.citation: Brain. 1994 Aug;117 ( Pt 4):877-97
references.pmid: 7922472
references.citation: Am J Med Genet. 2000 May 29;92(3):170-7
references.pmid: 10817650
references.citation: Neurology. 2009 Aug 11;73(6):430-7
references.pmid: 19535770
references.citation: PLoS One. 2010 Dec 13;5(12):e15010
references.pmid: 21179436
references.citation: AJNR Am J Neuroradiol. 2014 Jan;35(1):119-23
references.pmid: 23886747
references.citation: AJNR Am J Neuroradiol. 2007 Jan;28(1):79-83
references.pmid: 17213429
references.citation: J Natl Cancer Inst. 2005 Jun 1;97(11):813-22
references.pmid: 15928302
references.citation: J Neurol Sci. 2006 Feb 15;241(1-2):1-6
references.pmid: 16380133
references.citation: Cerebellum. 2010 Jun;9(2):190-7
references.pmid: 19898915
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1187-96
references.pmid: 15279807
references.citation: J Neurochem. 1977 May;28(5):897-916
references.pmid: 864466
references.citation: Neuroradiology. 2003 May;45(5):315-9
references.pmid: 12740724
references.citation: Am J Hum Genet. 1986 Nov;39(5):573-83
references.pmid: 3788973
references.citation: Ann Neurol. 1979 Nov;6(5):371-88
references.pmid: 117743
references.citation: Front Syst Neurosci. 2013 Oct 01;7:56
references.pmid: 24101896
references.citation: Curr Biol. 2009 Dec 29;19(24):2091-6
references.pmid: 19962314
references.citation: Radiology. 1993 Jan;186(1):59-65
references.pmid: 8416587
references.citation: Neuroimage. 2012 Jul 16;61(4):1213-25
references.pmid: 22525876
references.citation: J Cereb Blood Flow Metab. 2007 Mar;27(3):597-605
references.pmid: 16804550
references.citation: Ann Neurol. 1999 Sep;46(3):287-95
references.pmid: 10482258
references.citation: Trends Neurosci. 2009 Oct;32(10):548-57
references.pmid: 19765835
references.citation: Cerebellum. 2011 Sep;10(3):422-34
references.pmid: 20838950
references.citation: Neurosurgery. 2012 Jan;70(1):162-9; discussion 169
references.pmid: 22158304
references.citation: J Neurosci. 2005 Apr 13;25(15):3932-9
references.pmid: 15829645