Abnormal N400 word repetition effects in fragile X-associated tremor/ataxia syndrome.
Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the FMR1 gene, affects many carriers in late-life. Patients with fragile X-associated tremor/ataxia syndrome typically have cerebellar ataxia, intranuclear inclusions in neurons and astrocytes, as well as cognitive impairment. Dementia can also be present with cognitive deficits that are as severe as in Alzheimer's disease, however frontosubcortical type impairment is more pronounced in fragile X-associated tremor/ataxia syndrome. We sought to characterize the P600 and N400 word repetition effects in patients with fragile X-associated tremor/ataxia syndrome, using an event-related potential word repetition paradigm with demonstrated sensitivity to very early Alzheimer's disease. We hypothesized that the fragile X-associated tremor/ataxia syndrome-affected participants with poor declarative verbal memory would have pronounced abnormalities in the P600 repetition effect. In the event-related potential experiment, subjects performed a category decision task whilst an electroencephalogram was recorded. Auditory category statements were each followed by an associated visual target word (50% 'congruous' category exemplars, 50% 'incongruous' nouns). Two-thirds of the stimuli (category statement-target word pairs) were repeated, either at short-lag (approximately 10-40 s) or long-lag (approximately 100-140 s). The N400 and P600 amplitude data were submitted to split-plot analyses of variance. These analyses of variance showed a highly significant reduction of the N400 repetition effect (F = 22.5, P < 0.001), but not of the P600 repetition effect, in mild fragile X-associated tremor/ataxia syndrome (n = 32, mean age = 68.7, mean Mini-Mental State Examination score = 26.8). Patients with fragile X-associated tremor/ataxia syndrome had significantly smaller late positive amplitude (550-800 ms post-stimulus onset) to congruous words (P = 0.04 for group effect). Reduced P600 repetition effect amplitude was associated with poorer recall within fragile X-associated tremor/ataxia syndrome patients (r = 0.66) and across all subjects (r = 0.52). Larger P600 amplitude to new congruous words also correlated significantly with higher free recall scores (r = 0.37, P < 0.01) across all subjects. We found a correlation between the amplitude of late positivity and CGG repeat length in those with fragile X-associated tremor/ataxia syndrome (r = 0.47, P = 0.006). Higher levels of FMR1 mRNA were associated with smaller N400s to incongruous words and larger positive amplitudes (between 300 and 500 ms) to congruous words. In conclusion, event-related potential word repetition effects appear sensitive to the cognitive dysfunction present in patients with mild fragile X-associated tremor/ataxia syndrome. Their more severe reduction in N400 repetition effect, than P600, is in contrast to the reverse pattern reported in amnestic mild cognitive impairment and incipient Alzheimer's disease (Olichney et al., 2008).
Olichney
John M
JM
Department of Neurology, University of California Davis, Davis, CA 95618, USA. jmolichney@ucdavis.edu
Chan
Shiaohui
S
Wong
Ling M
LM
Schneider
Andrea
A
Seritan
Andreea
A
Niese
Adam
A
Yang
Jin-Chen
JC
Laird
Kelsey
K
Teichholtz
Sara
S
Khan
Sara
S
Tassone
Flora
F
Hagerman
Randi
R
D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D004569:Electroencephalography; D005071:Evoked Potentials; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008568:Memory; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D013577:Syndrome; D014202:Tremor / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D018911:Trinucleotide Repeats; D014705:Verbal Behavior
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human
Psychophysiology. 1986 Jul;23(4):367-84
3774922
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12085-9
10518580
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5973-8
9159185
Lancet Neurol. 2007 Jan;6(1):45-55
17166801
Clin EEG Neurosci. 2007 Jan;38(1):8-17
17319587
Trends Neurosci. 2004 Jul;27(7):370-7
15219735
Psychophysiology. 1998 Nov;35(6):709-20
9844432
J Cogn Neurosci. 1999 Jul;11(4):437-58
10471850
Neuropsychology. 1997 Jan;11(1):59-69
9055270
Biol Psychiatry. 1987 Mar;22(3):303-12
2949781
Psychophysiology. 1995 May;32(3):274-85
7784536
Behav Neurosci. 1987 Jun;101(3):347-51
2955793
Curr Opin Neurobiol. 1996 Apr;6(2):179-86
8725959
Hum Brain Mapp. 2001 Dec;14(4):251-60
11668656
Am J Hum Genet. 2004 May;74(5):805-16
15052536
Brain Cogn. 1997 Mar;33(2):135-50
9073369
J Physiol Paris. 1994;88(1):1-50
8019524
Electroencephalogr Clin Neurophysiol. 1987 Oct;67(4):360-71
2441971
Nature. 1994 Nov 17;372(6503):260-3
7969469
Neurology. 2007 Aug 28;69(9):851-9
17724287
J Cogn Neurosci. 1992 Fall;4(4):375-92
23968130
Psychol Aging. 2001 Mar;16(1):161-76
11302364
J Exp Psychol Learn Mem Cogn. 1985 Jul;11(3):501-18
3160813
Electroencephalogr Clin Neurophysiol. 1996 Sep;100(5):392-406
8893657
Brain Topogr. 2003 Spring;15(3):165-71
12705812
Brain. 2002 Aug;125(Pt 8):1760-71
12135967
J Neurol Neurosurg Psychiatry. 2002 Oct;73(4):377-84
12235303
Neuropsychology. 2000 Apr;14(2):209-23
10791861
J Neurochem. 2008 Dec;107(6):1671-82
19014369
Biol Psychol. 1988 Jun;26(1-3):269-76
3207786
Pediatrics. 2009 Jan;123(1):378-90
19117905
Neuroimage. 2002 Nov;17(3):1101-16
12414253
Neurology. 2001 Jul 10;57(1):127-30
11445641
J Consult Clin Psychol. 1988 Dec;56(6):893-7
3204199
J Neurol Sci. 2006 Oct 25;248(1-2):227-33
16780889
J Neurosci. 2000 Jul 1;20(13):5083-101
10864966
RNA. 2002 Dec;8(12):1482-8
12515381
Brain. 2000 Sep;123 ( Pt 9):1948-63
10960058
Brain. 2006 Jan;129(Pt 1):243-55
16332642
Am J Hum Genet. 2003 Apr;72(4):869-78
12638084
Neurology. 2008 May 6;70(19 Pt 2):1763-70
18077800
Exp Brain Res. 1994;99(3):411-22
7957720
J Exp Psychol Learn Mem Cogn. 1990 Nov;16(6):1021-32
2148576
Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1138-44
18384046
Science. 1999 Sep 3;285(5433):1582-5
10477525
Clin Neurophysiol. 2006 Jun;117(6):1319-30
16644278
Neuropsychology. 2008 Jan;22(1):48-60
18211155
J Am Geriatr Soc. 1990 Dec;38(12):1304-10
2254568