Longitudinal Cognitive and Motor Changes Among Presymptomatic Huntington Disease Gene Carriers

Kirkwood, Sandra C.; Siemers, Eric; Stout, Julie C.; Hodes, M. E.; Conneally, P. Michael; Christian, Joe C.; Foroud, Tatiana

doi:10.1001/archneur.56.5.563

Cited by 124 publications

(117 citation statements)

References 39 publications

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“…For example, HD gene carriers (with a CAG repeat expansion) who were not displaying any of the clinical symptoms of Huntington's disease had significantly worse scores in the Wechsler Adult Intelligence Scale (Revised) compared with non-gene carriers (Foroud et al, 1995). Similar conclusions have also been reported in other studies (Kirkwood et al, 1999(Kirkwood et al, , 2000.…”

Section: Introductionsupporting

confidence: 82%

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

et al. 2005

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Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

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Section: Introductionsupporting

confidence: 82%

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

et al. 2005

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“…Most frequently, the disease becomes manifest in the third to fifth decade of subjects with 40 or more CAG repeats on chromosome 4 and leads to death 15 or 20 years after onset. HD is usually diagnosed when motor symptoms first appear [1]. Cognitive dysfunction becomes more evident with disease progression [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Implicit and explicit aspects of sequence learning in pre-symptomatic Huntington's disease

Ghilardi

Silvestri

Feigin

et al. 2008

Parkinsonism & Related Disorders

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Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in eleven pre-symptomatic HD gene carriers (pHD) and eleven normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQtest). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQtest these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve.

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“…[2][3][4][5][6][7] In addition, subtle oculomotor and other movement peculiarities and neuropsychiatric changes have been reported in some mutation-positive individuals prior to the onset of clinical signs and symptoms sufficient for diagnosis. [8][9][10][11][12] However, the search for presymptomatic changes in cognition among those with the huntingtin mutation has met with mixed results. Several investigations reported no significant differences in neuropsychological functioning between those with and those without the Huntington's disease mutation.…”

mentioning

confidence: 99%

“…[13][14][15][16][17] Others, however, have found such differences. [8][9][10]18 Deficits in reaction time, psychomotor and processing speed, 10,18,[20][21][22] executive functioning, [23][24][25] spatial analysis and constructional praxis, 26 verbal fluency, 23 verbal memory, [26][27][28] and mental arithmetic 9,10 have all been reported among mutation carriers, albeit inconsistently.…”

mentioning

confidence: 99%

Neuropsychological Deficits in Huntington's Disease Gene Carriers and Correlates of Early "Conversion"

Brandt¹,

Inscore²,

Ward³

et al. 2008

Journal of Neuropsychiatry

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The authors examined whether the baseline cognitive functioning of 21 clinically normal huntingtin mutation carriers who developed manifest Huntington's disease on follow-up differed from that of 49 mutation carriers who remain asymptomatic over the same period in a longitudinal study. One hundred thirty-four gene-negative offspring of Huntington's disease patients were studied as well. Overall, there were no differences in cognitive test performance among the three groups. However, "converters" who developed signs of Huntington's disease within 8.6 years demonstrated poorer performance on the Wisconsin Card Sorting Test at baseline. People with the Huntington's disease mutation who are carefully examined neurologically and found to be asymptomatic have, at most, very minimal problem-solving impairment, and only if they are within a few years of clinical onset.Since the discovery of the genetic mutation responsible for Huntington's disease, 1 there have been many attempts to determine whether people who carry the mutation, but who are not yet clinically ill, can be distinguished from those without the mutation. Brain imaging studies have often demonstrated structural and/or functional abnormalities in the striatum in presymptomatic individuals. [2][3][4][5][6][7] In addition, subtle oculomotor and other movement peculiarities and neuropsychiatric changes have been reported in some mutation-positive individuals prior to the onset of clinical signs and symptoms sufficient for diagnosis. [8][9][10][11][12] However, the search for presymptomatic changes in cognition among those with the huntingtin mutation has met with mixed results. Several investigations reported no significant differences in neuropsychological functioning between those with and those without the Huntington's disease mutation. [13][14][15][16][17] Others, however, have found such differences. [8][9][10]18 Deficits in reaction time, psychomotor and processing speed, 10,18,[20][21][22] executive functioning, 23-25 spatial analysis and constructional praxis, 26 verbal fluency, 23 verbal memory, [26][27][28] and mental arithmetic 9,10 have all been reported among mutation carriers, albeit inconsistently.The discrepant findings among studies are due, in large part, to methodological differences. First, studies have varied in the degree of neurologic abnormality tolerated in the "asymptomatic" mutation-positive group. 29 While some researchers enrolled only persons with no, or very minimal, nonspecific neurological signs, 22,27 others included subjects with "major signs consistent with Huntington's disease." 8,9,20,28 In addition, some studies were of young mutation carriers who were almost certainly many years from disease onset, whereas others were of older subjects nearing the age of likely clinical onset. In those studies where NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript proximity to clinical onset was explicitly addressed, time to disease onset ("conversion") was most often estimated. 10,[15][16][17]28 The pre...

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Longitudinal Cognitive and Motor Changes Among Presymptomatic Huntington Disease Gene Carriers

Cited by 124 publications

References 39 publications

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

Implicit and explicit aspects of sequence learning in pre-symptomatic Huntington's disease

Neuropsychological Deficits in Huntington's Disease Gene Carriers and Correlates of Early "Conversion"

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