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

Abstract

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...

Modeling longitudinal change in motor and cognitive processing speed in presymptomatic Huntington's disease

“…Brain morphometric (Aylward et al, 2004) and functional changes have been documented years prior to clinical symptoms sufficiently severe and specific for diagnosis, as have lower cognitive performance scores (Brandt et al, 2008;Kirkwood et al, 1999;Solomon et al, 2007). Quantifying neuropsychological performance in This research was supported, in part, by Grant NS16375 from the National Institute on Neurological Disorders and Stroke and a Center of Excellence Award from the Huntington's Disease Society of America.…”

“…Smaller but still significant declines were observed on psychomotor tasks. More recently, Brandt et al (2008) found subtle differences between "early" converters and "late" converters at baseline on a single problem-solving task (Wisconsin Card Sorting Test) among mutation carriers who became diagnosable ("converted") some years later. More specifically, when the participants were stratified into early converters (i.e., an average time to conversion of 3.7 years) and late converters (i.e., an average time to conversion of 11.8 years), the early converters achieved fewer sorts, were less efficient (i.e., they required more cards to achieve completed sorts), and made more perseverative and nonperseverative errors.…”

Early Dysfunction of Neural Transmission and Cognitive Processing in Huntington’s Disease

“…It is easy to imagine that when circumstances become complex and patients become overloaded, frustration and disappointment lead to irritation or apathy, which can be difficult for companions (Quarrell, 2008;Bourne et al, 2006). Assessments of cognitive inflexibility in pre-HD typically requires the use of specialized tasks, such as the Wisconsin Card Sorting and Tower of London tasks (Brandt et al, 2008), whereby patients are challenged to routinely shift strategies, depending on circumstances. Complicated and multifaceted tasks are otherwise rare, and, as such, pre-HD patients are typically able to cope in their day-today functions.…”

“…Two extensive studies demonstrated that testing pre-HD patients just prior to motoric symptom expression, using tests such as the Wisconsin Card Sorting task, resulted in greater difficulties than both mutation-free and pre-HD subjects who were further from motor symptom expression (Brandt et al, 2008;Snowden et al, 2002). In the first of these studies (Snowden et al, 2002), the data indicated that working memory malfunctions may arise earlier in the disease progression than problems with executive function.…”

The Functional Implications of Motor, Cognitive, Psychiatric, and Social Problem-Solving States in Huntington's Disease

“…Although, motor symptoms are the marker most often used in the diagnosis of HD (Chatterjee, Anderson, Moskowitz, Hauser, & Marder, 2005;Marshall et al, 2007), over the past decade, a resurgence of research has examined cognitive and psychiatric symptoms as early markers of HD and as a means of obtaining a more comprehensive picture of the disease (e.g., Brandt et al, 2008;Johnson et al, 2007;Julien et al, 2007;Paulsen et al, 2008;Solomon et al, 2007;Stout et al, 2010).…”