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Background: In 1983, Huntington's disease (HD) was the first genetic disease mapped using DNA polymorphisms. Shortly thereafter, presymptomatic genetic testing for HD began in the context of two research studies. One of these trials was at the Johns Hopkins University Huntington's Disease Center., Methods: As part of the protocol, risk perception (RP) values were collected at 16 time points before and after testing. The current study investigated changes in RP scores before and after genetic testing. Of the 186 participants with pre- and post-testing RP values, 39 also had contemporaneous research clinic notes and recent semi-structured interviews available for analysis., Results: The data reveal tremendous diversity in RP. While the RP scores of most individuals change in the way one would expect, 27% of participants demonstrated unexpected changes in RP after disclosure. A significantly higher proportion of individuals who received an expanded repeat result had unexpected changes in RP, compared with those who received normal repeat results., Conclusions: The data suggest that individuals' RP is influenced by more than merely the results of genetic testing. This finding is important for genetic counselors and healthcare providers, as it suggests that even comprehensive patient education and disclosure of genetic test results may not ensure that people fully appreciate their disease risk., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

The clinical syndrome of Huntington's disease (HD) is notable for a triad of motor, cognitive, and emotional features. All HD patients eventually become occupationally disabled; however, the factors that render HD patients unable to maintain employment have not been extensively studied. This review begins by discussing the clinical triad of HD, highlighting the distinction in the motor disorder between involuntary movements, such as chorea, and voluntary movement impairment, with the latter contributing more to functional disability. Cognitive disorder clearly contributes to disability, though the relative contribution compared to motor is difficult to unravel, especially because many of the tests used to asses "cognition" have a strong motor component. The role of emotional changes in disability needs more study. The literature on contributions to functional disability, driving impairment, and nursing home placement is reviewed. Relevant experience is presented from the long-standing JHU HD observational study on motor versus cognitive onset, as well as on cognitive and motor features at the time when individuals discontinued working. Finally, we briefly review government policies in several countries on disability determination. We interpret the data from our own studies and from the literature to indicate that there is usually a close relationship between cognitive and motor dysfunction, and that it is critical to take both into consideration in determining disability. © 2014 International Parkinson and Movement Disorder Society., (© 2014 International Parkinson and Movement Disorder Society.)

Huntington's disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Huntington's disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high-field-strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early-stage disease versus 12 healthy controls underwent (1)H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1-weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (-9.6%, P = .02) and glutamate (-10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r(2) = 0.50, P = .01) and glutamate (NAA) (r(2) = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N-acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor., (Copyright © 2012 Movement Disorder Society.)

Persons who have the genetic mutation responsible for Huntington's disease (HD) have been shown to exhibit lower cognitive test scores years prior to manifest HD. Most studies have examined cognitive performance in presymptomatic persons by using estimated times to manifest HD based on published algorithms. We followed 19 gene-positive persons who were presymptomatic using an objective criterion (i.e., Quantified Neurological Exam score ≤ 10) at baseline for up to 21 years (median = 5 years) with periannual neuropsychological assessments until a diagnosis of manifest HD. Results showed that our tests of information- and psychomotor-processing speed that place minimal demands on cognition, worsening performance became evident 5-10 years prior to the development of manifest HD. In conclusion, cognitive decline precedes motor signs in HD and may be an important target in clinical trials and early intervention. Cognitive test scores may also improve the ability to predict disease onset among gene mutation carriers and help families to better plan for potential personal and economic hardship.

Differences in the memory characteristics of patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD) were investigated with tests that assess learning and retention of words, line-drawn objects, and locations. Large groups of AD, HD, and PD patients were administered the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Hopkins Board (HB). Eight learning and memory measures were subjected to discriminant function analysis. A 91% classification accuracy was achieved for the separation of cortical and subcortical dementias and 79% accuracy for the discrimination of the three groups. The delayed recall of items was the best discriminator. Receiver-operating curve analysis indicated up to 90% sensitivity and 90% specificity in differentiating the three diseases using the discriminant scores. Individual learning and memory measures of the HVLT-R and the HB provided very high sensitivity and specificity in distinguishing cortical versus subcortical dementias and modest accuracy in separating the two subcortical diseases.

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.

Previous studies of verbal episodic memory in pre-diagnostic Huntington's disease (HD) have yielded mixed results; some evidence suggests that memory decline is evident prior to the onset of pronounced neurological signs of HD, whereas other data indicate that memory function remains normal throughout the pre-diagnostic period. This study examines verbal episodic memory in a sample of CAG expanded individuals who have not yet been clinically diagnosed, and who represent a wide range of points along the continuum from health to disease. The Hopkins Verbal Learning Test-Revised (HVLT-R) was administered to 479 participants (428 with the HD CAG expansion and 51 without), and performance was compared to neurobiological indices of disease progression, including a DNA-based estimate of proximity to clinical diagnosis, magnetic resonance imaging (MRI) measures of striatal volume, and neurologist ratings of motor signs. Lower HVLT-R scores were associated with closer proximity to clinical diagnosis and smaller striatal volumes; these relationships were found even in groups with no neurological signs of HD. The CAG expanded groups, including those with only minimal neurological signs, had significantly lower HVLT-R scores than the control group, and performance was worse in sub-groups that had more neurological signs consistent with HD. These findings indicate that verbal episodic memory is affected in early pre-diagnostic HD and may decline as striatal volumes decrease and individuals approach the motor diagnostic threshold.

The contribution of neurologic, genetic, and demographic variables to decline in cognition was examined in 70 early- to mid-stage patients with Huntington's disease (HD) using random effects modeling. Study participants were followed prospectively at baseline and at four annual reevaluations. Only modest decline was noted on most neuropsychological variables. Neurologic dysfunction, assessed using the Quantified Neurologic Examination (QNE), proved to be the strongest predictor of cognitive decline. While significantly predictive of more rapid decline in neurologic functioning, CAG repeat length was not generally related to cognitive decline after adjusting for QNE, with the exception of performance on a single test of visual scanning and psychomotor speed (i.e., Trail Making Test, Part A). We propose that CAG repeat length is more closely linked with changes in basal ganglia that predominate in early- to mid-stage HD than with cortical degeneration seen later in disease progression. Such a relationship would explain the predictive value that CAG repeat length plays in changes associated with automatic motor response programs (e.g., QNE and Trail Making Test, Part A) but not in dysfunction on tasks requiring higher-order processing.

The pathology of Huntington's disease (HD) is characterized by diffuse brain atrophy, with the most substantial neuronal loss occurring in the caudate and putamen. Recent evidence suggests that there may be more widespread neuronal degeneration with significant involvement of extrastriate structures, including white matter. In this study of pre-symptomatic carriers of the HD genetic mutation, we have used diffusion tensor imaging to examine the integrity and organization of white matter in a group of individuals who previously demonstrated abnormalities in response to a functional magnetic resonance imaging paradigm. Our results indicate that, before the onset of manifest HD, there are regional decreases in fractional anisotropy, indicating early white matter disorganization.

Psychiatric hospitalizations, completed suicides, and suicide attempts are rare after predictive testing for Huntington's disease (HD). Case studies have shown that major depression can be a consequence of being tested, although no studies have shown how common this is. The present study evaluated the prevalence of major depression during the first year after disclosure. We conducted retrospective data and chart reviews of 153 persons (50 testing positive, 103 testing negative) evaluated every 3 months for depression. There was no significant baseline difference in the percentage of "positives" and "negatives" who had pre-testing major depressive episodes (14% vs. 12%, respectively). A senior psychiatrist reviewed data from the Schedule for Affective Disorders and Schizophrenia-Change Version, from the Beck Depression Inventory, and from clinical notes for every follow-up contact completed. The 1-year prevalence of major depression among positives was 6.0%, compared to 3.0% among negatives (p = 0.30), and an estimated 3% population prevalence. One-year prevalence of clinically significant depressive symptoms, whether or not major depression was diagnosed, was 20.0% in positives and 12.6% in negatives (p = 0.17). Although not statistically significant, depressive symptoms and major depression occurred more frequently among those who tested positive. Despite some evidence to the contrary, including our own studies, a positive predictive test for HD is not psychologically benign. Clinical testing programs should assess patients for depressive symptoms after testing, and patients with clinically significant complaints should be referred to a mental health professional.

Evidence suggests early structural brain changes in individuals with the Huntington's disease (HD) genetic mutation who are presymptomatic for the movement symptoms of the illness. The aim of this study was to investigate the presence of functional brain changes in this same population using functional magnetic resonance imaging. Subjects and matched controls underwent an functional magnetic resonance imaging "interference" protocol, a task known to be mediated in part by corticostriatal circuitry. In the setting of normal cognitive performance, presymptomatic HD subjects had significantly and specifically less activation in the left anterior cingulate cortex (BA 24, 32) compared with matched controls.

To determine the specificity of cognitive impairments in patients with cerebellar degeneration (CD), the neuropsychological test performance of 31 CD patients was compared to that of 21 patients with Huntington's disease (HD) and 29 normal adults. The CD and HD groups did not differ in age, education, or duration of illness, and their overall severity on a quantified neurological examination was similar. Fifteen neuropsychological test variables were reduced to five underlying domains: motor, verbal, spatial, memory, and executive functioning. The CD patients had their greatest impairment in the executive domain and their least in the memory domain. In contrast, the HD patients had very substantial spatial deficits and significant memory impairment, in addition to executive dysfunction. The findings indicate that 1) the cognitive impairment in CD is not as severe as in HD, and 2) the pattern of deficits in CD, while consistent with a subcortical dementia, differs in important ways from that in HD. These differences may reflect the involvement of the cerebellar dentate nucleus and the striatal nuclei in separate "loops" or closed circuits, linking them with specific areas of cerebral neocortex.

Subjects were followed in the Longitudinal Core Study of the Baltimore Huntington's Disease Center and given annual neurological, cognitive, and psychiatric examinations. Postmortem neuropathological grade was assigned using the system of Vonsattel and colleagues. We examined the correlations between the neuropathological grade and scores on the Quantified Neurological Examination (QNE) and its chorea and motor impairment subscales, the Mini-Mental State Examination (MMSE), the HD Activities of Daily Living (ADL) Scale, and a number of demographic variables (CAG number, age of onset, age at death, disease duration) in 100 subjects who had been examined within 1,000 days of death. All measures showed significant correlation with Vonsattel score except for chorea. The strongest effect was that of motor impairment score (r(2) = 0.351, p < 0.0001). In a stepwise correlation of clinical variables, motor impairment remained significant. The largest effect for a demographic variable was for age of onset (r(2) = 0.226, p < 0.0001) A partial correlation was significant between CAG number and Vonsattel grade, controlling for age at death or disease duration. Motor impairment appears to be a good clinical measure of neuronal cell loss, at least late in the course of HD and therefore may prove useful in observational and treatment studies.

A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4 is responsible for Huntington's disease (HD). Presymptomatic genetic testing for this mutation has identified clinically normal persons who are virtually certain to develop this dementing illness if they live a normal lifespan. The present study sought to determine whether these "mutation-positive" persons have impairments in cognitive functioning. Seventy-five mutation-positive persons did not differ from 128 mutation-negative persons on tests selected for their sensitivity to early-stage HD. Interestingly, however, those with the mutation viewed themselves as more likely to develop HD than did those without the mutation. Among mutation-positive subjects, having a longer CAG repeat mutation was likewise not associated with cognitive impairment. However, being closer to estimated disease onset (a product of repeat length and parent's age at onset) was associated with selected cognitive impairments. When viewed in light of previous studies showing atrophy of the caudate nucleus and putamen in mutation-carriers who are close to onset but not those far from onset, these results suggest that subtle changes in brain and behavior may be detected shortly before subjects with the HD mutation develop sufficient signs and symptoms for diagnosis. Conceptual and methodological problems associated with the search for presymptomatic cognitive and behavioral indicators of dementing illness are discussed.

Objective: This study estimated the psychiatric morbidity of patients with degenerative cerebellar diseases., Method: The study included a series of 31 patients with degenerative cerebellar diseases, compared with 21 patients with Huntington's disease and 29 neurologically healthy comparison subjects. Comprehensive psychiatric evaluations, including the Structured Clinical Interview for DSM-IV and psychopathology rating scales, were administered., Results: The overall rate of noncognitive psychiatric disorders was 77% in the patients with degenerative cerebellar diseases, nearly identical to that in the patients with Huntington's disease (81%) and about double that seen in the neurologically healthy subjects (41%). There were high rates of all mood disorders in both the degenerative cerebellar diseases group (68%) and the Huntington's disease group (43%); the rate in the degenerative cerebellar diseases group was significantly higher than that in the neurologically healthy subjects (31%). The frequency of personality change in the three groups was striking: change was present in 26% of the degenerative cerebellar diseases patients, 48% of the Huntington's disease patients, and none of the neurologically healthy comparison subjects. A total of 19% of the degenerative cerebellar diseases subjects and 71% of the Huntington's disease subjects met DSM-IV criteria for either cognitive disorder or dementia., Conclusions: The high rate of psychiatric and cognitive disorders in the patients with degenerative cerebellar diseases suggests that many, if not most, patients with degenerative cerebellar diseases may benefit from psychiatric interventions. These results also support previous findings that the cerebellum may have a role in modulating emotion and cognition.

OBJECTIVES: To estimate the association between dementia and time to discharge from individual assisted living (AL) facilities and examine, in residents with dementia, factors associated with shorter duration of residence in individual AL facilities. DESIGN: Prospective cohort study. SETTING: Twenty-two AL facilities in central Maryland. PARTICIPANTS: Stratified random sample of 198 AL residents followed for a median of 18 months. MEASUREMENTS: Detailed assessments to diagnose dementia; assess treatment of dementia; and rate clinical; cognitive, functional, and quality-of-life measures. RESULTS: Residents with dementia remained in a facility 209 fewer days at the median ( P=.001) than residents without dementia. After adjustment for other variables, lack of treatment for dementia ( P=.01) and more-serious medical comorbidity ( P=.02) were associated with earlier discharge in participants with dementia. Impaired mobility and limited activity participation had weaker associations with earlier time to discharge. CONCLUSION: Dementia may accelerate time to discharge, and its treatment may attenuate this effect. The hypothesis that the detection and treatment of dementia might delay discharge from AL should be tested in randomized trials. [ABSTRACT FROM AUTHOR]

Reports that movement jerkiness, which characterizes the smoothness and efficiency of motion was a sensitive indicator of presymptomatic Huntington's disease (HD). Observation that a large fraction of asymptomatic HD gene-carriers displayed elevated jerk even when more than seven years remained until predicted disease onset; Suggestion that a dysfunction in error correction characterizes the motor control deficit in early HD.

Reports on the Johns Hopkins University School of Medicine's initiation of a voluntary program of presymptomatic genetic testing for Huntington's disease for persons at 50 percent risk. Absence of severe depressive reactions; Suggestion that people who receive genetic test results cope well, al least over the short term, when the testing is performed in a clinical context.

Objectives: To describe and contrast functional dependency (FD) levels among recently admitted AL residents with and without dementia and to assess the differential contribution of cognitive, behavioral, medical, and social factors on FD within each group. Design: A cross-sectional study. Setting: A random sample of 28 AL facilities in the Central Maryland region. Participants: Two hundred and sixty-two AL residents assessed less than1 year after admission. Measurements: Participants were given comprehensive in-person dementia assessments. Cognitive, behavioral, medical, and social factors were also assessed. FD was operationalized as impairment in activities of daily living. Results: The 59% of residents with dementia had higher levels of FD (P < .001) and were more likely to require assistance in all assessed task-specific ADL domains (P < .001) except mobility (P = .653). In multivariate models, global cognition, medical health status, and presence of diabetes explained 43% of the variance in FD in the dementia group. Twenty-five percent of the variance in FD was explained by depression, neuropsychiatric symptoms, and global cognition in those without dementia. Conclusions: Recently admitted AL residents have substantial levels of FD. FD is higher among residents with dementia compared with those without and the association of cognitive, mental health, and medical variables with FD differ as a function of dementia status. Future research should examine how these dimensions affect FD longitudinally and whether they may serve as targets for interventions and quality of care improvement initiatives. [Copyright &y& Elsevier]