Ten‐year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease

Solomon, Andrea C.; Stout, Julie C.; Weaver, Marjorie; Queller, Sarah; Tomusk, A.; Whitlock, Kathryn B.; Hui, Siu L.; Marshall, Jessica; Jackson, Jacqueline; Siemers, Eric; Beristaín, Xabier; Wojcieszek, Joanne; Foroud, Tatiana

doi:10.1002/mds.22097

Cited by 52 publications

(44 citation statements)

References 21 publications

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“…The largest effect size was found for the SDMT, a task requiring coordination of visual scanning, working memory, fine motor speed, and concentration. These findings replicate those reported in the literature from at least six different studies7 8 10 11 13 15 and suggest that this task is highly sensitive and consistent for tracking decline in prodromal HD. Longitudinal change for every prodromal group was substantially different from the normal control group, suggesting the SDMT might serve as a sufficient outcome measure to detect alleviation of decline over time from an effective compound or intervention.…”

Section: Discussionsupporting

confidence: 89%

“…Six of the studies reviewed (see table 1) showed significant changes over time using the Stroop Color Word Test8 10 14–16; the TMT,14–16 or other measures of reaction or movement time,13 14 all of which were found to have substantial effects in the current study. Some have interpreted this finding as reason to emphasise motor and psychomotor measures of HD as superior to other potential assessed outcomes 12.…”

Section: Discussionmentioning

confidence: 52%

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Cognitive decline in prodromal Huntington Disease: implications for clinical trials

Paulsen¹,

Smith

Long

2013

J Neurol Neurosurg Psychiatry

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Controversy exists regarding the feasibility of preventive clinical trials in prodromal Huntington disease (HD). A primary limitation is a lack of outcome measures for persons with the gene mutation who have not yet been diagnosed with HD. Many longitudinal studies of cognitive decline in prodromal HD have not stratified samples based on disease progression, thereby obscuring differences between symptomatic and nonsymptomatic individuals. Prodromal participants from PREDICT-HD were stratified by disease progression into one of three groups: those having a High, Medium, or Low probability of motor manifestation within the next five years. Data from a total of N = 1299 participants with up to 5950 data points were subjected to linear mixed effects regression on 29 longitudinal cognitive variables, controlling for age, education, depression, and gender. Performance of the three prodromal HD groups was characterized by insidious and significant cognitive decline over time. Twenty-one variables from 19 distinct cognitive tasks revealed evidence of a disease progression gradient, meaning that the rate of deterioration varied as a function of progression level, with faster deterioration associated with greater disease progression. Nineteen measures showed significant longitudinal change in the High group, nine showed significant change in the Medium group and four showed significant cognitive decline in the Low group. Results indicate that clinical trials may be conducted in prodromal HD using the outcome measures and methods specified. The findings may help inform interventions in HD as well as other neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 52%

Cognitive decline in prodromal Huntington Disease: implications for clinical trials

Paulsen¹,

Smith

Long

2013

J Neurol Neurosurg Psychiatry

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“…Discrepancy due to overestimation on the sensitivity of measurements in cross-sectional studies suggests the importance of unbiased longitudinal studies for precise interpretation of the results and for determining possible clinical applications [1,6-8,37,38]. Unlike the cognitive behavioral assessment, non-invasive MRI provides an optimal quantitative tool for determining anatomical changes that may associate with the disease progression.…”

Section: Discussionmentioning

confidence: 99%

A two years longitudinal study of a transgenic Huntington disease monkey

Chan

Jiang

et al. 2014

BMC Neurosci

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BackgroundA two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington’s disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements.ResultsChanges in striatal and hippocampal volumes in rHD1 were observed with progressive impairment in motor functions and cognitive decline, including deficits in learning stimulus-reward associations, recognition memory and spatial memory. The results demonstrate a progressive cognitive decline and morphometric changes in the striatum and hippocampus in a transgenic HD monkey.ConclusionsThis is the first study on a primate model of human HD based on longitudinal clinical measurements. While this study is based a single HD monkey, an ongoing longitudinal study with additional HD monkeys will be important for the confirmation of our findings. A nonhuman primate model of HD could complement other animal models of HD to better understand the pathogenesis of HD and future development of diagnostics and therapeutics through longitudinal assessment.

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“…9 years) [39] . Participants were stratified according to proximity to diagnosis because changes in behavior, cognition, emotional regulation, and motor function have been demonstrated prior to HD diagnosis [36,[40][41][42] , and being early in the course of illness has previously been suggested as a risk factor for suicide in HD.…”

Section: Methodsmentioning

confidence: 99%

Suicidal Behavior in Prodromal Huntington Disease

Fiedorowicz

Mills²,

Ruggle³

et al. 2011

Neurodegener Dis

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Background: Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established. Objective: We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD. Methods: From the prospective PREDICT-HD cohort, we identified 735 cases with HD gene expansion but no manifest symptoms of HD and 194 non-gene-expanded controls. In survival analysis, a number of potential risk factors for suicidal behavior were assessed, including symptoms of depression, hopelessness, substance abuse, marital status, gender, and psychiatric history. Results: During a mean of 3.7 years of prospective follow-up, 12 cases (1.6%) attempted suicide and 1 completed suicide (0.1%). No suicides were observed among controls. In univariate Cox proportional hazards regression models, a history of suicide attempts (HR 8.5, 95% CI 2.8–26.1, p < 0.0002) and a Beck Depression Inventory II score >13 (HR 7.2, 95% CI 2.3–22.0, p < 0.0006) were associated with suicidal behavior. These risk factors had independent effects in multivariate models. A history of incarceration in the past 2 years was also associated (HR 12.5, 95% CI 2.7–56.6, p < 0.002), though uncommon. No further risk factors were identified. Conclusion: A history of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in prodromal HD. As these risk factors are among the most robust risk factors for suicide, established suicide risk factors appear applicable to those with prodromal HD.

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Ten‐year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease

Cited by 52 publications

References 21 publications

Cognitive decline in prodromal Huntington Disease: implications for clinical trials

Cognitive decline in prodromal Huntington Disease: implications for clinical trials

A two years longitudinal study of a transgenic Huntington disease monkey

Suicidal Behavior in Prodromal Huntington Disease

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