Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease

Stout, Julie C.; Jones, Rebecca; Labuschagne, Izelle; O'Regan, A; Say, Miranda J.; Dumas, Eve M.; Queller, Sarah; Justo, Damián; Santos, Rachelle C. Dar; Coleman, Allison; Hart, Ellen P.; Dürr, Alexandra; Leavitt, Blair R.; Roos, Raymund A.C.; Langbehn, Douglas R.; Tabrizi, Sarah J.; Frost, Chris

doi:10.1136/jnnp-2011-301940

Cited by 123 publications

(139 citation statements)

References 29 publications

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“…While we found significant differences between HCs and geneexpanded carriers at baseline in many cognitive measures, most failed to provide the necessary sensitivity to usefully measure change over the duration of PRECREST. This has been a consistent finding in other studies evaluating the feasibility of using cognitive measures in trials in this population, 2,4,19 and speaks to the limitations of applying cross-sectional models to predict longitudinal change. It can also be understood when considering that the HD prodrome is slowly progressive over more than 2 decades before discernable clinical symptoms, signs, or manifestations occur.…”

Section: Figuresupporting

confidence: 82%

PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease

et al. 2014

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Objective: To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers.Methods: Sixty-four eligible consenting participants were randomly allocated (1:1) to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers.Results: Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months. Conclusion:We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers. Classification of evidence:This study provides Class I evidence that high-dose creatine is safe and tolerable. Neurology ® 2014;82:850-857 GLOSSARY AD 5 axial diffusivity; HC 5 healthy control; HD 5 Huntington disease; PHD 5 premanifest Huntington disease; PRECREST 5 Creatine Safety and Tolerability in Premanifest HD.Huntington disease (HD) is a progressive autosomal dominant inherited disorder that typically manifests clinically in the third to fifth decades. Genetic testing enables the unambiguous identification of those destined to develop HD and the possibility of initiating preventive treatments during the disease prodrome. Emerging neuroprotective therapies have set the stage for secondary prevention trials with the goal of delaying the onset of symptoms. Demonstrating prevention is a major challenge because very large trials are necessary to demonstrate reduced rates of clinical onset. Furthermore, while subtle cognitive and motor dysfunction and changes on neuroimaging measures occur as early as 2 decades before symptoms, 1,2 reliable markers of prodromal progression remain elusive. PRECREST (Creatine Safety and Tolerability in Premanifest HD) is a secondary prevention trial using up to 30 g daily of creatine monohydrate, a high-energy phosphate buffer that restores adenosine triphosphate from adenosine diphosphate. We used a novel study design that included asymptomatic individuals who were either 50% at risk on the basis of an affected first-degree relative but not wishi...

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Section: Figuresupporting

confidence: 82%

PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease

et al. 2014

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“…Stout et al [28] also conducted a longitudinal evaluation at 12 and 24 months of cognitive outcomes in controls ( n = 116) and premotor HD ( n = 117) and early HD ( n = 116) patients from the TRACK-HD database. They concluded that (in contrast with the findings in early HD) the rate of deterioration of these cognitive outcomes was not statistically different from that of the controls.…”

Section: Cognitive Symptomsmentioning

confidence: 99%

“…However, this data does not mean that there is no cognitive impairment progression throughout the premotor phase. It seems that the decline in premotor HD is too slow to be perceived at 12 or 24 months, even with a reasonable sample size [28]. …”

Section: Cognitive Symptomsmentioning

confidence: 99%

Huntington's Disease: Premotor Phase

Ramos

Garrett

2017

Neurodegener Dis

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Huntington's disease (HD) is an incurable, neurodegenerative disease, which manifests via a triad of progressive symptoms: motor impairment, psychiatric disorders, and cognitive decline. Conventionally, the HD diagnosis is based on the presence of involuntary choreiform movements and a positive genetic test for the CAG-expanded allele gene. Although the diagnosis focuses on the motor part of the triad, there is increasing evidence that both cognitive and neuropsychiatric symptoms can, and often do, present decades before the onset of motor symptoms. In this paper, we review the evidence regarding the symptoms in the HD premotor phase and summarize the most relevant and robust studies in the last few years. Regarding neuropsychiatric symptoms, higher levels of depression, anxiety, apathy, irritability, psychosis, disinhibition, hostility, and sleeping problems were found. In terms of cognition, there was impairment in attention, working memory, episodic memory, language, recognition of facial emotions, empathy, and theory of mind. These early symptoms of HD can be very debilitating and are often disregarded by doctors. It is necessary to acknowledge them so that they can be treated or alleviated. Moreover, an earlier diagnosis can lead to the implementation of neurodegenerative prevention therapies, which may slow the progression of the disease and prolong overall functioning. This will improve the patient's independence and their quality of life.

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“…1 Clinical diag nosis is currently based on unequivocal motor signs of chorea and/or bradykinesia; 2 however, there are significant early cognitive deficits that may develop independently of motor signs. 3,4 In the symptomatic stages of Huntington disease (symp-HD), loss of medium spiny neurons and atrophy in the striatum are characteristic neuropathological changes. 5,6 Sensitive biomarkers of disease onset and progression during the premanifest (pre-HD) stages are urgently needed as possible candidate markers for use in therapeutic trials.…”

Section: Introductionmentioning

confidence: 99%

Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study

Poudel

Egan

Churchyard

et al. 2014

J Psychiatry Neurosci

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Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease

Cited by 123 publications

References 29 publications

PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease

PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease

Huntington's Disease: Premotor Phase

Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study

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