Specific Psychiatric Manifestations Among Preclinical Huntington Disease Mutation Carriers

Marshall, Jessica; White, Kerry; Weaver, Marjorie; Wetherill, Leah; Hui, Siu L.; Stout, Julie C.; Johnson, Shannon A.; Beristaín, Xabier; Gray, Jacqueline S.; Wojcieszek, Joanne; Foroud, Tatiana

doi:10.1001/archneur.64.1.116

Cited by 69 publications

(46 citation statements)

References 38 publications

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“…Clinical diagnosis of HD is determined on the basis of motor symptoms; however, the pre-motor stages of the disease are commonly associated with psychiatric manifestations including depression (Paulsen et al, 2005;Duff et al, 2007;Julien et al, 2007;Marshall et al, 2007). Depression is one of the most prevalent causes of disability worldwide and is diagnosed in women more frequently than in men (Fava and Kendler, 2000;Kornstein et al, 2000;Marcus et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Renoir

Pang

Zajac

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEDepression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACHWe performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT1A and 5-HT2A receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTSFemale HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT1A autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT1A and 5-HT2 heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONSWe report for the first time a crucial role for 5-HT1A autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.Abbreviations 5-CT, 5-carboxamidotryptamine; 5-HTT, 5-HT transporter; AUC, area under curve; BDNF, brain-derived neurotrophic factor; BrdU, 5-bromo-2′-deoxyuridine; FST, forced-swimming test; GR, glucocorticoid receptor; HD, Huntington's disease; HPA, hypothalamic-pituitary-adrenal; RW, running-wheel; SH, standard-housed; SSRIs, selective 5-HT re-uptake inhibitors; TST, tail-suspension test; WT, wild-type BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012) IntroductionHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats in exon 1 of the huntingtin gene (The Huntington's Disease Collaborative Research Group, 1993). Clinical diagnosis of HD is determined on the basis of motor symptoms; however, the pre-motor stages of the disease are commonly associated with psychiatric manifestations including depression (Paulsen et al., 2005;Duff et al., 2007;Julien et al., 2007;Marshall et al., 2007). Depression is one of the most prevalent causes of disability worldwide and is diagnosed in women more frequently than in men (Fava and Kendler, 2000;Kornstein e...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Renoir

Pang

Zajac

et al. 2012

British J Pharmacology

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“…Early in the progression of HD, motor changes include mild chorea, abnormal muscle stretch refl exes, and diminished rapid alternating movements. Marshall 15 describes the cognitive manifestations early in the course of the disorder, and they primarily consist of abnormalities in information progression, cognitive fl exibility, and memory retrieval 15,18 . These neurological symptoms are apparently associated with nuclear accumulation of mutant huntingtin protein and its eff ect on gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Among the pathophysiological and degenerative changes of somewhat moderate intensity, the striate spiny neurons have been implicated; such cells are known to induce GABAdescribed degenerative changes in the neocortex. The signifi cance and function of normal as well as mutagenous Huntingtin protein (htt) is currently the subject of intensive study 11,15,18 . Our study aims to focus on determining the role of a group of steroid receptors, mainly the estrogen hormone receptors (ER), in Huntington's Disease.…”

Section: Introductionmentioning

confidence: 99%

Huntington's disease and steroid hormone receptors

Molikova¹,

Bezdickova²,

David³

et al. 2007

BIOMED PAP

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Background: Steroid hormone receptors constitute a special group of receptors having a wide range of effi ciency and distribution in the body. Androgen and estrogen receptors, and their expression in the body, are linked with attributes such as reproduction control and sexual behaviour, but their relation with behavioural models, perception, memory and stress remain unclear to date.Purpose: In this project we aim to focus on monitoring the expressive infl uence of steroid hormone receptors on embryonic tissues and subsequently, expand our study to include the expression on adult tissues such as the CNS and to monitor the developmental aspects and relations pertaining to neurodegenerative disorders, such as Huntington's disease. Material and Methods:We shall rely on immuno-histochemistry, immuno-fl uorescence and RT-PCR methods for detecting steroid hormone receptors and Huntingtin-associated protein 1 in the embryonic and adult tissue.Conclusion: Mapping the expression of steroid receptors during development represents an essential step in the quest for further studies and monitoring of the expression in adult tissues.

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“…29 Progressive atrophy of the striatum and cerebral cortex has been well documented to occur in the premanifest prodrome period, indicating that the neurodegenerative process is ongoing. 21,28,30 Subtle cognitive, motor, psychiatric, [31][32][33] and metabolic abnormalities 34,35 are detectable in premanifest HD, and biochemical alterations are beginning to be detected in blood. 24,36 It is unknown whether the HD prodrome represents a stable condition until some decompensation causes manifest HD to emerge, or whether it is a continuum in which clinically silent neurodegeneration gradually accumulates sufficiently to cause unequivocal symptoms.…”

Section: Neuroprotection In Premanifest Hdmentioning

confidence: 99%

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

Hersch

Rosas

2008

Neurotherapeutics

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Summary:The ultimate goal for Huntington's disease (HD) therapeutics is to develop disease-modifying neuroprotective therapies that can delay or prevent illness in those who are at genetic risk and can slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability, and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets, along with options for modulating them, with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development.

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Specific Psychiatric Manifestations Among Preclinical Huntington Disease Mutation Carriers

Cited by 69 publications

References 38 publications

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Huntington's disease and steroid hormone receptors

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

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