Psychiatric Symptoms in Huntington’s Disease before Diagnosis: The Predict-HD Study

Duff, Kevin; Paulsen, Jane S.; Beglinger, Leigh J.; Langbehn, Douglas R.; Stout, Julie C.

doi:10.1016/j.biopsych.2006.11.034

Cited by 349 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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“…5 The psychiatric disturbances often appear years before the onset of motor symptoms. 6 Cognitive decline may even lead to dementia. 5 Transcranial sonography (TCS) has become a reliable and sensitive diagnostic tool in the evaluation of extrapyramidal movement disorders, especially in the differentiation of parkinsonian syndromes.…”

Section: Introductionmentioning

confidence: 99%

“…5 Even in neurologically presymptomatic Huntington disease, depressive symptoms appear in 30%-58% of the mutation carriers. 6 The suicide rate among patients with Huntington disease varies between 3% and 7.3%. 17 The aim of our study was to evaluate echogenicity of the basal ganglia, especially in the brain stem raphe, and to correlate ultrasound findings with psychiatric features in particu lar, but also with neurologic and cognitive features.…”

Section: Introductionmentioning

confidence: 99%

Depression in patients with Huntington disease correlates with alterations of the brain stem raphe depicted by transcranial sonography

Krogias

Strassburger

Eyding

et al. 2011

jpn

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Background: Transcranial sonography (TCS) has become a new diagnostic tool in the evaluation of extrapyramidal disorders. Studies of TCS report alterations of the mesencephalic raphe in patients with depression. The aim of this study was to evaluate TCS findings in patients with Huntington disease in correlation with their neurologic and psychiatric status. Methods: We recruited patients with genetically confirmed Huntington disease. The neurological and psychiatric status of participants was assessed by independent physicians. Echogenicities were investigated according to examination protocol for extrapyramidal disorders using a Siemens Sonoline Elegra system. The sonography examiner was blinded for clinical data. Results: We included 39 patients in our study; 21 patients (53.8%) showed symptoms of depression at the time of evaluation and, of those, 15 (71.4%) had hypoechogenic raphe structures. Thirty patients (76.9%) had a history of depressive episodes, 19 (63.3%) of them with hypoechogenic raphe structures. All 9 patients without a history of depressive episodes showed normal echogenicity of raphe structures (sensitivity 63.3%, specificity 100%). Twelve (70.6%) of the 17 patients with Huntington disease who showed psychiatric disturbances prior to the occurrence of motor symptoms exhibited pathological raphe echogenicity (sensitivity 70.6%, specificity 68.2%). Limitations: Most of the patients were taking antichoreatic medication, which particularly influences neurologic status. Thus, a meaningful interpretation of the correlation between TCS findings and neurologic features was limited. Conclusion: As a novel finding, a relation between mesencephalic raphe echogenicity and depressive state could be identified in patients with Huntington disease. An alteration of the serotonergic brain stem raphe might be involved in the pathogenesis of depression in these patients.

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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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Psychiatric Symptoms in Huntington’s Disease before Diagnosis: The Predict-HD Study

Cited by 349 publications

References 18 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

Depression in patients with Huntington disease correlates with alterations of the brain stem raphe depicted by transcranial sonography

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

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