Dataset Information

Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington's Disease.

ABSTRACT:

Background

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown.

Methods

We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD.

Results

Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence.

Conclusions

Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

SUBMITTER: Ellis N

PROVIDER: S-EPMC7156911 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington's Disease.

Ellis Natalie N Tee Amelia A McAllister Branduff B Massey Thomas T McLauchlan Duncan D Stone Timothy T Correia Kevin K Loupe Jacob J Kim Kyung-Hee KH Barker Douglas D Hong Eun Pyo EP Chao Michael J MJ Long Jeffrey D JD Lucente Diane D Vonsattel Jean Paul G JPG Pinto Ricardo Mouro RM Elneel Kawther Abu KA Ramos Eliana Marisa EM Mysore Jayalakshmi Srinidhi JS Gillis Tammy T Wheeler Vanessa C VC Medway Christopher C Hall Lynsey L Kwak Seung S Sampaio Cristina C Ciosi Marc M Maxwell Alastair A Chatzi Afroditi A Monckton Darren G DG Orth Michael M Landwehrmeyer G Bernhard GB Paulsen Jane S JS Shoulson Ira I Myers Richard H RH van Duijn Erik E Rickards Hugh H MacDonald Marcy E ME Lee Jong-Min JM Gusella James F JF Jones Lesley L Holmans Peter P

Biological psychiatry 20191217 9

<h4>Background</h4>Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown.<h4>Methods</h4>We tested the hypothesis that ...[more]

PMID: 32087949

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Project description:ObjectivePsychiatric symptoms are a significant aspect of Huntington's disease, an inherited neurodegenerative illness. The presentation of these symptoms is highly variable, and their course does not fully correlate with motor or cognitive disease progression. The authors sought to better understand the development and longitudinal course of psychiatric manifestations in individuals who carry the Huntington's disease mutation, starting from the prodromal period prior to motor diagnosis.MethodLongitudinal measures for up to 10 years of psychiatric symptoms from the Symptom Checklist-90-Revised were obtained from 1,305 participants (1,007 carrying the Huntington's disease mutation and 298 without [classified as controls]) and 1,235 companions enrolled in the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Participants with the mutation were stratified into three groups according to probability of motor diagnosis within 5 years. Using linear mixed-effects regression models, differences in psychiatric symptoms at baseline and over time between the mutation-positive groups and the controls were compared, as well as between ratings by mutation-positive participants and their companions.ResultsNineteen of 24 psychiatric measures (12 participant ratings and 12 companion ratings) were significantly higher at baseline and showed significant increases longitudinally in the individuals with the Huntington's disease mutation compared with controls. The differences were greatest in comparisons of symptom reports from companions compared with self-reports, especially in participants who were closest to motor diagnosis.ConclusionsThe results indicate that psychiatric manifestations develop more often than previously thought in the Huntington's disease prodrome. Symptoms also increase with progression of disease severity. Greater symptom ratings by companions than by mutation-positive participants suggest decreasing awareness in those affected.

Project description:In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5-3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.

Project description:Lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the 2-fold aim of the present study was to (i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase and (ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnoea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analysed, and statistical intergroup analyses were then performed on behavioural and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed a significant decrease in connectivity, in the anosognosic group as compared with the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

Dataset Information

Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington's Disease.

Background

Methods

Results

Conclusions

Publications

Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington's Disease.

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