Impairments of social cognition significantly predict the progression of functional decline in Huntington's disease: A 6-year follow-up study.

This study sought to investigate if there was a significant difference between the Huntington's Disease gene expansion carriers who were impaired on the cognitive domains, social cognition and executive functions. Also, it was investigated which of the cognitive domains could predict the decrease in total functional capacity over a 6-year follow-up period. Premanifest and motor-manifest Huntington's Disease gene expansion carriers (N = 98), were examined with a neurological and neuropsychological examination at Time 1 (year 2012-2013). Regression-based normative data was used to classify impairments on the two cognitive domains. Follow-up participants (N = 80) had their functional capacity reexamined at Time 2 (year 2018-2020), to examine which cognitive domain could predict the decrease in functional capacity over the 6-year follow-up. More than 50% of the participants were impaired on the domain of social cognition. These participants were significantly different from the participants who were impaired on executive functions. The motor function and impairments on social cognition significantly predicted the decline in functional capacity. The Emotion Hexagon test was the only significant social cognitive task, that predicted the decline in functional capacity. Social cognition includes unique and separate functions in Huntington's Disease, unaffected by executive functions. This study emphasizes the importance of regular assessment of social cognition in Huntington's Disease and the clinical relevance of impaired social cognitive function.

Decreased CSF oxytocin relates to measures of social cognitive impairment in Huntington's disease patients.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition. METHODS: We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay. RESULTS: We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002). CONCLUSIONS: This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Endophenotypical drift in Huntington's disease: a 5-year follow-up study.

BACKGROUND: Huntington's disease (HD) is clinically characterized by progressing motor, cognitive and psychiatric symptoms presenting as varying phenotypes within these three major symptom domains. The disease is caused by an expanded CAG repeat tract in the huntingtin gene and the pathomechanism leading to these endophenotypes is assumed to be neurodegenerative. In 2012/2013 we recruited 107 HD gene expansion carriers (HDGECs) and examined the frequency of the three cardinal symptoms and in 2017/2018 we followed up 74 HDGECs from the same cohort to describe the symptom trajectories and individual drift between the endophenotypes as well as potential predictors of progression and remission. RESULTS: We found higher age to reduce the probability of improving on psychiatric symptoms; increasing disease burden score ((CAG-35.5) * age) to increase the risk of developing cognitive impairment; increasing disease burden score and shorter education to increase the risk of motor onset while lower disease burden score and higher Mini Mental State Examination increased the probability of remaining asymptomatic. We found 23.5% (N = 8) to improve from their psychiatric symptoms. CONCLUSIONS: There is no clear pattern in the development of or drift between endophenotypes. In contrast to motor and cognitive symptoms we find that psychiatric symptoms may resolve and thereby not entirely be caused by neurodegeneration. The probability of improving from psychiatric symptoms is higher in younger age and advocates for a potential importance of early treatment.

Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease.

OBJECTIVE: To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score. METHODS: We collected CSF from 32 premanifest and 48 manifest HD gene-expansion carriers and 24 gene-expansion negative at-risk controls. We examined biomarkers of neuroinflammation (matrix metalloproteinase 9, C-X-C motif chemokine 13, terminal complement complex, chitinase-3-like-protein 1 [CHI3L1], and osteopontin [OPN]) and neurodegeneration (microtubule-associated protein tau, neurofilament light polypeptide [NFL], and myelin basic protein [MBP]). The study was approved by the Ethics Committee of the Capital Region of Denmark (H2-2011-085) and written informed consent was obtained from each participant before enrollment. RESULTS: NFL was the only biomarker that increased in premanifest stages and no evidence of early involvement of neuroinflammation in HD was found. However, we found that the biomarkers for neurodegeneration, MBP and tau, increased during the disease course in manifest HD gene-expansion carriers and were associated with an increase of the neuroinflammation biomarkers CHI3L1 and OPN. Tau was also increased in all gene-expansion carriers with psychiatric symptoms compared to gene-expansion carriers without psychiatric symptoms. CONCLUSIONS: Neuroinflammation, which seems not to be an early event in our cohort, may be secondary to neurodegeneration in late HD. NFL is a possible disease burden correlate in HD, reflecting neuronal loss even before motor symptom onset, and may be useful as a dynamic biomarker in intervention studies.

A clinical classification acknowledging neuropsychiatric and cognitive impairment in Huntington's disease.

BACKGROUND: Involuntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington's disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. After investigating the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers, we propose a new clinical classification. METHODS: In this cross-sectional study, 107 gene-expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment. RESULTS: Among the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired in addition to motor symptoms, and 14.3% had neuropsychiatric symptoms along with motor symptoms. Only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two. CONCLUSION: This is the first study to report the frequencies of both motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene-expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group. Some premanifest gene-expansion carriers may have psychiatric and/or cognitive symptoms caused by reactive stress or other pathology than HD. Acknowledging this fact we, however, suggest classifying all HD gene-expansion carriers into three clinical categories: premanifest, non-motor manifest, and motor manifest.