Predictors of Working Capacity Changes Related to Huntington’s Disease: A Longitudinal Study

Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric symptoms. Although 65%of HD expanded gene carriers report changes in employment as the first functional loss, little is known about the predictors leading to changes of working capacity. Given the impact on quality of life, understanding of these factors is of great clinical value. Objective: This study evaluates disease specific characteristics and their predictive value in loss of working capacity in HD. Methods: Longitudinal data was collected through the worldwide observational study (Enroll-HD), with 15,301 participants in total and 2,791 HD and healthy control participants meeting the inclusion criteria. Changes in working capacity were analyzed by means of a survival analysis. Predictive values of demographic factors and clinical characteristics were assessed for premanifest and manifest HD through Cox regressions. Results: HD expanded gene carriers, manifest and premanifest combined, had a 31%chance of experiencing changes in employment after three years, compared to 4%in healthy controls. Apathy was found to be the most crucial determinant of working capacity changes in premanifest HD, while executive and motor dysfunction play an important role in manifest HD. Conclusion: HD expanded gene carriers are more likely to lose working capacity compared to healthy controls. Disease progression, altered motor function, cognitive decline, and in an early stage of the disease apathetic symptoms are indicative of negative changes in working capacity. Clinicians should recognize that early disease related changes, especially apathy, can affect working capacity.

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Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

International Journal of Comparative Psychology ◽

10.46867/ijcp.2014.27.03.08 ◽

2014 ◽

Vol 27 (3) ◽

Author(s):

Carol A. Murphy ◽

Neil E. Paterson ◽

Angela Chen ◽

Washington Arias ◽

Dansha He ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Psychiatric Symptoms ◽

Motor Dysfunction ◽

Cag Repeats ◽

Motor Deficits ◽

Cholinergic Function ◽

Severe Motor

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

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The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

Cell Death and Disease ◽

10.1038/s41419-020-02754-w ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

Author(s):

Alba Di Pardo ◽

Elena Ciaglia ◽

Monica Cattaneo ◽

Anna Maciag ◽

Francesco Montella ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Motor Dysfunction ◽

Cag Repeats ◽

Huntingtin Protein ◽

Human Microglia

Abstract The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD.

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Bioinformatic gene analysis for potential therapeutic targets of Huntington’s disease in pre-symptomatic and symptomatic stage

Journal of Translational Medicine ◽

10.1186/s12967-020-02549-9 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Chunchen Xiang ◽

Shengri Cong ◽

Bin Liang ◽

Shuyan Cong

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Differentially Expressed Genes ◽

Bioinformatics Analysis ◽

Neurodegenerative Disorder ◽

Psychiatric Symptoms ◽

Therapeutic Targets ◽

Differentially Expressed ◽

Hub Genes ◽

Transcriptional Dysregulation

Abstract Background Huntington’s disease (HD) is a neurodegenerative disorder characterized by psychiatric symptoms, serious motor and cognitive deficits. Certain pathological changes can already be observed in pre-symptomatic HD (pre-HD) patients; however, the underlying molecular pathogenesis is still uncertain and no effective treatments are available until now. Here, we reanalyzed HD-related differentially expressed genes from the GEO database between symptomatic HD patients, pre-HD individuals, and healthy controls using bioinformatics analysis, hoping to get more insight in the pathogenesis of both pre-HD and HD, and shed a light in the potential therapeutic targets of the disease. Methods Pre-HD and symptomatic HD differentially expressed genes (DEGs) were screened by bioinformatics analysis Gene Expression Omnibus (GEO) dataset GSE1751. A protein–protein interaction (PPI) network was used to select hub genes. Subsequently, Gene Ontology (GO) enrichment analysis of DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of hub genes were applied. Dataset GSE24250 was downloaded to verify our hub genes by the Kaplan–Meier method using Graphpad Prism 5.0. Finally, target miRNAs of intersected hub genes involved in pre-HD and symptomatic HD were predicted. Results A total of 37 and 985 DEGs were identified in pre-HD and symptomatic HD, respectively. The hub genes, SIRT1, SUZ12, and PSMC6, may be implicated in pre-HD, and the hub genes, FIS1, SIRT1, CCNH, SUZ12, and 10 others, may be implicated in symptomatic HD. The intersected hub genes, SIRT1 and SUZ12, and their predicted target miRNAs, in particular miR-22-3p and miR-19b, may be significantly associated with pre-HD. Conclusion The PSMC6, SIRT1, and SUZ12 genes and their related ubiquitin-mediated proteolysis, transcriptional dysregulation, and histone metabolism are significantly associated with pre-HD. FIS1, CCNH, and their related mitochondrial disruption and transcriptional dysregulation processes are related to symptomatic HD, which might shed a light on the elucidation of potential therapeutic targets in HD.

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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

Journal of Experimental Medicine ◽

10.1084/jem.20080178 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1869-1877 ◽

Cited By ~ 337

Author(s):

Maria Björkqvist ◽

Edward J. Wild ◽

Jenny Thiele ◽

Aurelio Silvestroni ◽

Ralph Andre ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Immune Activation ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Innate Immune ◽

Brain Pathology ◽

Clinical Onset ◽

Gene Carriers ◽

A Cell

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.

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Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington's disease gene carriers

Psychiatry Research ◽

10.1016/s0165-1781(01)00257-8 ◽

2001 ◽

Vol 102 (3) ◽

pp. 217-225 ◽

Cited By ~ 43

Author(s):

German E Berrios ◽

A.C Wagle ◽

Ivana S Marková ◽

S.A Wagle ◽

Luk W Ho ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Gene ◽

Psychiatric Symptoms ◽

Cag Repeats ◽

Gene Carriers

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SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington's disease progression

10.1101/2021.11.03.466767 ◽

2021 ◽

Author(s):

Alena Salašová ◽

Niels Sanderhoff Degn ◽

Mikhail Paveliev ◽

Niels Kjaergaard Madsen ◽

Saray Benito ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Neurodegenerative Disorder ◽

Dorsal Striatum ◽

Long Term Potentiation ◽

Motor Dysfunction ◽

Motor Deficits ◽

Bdnf Expression ◽

Term Potentiation

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Here we show that SorCS2 is expressed in MSNs with reduced expression in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. In contrast, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. To conclude, we uncovered that SorCS2 dynamically targets TrkB and GluN2B to orchestrate BDNF-dependent plasticity in MSNs of dorsal striatum. We propose that SorCS2 deficiency impairs MSN function thereby increasing neuronal vulnerability and accelerating the motor deficits in Huntington's disease.

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Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

10.21203/rs.2.10368/v3 ◽

2020 ◽

Author(s):

Nikhil Ratna ◽

Nitish L Kamble ◽

Sowmya D V ◽

Meera Purushottam ◽

Pramod K Pal ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Psychiatric Symptoms ◽

Tertiary Care ◽

Psychiatric Morbidity ◽

Cag Repeat ◽

Duration Of Illness ◽

Low Middle Income Countries

Abstract BACKGROUND: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n=81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p<0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

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Psychiatric symptoms in neurologically asymptomatic Huntington's disease gene carriers: a comparison with gene negative at risk subjects

Acta Psychiatrica Scandinavica ◽

10.1034/j.1600-0447.2002.0o456.x ◽

2002 ◽

Vol 105 (3) ◽

pp. 224-230 ◽

Cited By ~ 59

Author(s):

G. E. Berrios ◽

A. C. Wagle ◽

I. S. Marková ◽

S. A. Wagle ◽

A. Rosser ◽

...

Keyword(s):

At Risk ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Gene ◽

Psychiatric Symptoms ◽

Gene Carriers

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The molecular biology of Huntington's disease

Psychological Medicine ◽

10.1017/s0033291799002871 ◽

2001 ◽

Vol 31 (1) ◽

pp. 3-14 ◽

Cited By ~ 64

Author(s):

L. W. HO ◽

J. CARMICHAEL ◽

J. SWARTZ ◽

A. WYTTENBACH ◽

J. RANKIN ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cortical Neurons ◽

Neurodegenerative Disorder ◽

Psychiatric Symptoms ◽

Cag Repeat ◽

Cag Repeats ◽

Intranuclear Inclusions ◽

Progressive Dementia ◽

Cellular Models

Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).Methods. This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.Results. Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.Conclusions. Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.

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