Multimodal treatment strategies in Huntington’s disease

Huntington’s disease (HD) is an incurable neurodegenerative disease that causes involuntary movements, emotional lability, and cognitive dysfunction. HD symptoms usually develop between ages 30 and 50, but can appear as early as 2 or as late as 80 years. Currently no neuroprotective and neurorestorative interventions are available. Early multimodal intervention in HD is only possible if the genetic diagnosis is made early. Early intervention in HD is only possible if genetic diagnosis is made at the disease onset or when mild symptoms manifest. Growing evidence and understanding of HD pathomechanism has led researchers to new therapeutic targets. Here, in this article we will talk about the multimodal treatment strategies and recent advances made in this field which can be used to target the HD pathogenesis at its most proximal level.

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Premanifest and Early Huntington’s Disease

10.1093/med/9780199929146.003.0005 ◽

2014 ◽

Cited By ~ 2

Author(s):

Edward J. Wild ◽

Sarah J. Tabrizi

Keyword(s):

Clinical Trials ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Setting ◽

Disease Onset ◽

Multidisciplinary Care ◽

Subjective Symptoms ◽

Hd Gene ◽

Stochastic Event ◽

Made In

The traditional view that individuals carrying an expanded Huntington’s disease (HD) gene undergo phenoconversion, a stochastic event that takes them from symptom-free to symptomatic, is now disputed among clinicians, HD researchers, and patient and family advocates. Disease onset is officially declared when neurologic abnormalities that are unequivocally due to HD are diagnosed, but subjective symptoms and objective signs emerge gradually, and it is more helpful to consider and openly discuss a prodromal period, often as long as 10 years, which can provide a helpful framework for discussion and management. Considerable progress has been made in defining the neurobiologic processes that underlie the development of HD in humans and measures that can predict this for the purpose of conducting clinical trials, but these measures have not yet been validated sufficiently to make them useful in the clinical setting. This chapter discusses the multidisciplinary care of patients with premanifest, prodromal, and early manifest HD.

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Management of Traumatic Ulcerations of Lips in a Case of Huntington’s Disease: A Novel Application of Essix Retainer

The Journal of Indian Orthodontic Society ◽

10.1177/03015742211023469 ◽

2021 ◽

pp. 030157422110234

Author(s):

Mohamed Iqbal J

Keyword(s):

Quality Of Life ◽

Characteristic Feature ◽

Neurodegenerative Disease ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Complete Resolution ◽

Psychiatric Symptoms

Huntington’s disease is a progressive neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Dystonia of muscles is a characteristic feature of this condition. A case of Huntington’s disease, with orofacial dystonia, leading to severe uncontrolled biting of the lips, was referred by the Department of Neurology. Deep traumatic ulcerations were found in both upper and lower lips. A simple Essix retainer was fabricated and inserted, which acted as a barrier for the teeth from injuring the lips. The ulcers showed complete resolution in 3 to 4 weeks. The vacuum-formed retainers resulted in a good fit and resisted removal by the uncontrolled contortions of the orofacial muscles. The Essix retainer can be effectively used in improving the quality of life of patients, with Huntington’s disease, having such dystonia-related injuries to lips.

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Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

Neurotherapeutics ◽

10.1007/s13311-021-01023-8 ◽

2021 ◽

Author(s):

Danielle A. Simmons ◽

Brian D. Mills ◽

Robert R. Butler III ◽

Jason Kuan ◽

Tyne L. M. McHugh ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Treatment Response ◽

Diffusion Tensor ◽

Disease Onset ◽

Therapeutic Effects ◽

Plasma Cytokine ◽

Cytokine Levels ◽

Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Brain Sciences ◽

10.3390/brainsci11060710 ◽

2021 ◽

Vol 11 (6) ◽

pp. 710

Author(s):

Jannis Achenbach ◽

Simon Faissner ◽

Carsten Saft

Keyword(s):

Hiv Infection ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Diagnostic Delay ◽

Depression Scale ◽

Cag Repeat ◽

Psychiatric Disease ◽

Disease Manifestation ◽

Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

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C04 Protein coding tandem repeat in TCERG1 modifies huntington’s disease onset

10.1136/jnnp-2021-ehdn.28 ◽

2021 ◽

Author(s):

Sergey Lobanov ◽

Branduff McAllister ◽

Mia McDade-Kumar ◽

Jong-Min Lee ◽

Marcy MacDonald ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Tandem Repeat ◽

Disease Onset ◽

Protein Coding

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Cortical circuit alterations precede disease onset in Huntington’s disease mice

10.1101/391771 ◽

2018 ◽

Author(s):

Johanna Neuner ◽

Elena Katharina Schulz-Trieglaff ◽

Sara Gutiérrez-Ángel ◽

Fabian Hosp ◽

Matthias Mann ◽

...

Keyword(s):

Motor Cortex ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Primary Motor Cortex ◽

Disease Onset ◽

Single Neurons ◽

Two Photon ◽

Layer 2 ◽

Cortical Circuit

AbstractHuntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

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Neural Transplantation for Huntington's Disease: Experimental Rationale and Recommendations for Clinical Trials

Cell Transplantation ◽

10.1177/096368979600500222 ◽

1996 ◽

Vol 5 (2) ◽

pp. 339-352 ◽

Cited By ~ 12

Author(s):

Kathleen M. Shannon ◽

Jeffrey H. Kordower

Keyword(s):

Clinical Trials ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Treatment Strategies ◽

Neural Transplantation ◽

Trophic Factors ◽

Trophic Factor ◽

Striatal Neurons ◽

Variable Parameters

Huntington's disease (HD) is a neurodegenerative disorder affecting motor function, personality, and cognition. This paper reviews the experimental data that demonstrate the potential for transplantation of fetal striatum and trophic factor secreting cells to serve as innovative treatment strategies for HD. Transplantation strategies have been effective in replacing lost neurons or preventing the degeneration of neurons destined to die in both rodent and nonhuman primate models of HD. In this regard, a logical series of investigations has proven that grafts of fetal striatum survive, reinnervate the host, and restore function impaired following excitotoxic lesions of the striatum. Furthermore, transplants of cells genetically modified to secrete trophic factors such as nerve growth factor protect striatal neurons from degeneration due to excitotoxicity or mitochondrial dysfunction. Given the disabling and progressive nature of HD, coupled with the absence of any meaningful medical therapy, it is reasonable to consider clinical trials of neural transplantation for this disease. Fetal striatal implants will most likely be the first transplant strategy attempted for HD. This paper describes the variable parameters we believe to be critical for consideration for the design of clinical trials using fetal striatal implants for the treatment of HD.

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MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Brain ◽

10.1093/brain/awz115 ◽

2019 ◽

Vol 142 (7) ◽

pp. 1876-1886 ◽

Cited By ~ 25

Author(s):

Michael Flower ◽

Vilija Lomeikaite ◽

Marc Ciosi ◽

Sarah Cumming ◽

Fernando Morales ◽

...

Keyword(s):

Huntington's Disease ◽

Association Study ◽

Huntington’S Disease ◽

Myotonic Dystrophy ◽

Disease Onset ◽

Repeat Expansion ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Exon 1

Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

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Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

Journal of Probability and Statistics ◽

10.1155/2012/375935 ◽

2012 ◽

Vol 2012 ◽

pp. 1-19 ◽

Cited By ~ 3

Author(s):

Tianle Chen ◽

Yuanjia Wang ◽

Yanyuan Ma ◽

Karen Marder ◽

Douglas R. Langbehn

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Family Member ◽

Disease Onset ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Observational Research ◽

Accurate Estimation ◽

Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

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