Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntington’s Disease

2019 ◽  
Vol 19 (2) ◽  
pp. 78-87 ◽  
Author(s):  
Martin Kronenbuerger ◽  
Jun Hua ◽  
Jee Y.A. Bang ◽  
Kia E. Ultz ◽  
Xinyuan Miao ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Compensatory Mechanism ◽  
Motor Score ◽  
Cortical Areas ◽  
Motor Circuits ◽  
Neurophysiological Studies ◽  
Cortical Regions

Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.

scholarly journals Retinal and choroidal morphological changes in Huntington's disease

2019 ◽  
Vol 12 (1) ◽  
pp. 56-63
Author(s):  
S. N. Svetozarskiy ◽  
S. V. Kopishinskaya ◽  
I. G. Smetankin
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Choroidal Thickness ◽  
Disease Duration ◽  
Retinal Thickness ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Study Group ◽  
Motor Score ◽  
Cag Repeat Expansion

Purpose: to investigate the choroidal and retinal morphology in Huntington's disease (HD) using optical coherence tomography (OCT) and to analyze how the parameters studied correlate with the clinical data. Material and methods. The study included two groups of subjects, (1) 44 HD patients, averagely aged 37.6 ± 10.2 yrs, and (2) 31 healthy volunteers, averagely aged 37.3 ± 10.8 yrs. The groups had matching age, sex distribution, intraocular pressure and mean refractive error. In the study group, 21 patients had pre-manifest and 23, manifest HD stage. All patients underwent a thorough neurological and ophthalmic examination which included retinal OCT. The foveal choroidal thickness, retinal thickness in 9 areas of the macular zone, retinal ganglion cells complex (GCC) and peripapillary retinal nerve fiber layer thickness (RNFL) were evaluated in 4 quadrants. CAG repeat expansion size (cytosine-adenine-guanine) in the huntingtin gene, the disease duration and Unified HD Rating Scale motor scores (UHDRS) were evaluated for HD patients. Results. The range of the CAG repeat expansion size in the study group was 37–56 repeats (44.3 ± 3.8), the UHDRS motor score was 36.3 ± 29.7, disease duration was 13.7 ± 7.2 years. OCT revealed a significant decrease in the foveal choroidal thickness, GCC complex thickness, average, temporal, inferior and nasal RNFL thickness and total retinal thickness in the external temporal area in HD patients as compared to the controls. In addition, an inverse correlation between the disease duration, UHDRS Motor Score and a number of OCT parameters was found. Conclusion. The results confirm the promising potential of retinal tomographic parameters as a biomarker for early diagnosis and monitoring of the neurodegenerative process progression. The topography of retinal thickness reduction indicates a specific pattern of retinal neurodegeneration in HD. 

Subdural Hematoma as a Serious Complication of Huntington’s Disease: An Observational Study

2021 ◽  
pp. 1-6
Author(s):  
Marie Davis ◽  
Vicki Wheelock ◽  
Lauren Talman ◽  
Caitlin Latimer ◽  
Brenda Vicars ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Head Trauma ◽  
Ground Level ◽  
Altered Mental Status ◽  
Cag Repeat ◽  
Motor Score ◽  
Centers Of Excellence ◽  
Increased Risk ◽  
History Of

Background: Persons with Huntington’s disease (HD) are at increased risk for subdural hematomas (SDH) because of underlying brain atrophy and increased frequency of falls and head trauma. SDH can cause serious disability, but there is little information about the association of SDH with HD in the medical literature. Objective: To review the occurrence and characteristics of SDH seen in clinics specializing in HD. Methods: A retrospective review identifying the occurrence and manifestations of SDH in HD patients attending three HDSA Centers of Excellence. Results: Twenty-five HD patients (16F/9M) were identified with SDH. Twelve (44%) SDH were bilateral, 16 (60%) required surgical intervention, and 2 resulted in death. Mean age at the time of SDH was 60 years, mean duration of HD symptoms prior to event was 8 years, mean CAG repeat expansion size was 43 and mean UHDRS motor score obtained closest to time of SDH was 51 (16 patients). Most SDH occurred in the context of ground level falls or using stairs although 5 patients had no history of head trauma. Additional brain injury may occur along with the SDH. The most common symptoms were altered mental status, hemiparesis and loss of consciousness. The over-representation of females in this study requires replication and further investigation. Conclusion: Patients with HD are at increased risk for SDH. An increased suspicion for SDH in HD patients should be considered, as this phenomenon may be initially unrecognized, may require extensive utilization of medical resources and is a potential cause of death.

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

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.

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

2016 ◽  
Vol 126 (11) ◽  
pp. 4319-4330 ◽  
Author(s):  
Laura Rué ◽  
Mónica Bañez-Coronel ◽  
Jordi Creus-Muncunill ◽  
Albert Giralt ◽  
Rafael Alcalá-Vida ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Disease Phenotype

scholarly journals Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

2022 ◽  
Author(s):  
Sanzana Hoque ◽  
Marie Sjogren ◽  
Valerie Allamand ◽  
Kinga Gawlik ◽  
Naomi Franke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Damage ◽  
Satellite Cell ◽  
Mouse Models ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Cag Repeat ◽  
Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

scholarly journals Juvenile Huntington’s Disease and Other PolyQ Diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic and Proteomic Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Karolina Świtońska-Kurkowska ◽  
Bart Krist ◽  
Joanna Delimata ◽  
Maciej Figiel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Expression Patterns ◽  
Cag Repeat ◽  
Human Cognition ◽  
Expression Data ◽  
Neuronal Stem Cell ◽  
Polyq Diseases

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. In addition, we extended our bioinformatic transcriptomic analysis by proteomics data. We identified a group of 13 commonly downregulated genes and proteins in HD mouse models. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.

scholarly journals Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

2021 ◽  
Vol 15 ◽  
Author(s):  
Hidetoshi Komatsu
Keyword(s):  
Nucleic Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Throughput Screening ◽  
Neurodegenerative Disorder ◽  
Direct Injection ◽  
Cag Repeat ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Small Interfering Rnas

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.

Sign in / Sign up

Export Citation Format

Share Document