Journal of Huntington's Disease - Volume 8, issue 2

Authors: Arbez, Nicolas | Roby, Elaine | Akimov, Sergey | Eddings, Chelsy | Ren, Mark | Wang, Xiaofang | Ross, Christopher A.

Article Type: Research Article

Abstract: Background: The potential benefit of cysteamine for Huntington’s disease has been demonstrated in HD animal models. Cysteamine and its derivate cystamine were shown to reduce neuropathology and prolong lifespan. Human studies have demonstrated safety, and suggestive results regarding efficacy. Despite all the studies available in vivo , there are only few in vitro studies, and the mechanism of action of cysteamine remains unclear. Objective: The objective of this study is to assess the capacity of cysteamine for neuroprotection against mutant Huntingtin in vitro using cellular models of HD, and to provide initial data regarding mechanism of …action. Methods: We tested the neuroprotective properties of cysteamine in vitro in our primary neuron and iPSC models of HD. Results: Cysteamine showed a strong neuroprotective effect (EC50 = 7.1 nM) against mutant Htt-(aa-1-586 82Q) toxicity, in a nuclear condensation cell toxicity assay. Cysteamine also rescued mitochondrial changes induced by mutant Htt. Modulation of the levels of cysteine or glutathione failed to protect neurons, suggesting that cysteamine neuroprotection is not mediated through cysteine metabolism. Taurine and Hypotaurine, which are metabolites of cysteamine can protect neurons against Htt toxicity, but the inhibition of the enzyme converting cysteamine to hypotaurine does not block either protective activity, suggesting independent protective pathways. Cysteamine has been suggested to activate BDNF secretion; however, cysteamine protection was not blocked by BDNF pathway antagonists. Conclusions: Cysteamine was strongly neuroprotective with relatively high potency. We demonstrated that the main neuroprotective pathways that have been proposed to be the mechanism of protection by cysteamine can all be blocked and still not prevent the neuroprotective effect. The results suggest the involvement of other yet-to-be-determined neuroprotective pathways. Show more

Keywords: Huntington’s disease, huntingtin toxicity, primary neurons, neurodegeneration, neuroprotection, cysteamine, patient-derived induced pluripotent stem cells

DOI: 10.3233/JHD-180312

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 129-143, 2019

Authors: Kojer, Kerstin | Hering, Tanja | Bazenet, Chantal | Weiss, Andreas | Herrmann, Frank | Taanman, Jan-Willem | Orth, Michael

Article Type: Research Article

Abstract: Background: Cell or tissue specific background may influence the consequences of expressing the Huntington’s disease (HD) mutation. Aggregate formation is known to occur in skeletal muscle, but not heart of the R6/2 fragment HD model. Objective: We asked whether aggregate formation and the expression and subcellular localization of huntingtin species was associated with mitochondrial dysfunction. Methods: We analyzed levels of soluble HTT and HTT aggregates, as well as important fission and fusion proteins and mitochondrial respiratory chain activities, in quadriceps and heart of the R6/2 N-terminal fragment mouse model (12 weeks, 160±10 CAG repeats). …Results: Soluble mutant HTT was present in both tissues with expression higher in cytoplasmic/mitochondrial than nuclear fractions. HTT aggregates were only detectable in R6/2 quadriceps, in association with increased levels of the pro-fission factor DRP1 and its phosphorylated active form, and decreased levels of the pro-fusion factor MFN2. In addition, respiratory chain complex activities were decreased. In heart that was without detectable HTT aggregates, we found no evidence for mitochondrial dysfunction. Conclusion: Tissue specific factors may exist that protect the R6/2 heart from HTT aggregate formation and mitochondrial pathology. Show more

Keywords: Huntingtin, mitochondria, fission and fusion, respiratory chain, skeletal muscle

DOI: 10.3233/JHD-180324

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 145-159, 2019

Authors: Pfalzer, Anna C. | Wages, Phillip A. | Porter, Ned A. | Bowman, Aaron B.

Article Type: Research Article

Abstract: Background: Cholesterol is necessary for proper neurodevelopment and neuronal health. The brain relies on neural and astrocytic de novo cholesterol synthesis. Huntington’s disease presents with altered levels of cholesterol precursors however it is unknown when the disruption in this molecular pathway occurs and whether Manganese (Mn) may alter these metabolic alterations. Objective: To examine the effect of Mn exposure on cholesterol biosynthesis in pre-manifest and manifest Huntington’s disease mice. Methods: 12-week (pre-manifest) male and female and 42-week old (manifest) female YAC128 and littermate control (WT) mice received 3 subcutaneous Mn or vehicle injections. Animals were …sacrificed 24 hours after the final injection and striatum, cerebral cortex and cerebellum were collected to measure cholesterol and cholesterol precursors using LC/MS-MS. Results: Striatal desmosterol and cholesterol are increased in pre-manifest HD females compared to age-matched WT female mice. Striatal lanosterol, 8-DHC and desmosterol and cholesterol are reduced in manifest HD females compared to age-and sex-matched WT mice with minimal effects in the cortex and cerebellum. Mn treatment had no effect in the pre-manifest or manifest female brain except reduced lanosterol levels in the cortex of pre-manifest female mice. Neither Mn or HD altered brain cholesterol precursor levels in the pre-manifest HD or WT male mouse. Conclusions: Cholesterol biosynthesis is impaired in early disease stage in female HD mice only and continues throughout disease. These alterations appear largely striatal-specific. Acute systemic exposure to Mn did not significantly alter cholesterol biosynthesis in the striatum at any disease stage. Show more

Keywords: Cholesterol, huntington’s disease, manganese, sterols, striatum

DOI: 10.3233/JHD-180321

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 161-169, 2019

Authors: Cronin, Thomas | Rosser, Anne | Massey, Thomas

Article Type: Research Article

Abstract: Background: Juvenile-onset Huntington’s disease (JHD) is defined by onset at the age of 20 or younger and represents approximately 5% of all HD cases. Patients with JHD present with a broad range of symptoms and signs that only overlap partially with adult-onset HD. A greater awareness and understanding of the presentation of JHD would improve the diagnosis and treatment of this condition. Objective: To undertake a systematic review of the literature relating to the clinical features at first presentation of JHD. Methods: We searched MEDLINE and EMBASE for all studies describing presenting features of JHD patients, …performed quality control, and collated and analysed the data. Results: We screened 2917 records for eligibility, and included 79 studies (n  = 285 individuals) in the analysis. All were case reports and case series, synthesising data from 25 different countries. Thirty-four different clinical features at presentation were identified. Four groups of symptoms or signs were present in more than 15% of cases: behavioural disturbance, falls/gait disturbance, cognitive impairment and parkinsonian features. Where data were available, the median age of onset was 9 years, 52% were female, the mutant HTT allele was transmitted paternally in 80% of cases, and the median CAG repeat length was 64. Conclusions: JHD can present with a wide variety of symptoms and signs, with non-motor characteristics being observed most frequently. Greater recognition of these presentations will facilitate early diagnosis and management. Tailored rating scales to score motor, non-motor, and functional impairments specifically in JHD are required to standardise research studies, and are under development. Show more

Keywords: Huntington’s disease, juvenile onset Huntington’s disease, review, diagnosis, signs and symptoms

DOI: 10.3233/JHD-180339

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 171-179, 2019

Authors: Horton, Mike C. | Nopoulos, Peggy | Nance, Martha | Landwehrmyer, G. Bernhard | Barker, Roger A. | Squitieri, Ferdinando | REGISTRY Investigators of the European Huntington’s Disease Network | Burgunder, Jean-Marc | Quarrell, Oliver

Article Type: Research Article

Abstract: Background: Huntington’s disease can present at almost any age but traditionally, those with an onset ≤20 years are described as having juvenile onset Huntington’s disease (JOHD). They are more likely to have bradykinesia and dystonia earlier in the course of the disease. The Total Motor Score of the Unified Huntington’s Disease Rating Scale (UHDRS-TMS) is often used as the principal outcome measure in clinical trials. Objective: To identify a motor scale more suitable for JOHD patients. Methods: A working group reviewed the UHDRS-TMS and modified it by adding four further assessment items. Rasch analysis was used …to study the performance of the modified scale in 95 patients with a mean age of 19.4 (SD 6.6) years. Results: The initial analysis showed a significant overall misfit to the Rasch model and a number of individual items displayed poor measurement properties: all items relating to chorea displayed significant misfit due to under-discrimination. Additionally, a number of items displayed disordered response category thresholds, and a large amount of dependency was present within the item set (96 out of 741 pairwise differences = 13%). An iterative process of scale re-structuring and evaluation was then undertaken, with a view to eliminating the largest sources of misfit and generating a set of items that would conform to Rasch model expectations. Conclusion: This post-hoc scale restructuring appears to provide a valid motor score that is psychometrically robust in a JOHD population. This scale restructuring offers a pragmatic solution to measuring motor function in a JOHD population, and it could provide the basis for the further iterative development of a more useful clinical rating scale for patients with JOHD. Show more

Keywords: Rasch, juvenile onset Huntington’s disease, total motor score

DOI: 10.3233/JHD-180306

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 181-193, 2019

Authors: Rojas, Natalia González | Ziliani, Javier Enrique | Cesarini, Martin Emilano | Etcheverry, José Luis | Da Prat, Gustavo Andrés | McCusker, Elizabeth | Gatto, Emilia Mabel

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a neurodegenerative disorder that includes motor, psychiatric and cognitive manifestations with typical onset of symptoms is in the forties. A percentage of patients (4.4% – 11.5%) may be exceptions to this and manifest symptoms later (>60 years old). Diagnosis of Late onset HD (LoHD) can be a challenge, due to the low suspicion of the disease at this age. Objective: To review the genotype and phenotype of LoHD in an Argentinian cohort. Methods: We reviewed the medical records and genetic testing of a total of 95 individuals with clinical and molecular …diagnosis of Huntington’s disease, based on 2 institution’s registry. Results: Among our HD cohort, 10 patients (10.52%) had LoHD, with variable results regarding family history. The average of repetitions of the expanded allele was 40 (range 38–44). All cases had mild motor symptoms at onset. Conclusions: Late onset HD can be a diagnostic challenge, due to its slow progression, unawareness of manifestations among patients and in many cases, mild symptomatology that does not warrant medical attention. Show more

DOI: 10.3233/JHD-180330

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 195-198, 2019

Authors: Ciarochi, Jennifer A. | Johnson, Hans J. | Calhoun, Vince D. | Liu, Jingyu | Espinoza, Flor A. | Bockholt, Henry J. | Misiura, Maria | Caprihan, Arvind | Plis, Sergey | Paulsen, Jane S. | Turner, Jessica A. | the PREDICT-HD Investigators and Coordinators of the Huntington Study Group

Article Type: Research Article

Abstract: Background: Gray matter (GM) atrophy in the striatum and across the brain is a consistently reported feature of the Huntington Disease (HD) prodrome. More recently, widespread prodromal white matter (WM) degradation has also been detected. However, longitudinal WM studies are limited and conflicting, and most analyses comparing WM and clinical functioning have also been cross-sectional. Objective: We simultaneously assessed changes in WM and cognitive and motor functioning at various prodromal HD stages. Methods: Data from 1,336 (1,047 prodromal, 289 control) PREDICT-HD participants were analyzed (3,700 sessions). MRI images were used to create GM, WM, and cerebrospinal …fluid probability maps. Using source-based morphometry, independent component analysis was applied to WM probability maps to extract covarying spatial patterns and their subject profiles. WM profiles were analyzed in two sets of linear mixed model (LMM) analyses: one to compare WM profiles across groups cross-sectionally and longitudinally, and one to concurrently compare WM profiles and clinical variables cross-sectionally and longitudinally within each group. Results: Findings illustrate widespread prodromal changes in GM-adjacent-WM, with premotor, supplementary motor, middle frontal and striatal changes early in the prodrome that subsequently extend sub-gyrally with progression. Motor functioning agreed most with WM until the near-onset prodromal stage, when Stroop interference was the best WM indicator. Across groups, Trail-Making Test part A outperformed other cognitive variables in its similarity to WM, particularly cross-sectionally. Conclusions: Results suggest that distinct regions coincide with cognitive compared to motor functioning. Furthermore, at different prodromal stages, distinct regions appear to align best with clinical functioning. Thus, the informativeness of clinical measures may vary according to the type of data available (cross-sectional or longitudinal) as well as age and CAG-number. Show more

Keywords: Cognition, magnetic resonance imaging, movement, multivariate analysis, prodromal symptoms, white matter

DOI: 10.3233/JHD-180332

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 199-219, 2019

Authors: Ready, Rebecca E. | Boileau, Nicholas R. | Barton, Stacey K. | Lai, Jin-Shei | McCormack, Michael K. | Cella, David | Fritz, Nora E. | Paulsen, Jane S. | Carlozzi, Noelle E.

Article Type: Research Article

Abstract: Background: Positive affect is associated with resiliency and beneficial health outcomes, but little is known about associations between positive affect and health-related quality of life (HRQOL) in Huntington’s disease (HD). Objective: This longitudinal study determined the association between positive affect and several HRQOL outcomes in persons with HD. Functional status was examined as a moderator of the association between positive affect and HRQOL. Methods: Participants, with premanifest (i.e., genetically at risk but no clinical diagnosis, n  = 50) and manifest HD (early-stage n  = 171; late-stage n  = 101), completed a measure of positive affect and well-being and several …HRQOL measures at baseline, 12-, and 24-month follow-ups. UHDRS Functional Assessment scale indicated functional status. Results: Positive affect was associated with better HRQOL for persons with premanifest and manifest HD over the 24-month time frame. These associations were moderated by functional status. For persons with higher functional status, positive affect was associated with better HRQOL, including less depression, lower anxiety, less anger, better social role satisfaction, better executive functions, greater upper extremity function, less dyscontrol, and less concern with death and dying. For persons with lower functional status, positive affect was not associated with HRQOL. Conclusions: Positive affect predicted better self-reported HRQOL over a 24-month period in persons with premanifest and manifest HD, particularly when participnats had better functional status. Interventions to enhance positive affect in HD may have beneficial effects on HRQOL. Show more

Keywords: Quality of life, positive affect, functional assessment, Huntington’s disease, longitudinal

DOI: 10.3233/JHD-180341

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 221-232, 2019

Authors: Dhalla, Amit | Pallikadavath, Susil | Hutchinson, Claire V.

Article Type: Research Article

Abstract: It is well-documented that patients with Huntington’s disease (HD) exhibit specific deficits in visual cognition. A less well-documented literature also exists that suggests people with HD experience a number of disease-related changes to more rudimentary sensory visual processing. Here, we review evidence for the effects of HD on the integrity of the early visual pathways in humans along with changes to low-level visual sensitivity. We find evidence for reduced structural and functional integrity of the visual pathways, marked by retinal thinning, reduced VEP amplitude, and cell loss and thinning in visual cortex. We also find evidence of visual perceptual deficits, …particularly for colour and motion. We suggest that future studies with well-defined HD and HD-related groups in appropriate numbers that systematically examine the relationship between structural changes to the visual system, basic visual perceptual deficits and disease stage/severity are therefore likely to yield promising results. Show more

Keywords: Huntington’s disease, vision, retina, visual pathways, primary visual cortex, colour vision, contrast sensitivity, motion perception

DOI: 10.3233/JHD-180340

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 233-242, 2019

Article Type: Meeting Report

DOI: 10.3233/JHD-199001

Citation: Journal of Huntington's Disease, vol. 8, no. 2, pp. 243-243, 2019