Journal of Huntington's Disease - Volume 10, issue 3

Authors: Puig-Davi, Arnau | Martinez-Horta, Saul | Sampedro, Frederic | Horta-Barba, Andrea | Perez-Perez, Jesus | Campolongo, Antonia | Izquierdo-Barrionuevo, Cristina | Pagonabarraga, Javier | Gomez-Anson, Beatriz | Kulisevsky, Jaime

Article Type: Research Article

Abstract: Background: Empathy is a multidimensional construct and a key component of social cognition. In Huntington’s disease (HD), little is known regarding the phenomenology and the neural correlates of cognitive and affective empathy, and regarding how empathic deficits interact with other behavioral and cognitive manifestations. Objective: To explore the cognitive and affective empathy disturbances and related behavioral and neural correlates in HD. Methods: Clinical and sociodemographic data were obtained from 36 healthy controls (HC) and 54 gene-mutation carriers (17 premanifest and 37 early-manifest HD). The Test of Cognitive and Affective Empathy (TECA) was used to characterize cognitive …(CE) and affective empathy (AE), and to explore their associations with grey matter volume (GMV) and cortical thickness (Cth). Results: Compared to HC, premanifest participants performed significantly worse in perspective taking (CE) and empathic distress (AE). In symptomatic participants, scores were significantly lower in almost all the TECA subscales. Several empathy subscales were associated with the severity of apathy, irritability, and cognitive deficits. CE was associated with GMV in thalamic, temporal, and occipital regions, and with Cth in parietal and temporal areas. AE was associated with GMV in the basal ganglia, limbic, occipital, and medial orbitofrontal regions, and with Cth in parieto-occipital areas. Conclusion: Cognitive and affective empathy deficits are detectable early, are more severe in symptomatic participants, and involve the disruption of several fronto-temporal, parieto-occipital, basal ganglia, and limbic regions. These deficits are associated with disease severity and contribute to several behavioral symptoms, facilitating the presentation of maladaptive patterns of social interaction. Show more

Keywords: Huntington’s disease, social cognition, empathy, magnetic resonance imaging, voxel-based morphometry

DOI: 10.3233/JHD-210469

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 323-334, 2021

Authors: Sap, Karen A. | Guler, Arzu Tugce | Bury, Aleksandra | Dekkers, Dick | Demmers, Jeroen A.A. | Reits, Eric A.

Article Type: Research Article

Abstract: Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). …Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology. Show more

Keywords: Huntington’s disease, huntingtin protein, cerebral cortex, protein interaction mapping, cross-linking reagents, immunoprecipitation, proteomics

DOI: 10.3233/JHD-210476

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 335-347, 2021

Authors: Fisher, Emily R. | Rocha, Natalia P. | Morales-Scheihing, Diego A. | Venna, Venugopal Reddy | Furr-Stimming, Erin E. | Teixeira, Antonio L. | Rossetti, Maria A.

Article Type: Short Communication

Abstract: The role of oxytocin (OT) in social cognition of patients with Huntington’s disease (HD) has been studied, but its impact on executive functioning has not been explored yet. Healthy controls, premanifest HD, and manifest HD participants underwent executive functioning assessment and OT plasma measurement. There were no significant group differences in plasma OT levels. Higher OT levels were associated with better executive functioning in premanifest HD participants. Our findings revealed an association between OT levels and depressive symptoms in premanifest and manifest HD participants. The potential role of OT in HD deserves further investigation.

Keywords: Huntington’s disease, cognition, oxytocin, depression

DOI: 10.3233/JHD-210467

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 349-354, 2021

Authors: Caron, Nicholas S. | Anderson, Christine | Black, Hailey Findlay | Sanders, Shaun S. | Lemarié, Fanny L. | Doty, Crystal N. | Hayden, Michael R.

Article Type: Research Article

Abstract: Background: Therapeutics that lower mutant huntingtin (mHTT) have shown promise in preclinical studies and are in clinical development for the treatment of Huntington disease (HD). Multiple assays have been developed that either quantify mHTT or total HTT but may not accurately measure levels of wild type HTT (wtHTT) in biological samples. Objective: To optimize a method that can be used to resolve, quantify and directly compare levels of full length wtHTT and mHTT in HD samples. Methods: We provide a detailed quantitative immunoblotting protocol to reproducibly resolve full length wtHTT and mHTT in multiple HD mouse …and patient samples. Results: We show that this assay can be modified, depending on the sample, to resolve wtHTT and mHTT with a wide range of polyglutamine length differences (ΔQs 22–179). We also demonstrate that this method can be used to quantify allele-selective lowering of mHTT using an antisense oligonucleotide in HD patient-derived cells. Conclusion: This quantitative immunoblotting method can be used to reliably resolve full-length HTT alleles with ΔQs≥22 and allows for direct comparison of wtHTT and mHTT levels in HD samples. Show more

Keywords: Huntington’s disease, huntingtin, immunoblotting, oligonucleotides, antisense

DOI: 10.3233/JHD-200463

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 355-365, 2021

Authors: Hong, Eun Pyo | Chao, Michael J. | Massey, Thomas | McAllister, Branduff | Lobanov, Sergey | Jones, Lesley | Holmans, Peter | Kwak, Seung | Orth, Michael | Ciosi, Marc | Monckton, Darren G. | Long, Jeffrey D. | Lucente, Diane | Wheeler, Vanessa C. | MacDonald, Marcy E. | Gusella, James F. | Lee, Jong-Min

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Objective: We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. Methods: We …imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. Results: In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p -value, 1.4E-6), near moesin (MSN ), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Conclusion: Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download. Show more

Keywords: Genetic modifier, Huntington’s disease, residual age-at-onset, XWAS

DOI: 10.3233/JHD-210485

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 367-375, 2021

Authors: Ferrari Bardile, Costanza | Sidik, Harwin | Quek, Reynard | Yusof, Nur Amirah Binte Mohammad | Garcia-Miralles, Marta | Pouladi, Mahmoud A.

Article Type: Research Article

Abstract: Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods: Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze …myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results: We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion: Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities. Show more

Keywords: Huntington’s disease, spinal cord, white matter, oligodendroglia, myelin sheath

DOI: 10.3233/JHD-210495

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 377-384, 2021

Authors: Davis, Marie | Wheelock, Vicki | Talman, Lauren | Latimer, Caitlin | Vicars, Brenda | Lin, Anny | Jayadev, Suman | Bird, Thomas

Article Type: Research Article

Abstract: 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. Show more

Keywords: Head trauma, subdural hematoma, Huntington’s disease, falls, chorea

DOI: 10.3233/JHD-210478

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 385-390, 2021

Authors: Yamin, Hagar G. | Menkes-Caspi, Noa | Stern, Edward A. | Cohen, Dana

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an inherited fatal neurodegenerative disease, leading to neocortical and striatal atrophy. The commonly studied R6/2 HD transgenic mouse model displays progressive motor and cognitive deficits in parallel to major pathological changes in corticostriatal circuitry. Objective: To study how disease progression influences striatal encoding of movement. Methods: We chronically recorded neuronal activity in the dorsal striatum of R6/2 transgenic (Tg) mice and their age-matched nontransgenic littermate controls (WTs) during novel environment exposure, a paradigm which engages locomotion to explore the novel environment. Results: Exploratory locomotion degraded with age in Tg …mice as compared to WTs. We encountered fewer putative medium spiny neurons (MSNs)—striatal projection neurons, and more inhibitory interneurons—putative fast spiking interneurons (FSIs) in Tg mice as compared to WTs. MSNs from Tg mice fired less spikes in bursts without changing their firing rate, while FSIs from these mice had a lower firing rate and more of them were task-responsive as compared to WTs. Additionally, MSNs from Tg mice displayed a reduced ability to encode locomotion across age groups, likely associated with their low prevalence in Tg mice, whereas the encoding of locomotion by FSIs from Tg mice was substantially reduced solely in old Tg mice as compared to WTs. Conclusion: Our findings reveal an age-dependent decay in striatal information processing in transgenic mice. We propose that the ability of FSIs to compensate for the loss of MSNs by processes of recruitment and enhanced task-responsiveness diminishes with disease progression, possibly manifested in the displayed age-dependent degradation of exploratory locomotion. Show more

Keywords: Basal ganglia, electrophysiology, locomotion, neurons

DOI: 10.3233/JHD-210492

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 391-404, 2021

Authors: Aaronson, Jeff | Beaumont, Vahri | Blevins, Richard A. | Andreeva, Viktoria | Murasheva, Irina | Shneyderman, Anastasia | Armah, Kabenla | Gill, Rob | Chen, Jian | Rosinski, Jim | Park, Larry C. | Coppola, Giovanni | Munoz-Sanjuan, Ignacio | Vogt, Thomas F.

Article Type: Short Communication

Abstract: HDinHD (Huntington’s Disease in High Definition; HDinHD.org) is an open online portal for the HD research community that presents a synthesized view of HD-related scientific data. Here, we present a broad overview of HDinHD and highlight the newly launched HDinHD Explorer tool that enables researchers to discover and explore a wide range of diverse yet interconnected HD-related data. We demonstrate the utility of HDinHD Explorer through data mining of a single collection of newly released in vivo therapeutic intervention study reports alongside previously published reports.

Keywords: HDinHD, Huntington’s disease in high definition, data dissemination, rolipram

DOI: 10.3233/JHD-210491

Citation: Journal of Huntington's Disease, vol. 10, no. 3, pp. 405-412, 2021