Journal of Huntington's Disease - Volume 12, issue 3

Authors: McBride, Sebastian D. | Ober, Jan | Dylak, Jacek | Schneider, William | Morton, A. Jennifer

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is characterized by a loss of control of motor function that causes the presence of abnormal eye movements at early stages. Objective: To determine if, compared to normal sheep, HD sheep have abnormal eye movements. Methods: We measured eye movements in a transgenic sheep (Ovis aries) model of HD using a purpose-built, head-mounted sheep oculometer. This allows us to measure saccades without the need for either behavioral training or head fixation. At the age of testing (6 years old), the HD sheep were pre-manifest. We used 21 sheep (11 HD, 10 …normal). Results: We found small but significant differences in eye movements between normal (control) and HD sheep during vestibular ocular reflex (VOR)- and vestibular post-rotational nystagmus (PRN)-based tests. Conclusions: Two measures were identified that could distinguish normal from HD sheep; the number of PRN oscillations when tested in the dark and the gain (eye movement to head movement ratio) during the VOR when tested in the light. To our knowledge, this is the first study in which eye movements have been quantified in sheep. It demonstrates the feasibility of measuring and quantifying human-relevant eye movements in this species. The HD-relevant deficits show that even in ‘premanifest’ sheep there are measurable signs of neurological dysfunction that are characterized by loss of control of eye movements. Show more

Keywords: Huntington’s disease, sheep, oculometer, eye movement

DOI: 10.3233/JHD-230584

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 189-200, 2023

Authors: Sapp, Ellen | Boudi, Adel | Reid, Suzanne J. | Trombetta, Bianca A. | Kivisäkk, Pia | Taghian, Toloo | Arnold, Steven E. | Howland, David | Gray-Edwards, Heather | Kegel-Gleason, Kimberly B. | DiFiglia, Marian

Article Type: Research Article

Abstract: Background: Synaptic changes occur early in patients with Huntington’s disease (HD) and in mouse models of HD. An analysis of synaptic changes in HD transgenic sheep (OVT73) is fitting since they have been shown to have some phenotypes. They also have larger brains, longer lifespan, and greater motor and cognitive capacities more aligned with humans, and can provide abundant biofluids for in vivo monitoring of therapeutic interventions. Objective: The objective of this study was to determine if there were differences between 5- and 10-year-old OVT73 and wild-type (WT) sheep in levels of synaptic proteins in brain and …in neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma. Methods: Mutant huntingtin (mHTT) and other proteins were measured by western blot assay in synaptosomes prepared from caudate, motor, and piriform cortex in 5-year-old and caudate, putamen, motor; and piriform cortex in 10-year-old WT and OVT73 sheep. Levels of NfL, a biomarker for neuronal damage increased in many neurological disorders including HD, were examined in CSF and plasma samples from 10-year-old WT and OVT73 sheep using the Simoa NfL Advantage kit. Results: Western blot analysis showed mHTT protein expression in synaptosomes from OVT73 sheep was  23% of endogenous sheep HTT levels at both ages. Significant changes were detected in brain levels of PDE10A, SCN4B, DARPP32, calmodulin, SNAP25, PSD95, VGLUT 1, VAMP1, and Na+ /K+ -ATPase, which depended on age and brain region. There was no difference in NfL levels in CSF and plasma in OVT73 sheep compared to age-matched WT sheep. Conclusions: These results show that synaptic changes occur in brain of 5- and 10-year-old OVT73 sheep, but levels of NfL in biofluids are unaffected. Altogether, the data support a prodromal disease state in OVT73 sheep that involves the caudate, putamen and cortex. Show more

Keywords: Huntington’s disease, HD sheep, caudate, putamen, synaptosomes, neurofilament light chain levels, cerebrospinal fluid

DOI: 10.3233/JHD-230590

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 201-213, 2023

Authors: Simmons, Danielle A. | Belichenko, Nadia P. | Longo, Frank M.

Article Type: Research Article

Abstract: Background: Loss of neurotrophic support in the striatum, particularly reduced brain-derived neurotrophic factor (BDNF) levels, contributes importantly to Huntington’s disease (HD) pathogenesis. Another neurotrophin (NT), NT-3, is reduced in the cortex of HD patients; however, its role in HD is unknown. BDNF and NT-3 bind with high affinity to the tropomyosin receptor-kinases (Trk) B and TrkC, respectively. Targeting TrkB/TrkC may be an effective HD therapeutic strategy, as multiple links exist between their signaling pathways and HD degenerative mechanisms. We developed a small molecule ligand, LM22B-10, that activates TrkB and TrkC to promote cell survival. Objective: This study aimed …to determine if upregulating TrkB/TrkC signaling with LM22B-10 would alleviate the HD phenotype in R6/2 and Q140 mice. Methods: LM22B-10 was delivered by concomitant intranasal-intraperitoneal routes to R6/2 and Q140 mice and then motor performance and striatal pathology were evaluated. Results: NT-3 levels, TrkB/TrkC phosphorylation, and AKT signaling were reduced in the R6/2 striatum; LM22B-10 counteracted these deficits. LM22B-10 also reduced intranuclear huntingtin aggregates, dendritic spine loss, microglial activation, and degeneration of dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP-32) and parvalbumin-containing neurons in the R6/2 and/or Q140 striatum. Moreover, both HD mouse models showed improved motor performance after LM22B-10 treatment. Conclusions: These results reveal an NT-3/TrkC signaling deficiency in the striatum of R6/2 mice, support the idea that targeting TrkB/TrkC alleviates HD-related neurodegeneration and motor dysfunction, and suggest a novel, disease-modifying, multi-target strategy for treating HD. Show more

Keywords: Mutant huntingtin, neurotrophin, dendritic spine, striatum, AKT, parvalbumin interneurons, medium-spiny projection neurons, microglia

DOI: 10.3233/JHD-230589

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 215-239, 2023

Authors: Clabough, Erin B.D. | Aspili, Christia | Fussy, William S. | Ingersoll, James D. | Kislyakov, Amy | Li, Elizabeth S. | Su, Meng-Jiuan | Wiles, Dustin B. | Watson, Thomas E. | Willy, Aaron J. | Thomas Vinyard, H. | Mollica III, Philip J. | Taylor, James V. | Smith, Cody W. | Roark, Dallas A. | Tabrani, Zachary P. | Thomas, Harris L. | Shin, Mimi | Venton, B. Jill | Hayes, David | Sipe, Conor W.

Article Type: Research Article

Abstract: Background: Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington’s disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances. Objective: To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila. Methods: …We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhtt were also measured. Results: We found that dhtt -null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhtt are more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhtt mediates these effects at least in part through the dopaminergic system, as dhtt is required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum. Conclusions: Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli. Show more

Keywords: Drosophila , flies, huntingtin, ethanol, alcohol, dopamine, Huntington’s disease, loss-of-function

DOI: 10.3233/JHD-230581

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 241-252, 2023

Authors: Dickson, Elna | Fryklund, Claes | Soylu-Kucharz, Rana | Sjögren, Marie | Stenkula, Karin G. | Björkqvist, Maria

Article Type: Research Article

Abstract: Background: Metabolic alterations contribute to disease onset and prognosis of Huntington’s disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease. Objective: In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice. We further elaborated on the effect of leptin-deficiency and early obesity in R6/2 mice. Methods: We performed analyses at 12 weeks of age; a time point that coincides with the start of weight loss in our R6/2 …mouse colony. Gonadal (visceral) and inguinal (subcutaneous) WAT depot weights were monitored, as well as adipocyte size distribution. Response to isoprenaline-stimulated glycerol release and insulin-stimulated glucose uptake in adipocytes from gonadal WAT was assessed. Results: In R6/2 mice, WAT depot weights were comparable to wildtype (WT) mice, and the response to insulin and isoprenaline in gonadal adipocytes was unaltered. Leptin-deficient R6/2 mice exhibited distinct changes compared to leptin-deficient WT mice. At 12 weeks, female leptin-deficient R6/2 mice had reduced body weight accompanied by an increased proportion of smaller adipocytes, while in contrast; male mice displayed a shift towards larger adipocyte sizes without a significant body weight reduction at this timepoint. Conclusions: We here show that there are early sex-specific changes in adipocyte cell size distribution in WAT of R6/2 mice and leptin-deficient R6/2 mice. Show more

Keywords: Adipose tissue, body weight, Huntington’s disease, leptin, metabolism

DOI: 10.3233/JHD-230587

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 253-266, 2023

Authors: Petrozziello, Tiziana | Huntress, Sommer S. | Castillo-Torres, Ayleen L. | Quinn, James P. | Connors, Theresa R. | Auger, Corinne A. | Mills, Alexandra N. | Kim, Spencer E. | Liu, Sophia | Mahmood, Farah | Boudi, Adel | Wu, Muzhou | Sapp, Ellen | Kivisäkk, Pia | Sunderesh, Shekar R. | Pouladi, Mahmoud A. | Arnold, Steven E. | Hyman, Bradley T. | Rosas, H. Diana | DiFiglia, Marian | Mouro Pinto, Ricardo | Kegel-Gleason, Kimberly | Sadri-Vakili, Ghazaleh

Article Type: Research Article

Abstract: Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington’s disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. Objective: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in …HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ 111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ 111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusions: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC. Show more

Keywords: Huntington’s disease, total tau, phosphorylated tau, fractionations, postmortem brain, ESC-derived neurons, neuronal stem cells, mouse models, plasma

DOI: 10.3233/JHD-230588

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 267-281, 2023

Authors: Caligiuri, Michael | Culbert, Braden | Prasad, Nikita | Snell, Chase | Hall, Andrew | Smirnova, Anna | Churchill, Emma | Corey-Bloom, Jody

Article Type: Research Article

Abstract: Background: Prior studies have relied on conventional observer-based severity ratings such as the Unified Huntington’s Disease Rating Scale (UHDRS) to identify early motor markers of decline in Huntington’s disease (HD). Objective: The present study examined the predictive utility of graphomotor measures handwriting and drawing movements. Methods: Seventeen gene-positive premanifest HD subjects underwent comprehensive clinical, cognitive, motor, and graphomotor assessments at baseline and at follow-up intervals ranging from 9–36 months. Baseline graphomotor assessments were subjected to linear multiple regression procedures to identify factors associated with change on the comprehensive UHDRS index. Results: Subjects were followed …for an average of 21.2 months. Three multivariate regression models based on graphomotor variables derived from a complex loop task, a maximum speed circle drawing task and a combined task returned adjusted R2 coefficients of 0.76, 0.71, and 0.80 respectively accounting for a significant portion of the variability in cUHDRS change score. The best-fit model based on the combined tasks indicated that greater decline on the cUHDRS was associated with increased pen movement dysfluency and stroke-stroke variability at baseline. Conclusion: Performance on multiple measures of graphomotor dysfluency assessed during the premanifest or prodromal stage in at-risk HD individuals was associated with decline on a multidimensional index of HD morbidity preceding an HD diagnosis. Show more

Keywords: Huntington’s disease, premanifest HD, graphomotor, handwriting kinematics

DOI: 10.3233/JHD-230562

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 283-292, 2023

Authors: Fitzgerald, Emily S. | Stout, Julie C. | Glikmann-Johnston, Yifat | Anderson, Clare | Jackson, Melinda L.

Article Type: Research Article

Abstract: Background: In healthy people, sleep and circadian disruption are linked to cognitive deficits. People with Huntington’s disease (HD), who have compromised brain function and sleep and circadian disturbances, may be even more susceptible to these cognitive effects. Objective: To conduct a comprehensive review and synthesis of the literature in HD on the associations of cognitive dysfunction with disturbed sleep and circadian rhythms. Methods: We searched MEDLINE via OVID, CINAHL Plus, EMBASE via OVID, and PubMed in May 2023. The first author then screened by title and abstract and conducted a full review of remaining articles. …Results: Eight studies investigating the influence of sleep and/or circadian rhythms on cognitive function in HD were found. In manifest HD, poorer sleep was associated with worse cognitive function. For behavioral 24-hour (circadian) rhythms, two studies indicated that later wake times correlated with poorer cognitive function. No reported studies in HD examined altered physiological 24-hour (circadian) rhythms and cognitive impairment. Conclusion: Some associations exist between poor sleep and cognitive dysfunction in manifest HD, yet whether these associations are present before clinical diagnosis is unknown. Whether circadian disturbances relate to cognitive impairment in HD also remains undetermined. To inform sleep and circadian interventions aimed at improving cognitive symptoms in HD, future research should include a range of disease stages, control for external factors, and utilize robust cognitive batteries targeted to the aspects of cognitive function known to be adversely affected in HD. Show more

Keywords: Neurodegenerative diseases, neuropsychology, polysomnography, actigraphy, circadian rhythm, cognition.

DOI: 10.3233/JHD-230578

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 293-304, 2023

Authors: Watson, Kelly H. | Ciriegio, Abagail E. | Pfalzer, Anna C. | Snow, Abigail | Hale, Lisa | Diehl, Spencer | McDonell, Katherine E. | Claassen, Daniel O. | Compas, Bruce E.

Article Type: Research Article

Abstract: Background: Families in which a parent has Huntington’s disease (HD) are faced with significant stressors that can contribute to difficulties in communicating together about illness-related concerns. Family members who use more disengagement coping strategies, including denial and avoidance, to deal with illness-related stressors may have the greatest challenges to effective communication. Objective: The current study examined the associations of intrapersonal and interpersonal disengagement coping responses with observed and reported emotions of adolescents and young adults (AYA) at genetic risk for HD. Methods: Families included 42 AYA (n  = 26 females) ages 10 to 34 (M  = 19 years, …11 months; SD  = 7 years, 6 months) and their parent with HD (n  = 22 females, M age = 46 years, 10 months; SD = 9 years, 2 months). Dyads participated in observations of communication and completed questionnaires about disengagement coping and internalizing symptoms. Results: Disengagement coping of AYA was unrelated to their observed and reported emotional difficulties (intrapersonal coping). However, there was evidence for the importance of interpersonal disengagement coping, as AYA’s negative affect was observed and reported to be highest when both AYA and their parents reported using high levels of avoidance, denial, and wishful thinking to cope with HD-related stress. Conclusion: The findings underscore the importance of a family-oriented approach to coping and communication in families affected by HD. Show more

Keywords: Communication, coping strategies, Huntington’s disease, stress

DOI: 10.3233/JHD-230566

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 305-312, 2023

Article Type: Meeting Report

DOI: 10.3233/JHD-239006

Citation: Journal of Huntington's Disease, vol. 12, no. 3, pp. 313-313, 2023