Sphingosine kinase 2 regulates protein ubiquitination networks in neurons.

Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize the lipid sphingosine-1-phosphate (S1P) by phosphorylating sphingosine. SPHK1 is a cytoplasmic kinase and SPHK2 is localized to the nucleus and other organelles. In the cytoplasm, the SPHK1/S1P pathway modulates autophagy and protein ubiquitination, among other processes. In the nucleus, the SPHK2/S1P pathway regulates transcription. Here, we hypothesized that the SPHK2/S1P pathway governs protein ubiquitination in neurons. We found that ectopic expression of SPHK2 increases ubiquitinated substrate levels in cultured neurons and pharmacologically inhibiting SPHK2 decreases protein ubiquitination. With mass spectrometry, we discovered that inhibiting SPHK2 affects lipid and synaptic protein networks as well as a ubiquitin-dependent protein network. Several ubiquitin-conjugating and hydrolyzing proteins such as the E3 ubiquitin-protein ligases HUWE1 and TRIP12, the E2 ubiquitin-conjugating enzyme UBE2Z, and the ubiquitin-specific proteases USP15 and USP30 were downregulated by SPHK2 inhibition. Using RNA sequencing, we found that inhibiting SPHK2 altered lipid and neuron-specific gene networks, among others. Genes that encode the corresponding proteins from the ubiquitin-dependent protein network that we discovered with mass spectrometry were not affected by inhibiting SPHK2, indicating that the SPHK2/S1P pathway regulates ubiquitination at the protein level. We also show that both SPHK2 and HUWE1 were upregulated in the striatum of a mouse model of Huntington's disease, the BACHD mice, indicating that our findings are relevant to neurodegenerative diseases. Our results identify SPHK2/S1P as a novel regulator of protein ubiquitination networks in neurons and provide a new target for developing therapies for neurodegenerative diseases.

Treatment of Depression in Huntington's Disease: A Systematic Review.

Depression is a common psychiatric disorder among individuals with Huntington's disease (HD). Depression in HD and major depressive disorder appear to have different pathophysiological mechanisms. Despite the unique pathophysiology, the treatment of depression in HD is based on data from the treatment of major depressive disorder in the general population. The objective of this systematic review was to conduct a comprehensive evaluation of the available evidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies on the treatment of depression in HD were identified by searching MEDLINE, Embase, and PsycInfo. The initial search yielded 2,771 records, 41 of which were ultimately included. There were 19 case reports, seven case series, three cross-sectional studies, one qualitative study, nine nonrandomized studies, and two randomized trials among the included studies. The most common assessment tools were the Hospital Anxiety and Depression Scale (N=8), the Beck Depression Inventory (N=6), and the Hamilton Depression Rating Scale (N=6). Only 59% of the included studies assessed depressive symptoms with a scoring system. The pharmacological options for the treatment of depression included antidepressants and antipsychotics. Nonpharmacological approaches were multidisciplinary rehabilitation, psychotherapy, and neurostimulation. Limited evidence on the treatment of depression in HD was available, and this literature consisted mainly of case reports and case series. This systematic review highlights the knowledge gap and the pressing need for HD-specific research to determine the efficacy of treatment approaches for depression in HD.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Clinical Correlates of Depression and Suicidality in Huntington Disease: An Analysis of the Enroll-HD Observational Study.

BACKGROUND: Depression and suicidality are commonly experienced by Huntington disease (HD) gene carriers. Research on these behavioral symptoms is imperative, not only to increase our understanding of the symptoms and how they relate to HD, but also to contribute to improving patients' care and quality of life. OBJECTIVE: To identify clinical variables associated with a history of depression and suicidality in HD gene carriers. METHOD: We conducted a cross-sectional study of HD gene carriers from the Enroll-HD database PDS4 (periodic data set 4; N = 11,582). Data from baseline visits were obtained, and binary logistic regression models were used to ascertain the effects of clinical variables on the likelihood that HD gene carriers would have previous depression and suicidal ideation/attempts. RESULTS: Approximately 65% (n = 7526) of the HD gene carriers had a history of depression, and ~27% (n = 3152) had previous suicidal ideation/attempts. Female sex; diagnosis of manifest HD; history of perseverative/obsessive behavior, apathy, and psychosis; and previous suicidal ideation/attempts were significantly associated with a history of depression in the HD gene carriers. Medical history of apathy, psychosis, and depression, as well as worse scores on the Total Functional Capacity and Irritability Scales, were significantly associated with previous suicidal ideation/attempts in the HD gene carriers. CONCLUSION: The prevalence of depression and suicidality is high among HD gene carriers. An improved understanding of the risk factors for depression and suicide in HD gene carriers can assist providers in recognizing at-risk individuals and allow providers to implement therapeutic strategies.

Renin-Angiotensin System in Huntington's Disease: Evidence from Animal Models and Human Patients.

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Stem cells in animal models of Huntington disease: A systematic review.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder encoding a mutant form of the huntingtin protein (HTT). HD is pathologically characterized by loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. Stem cell-based therapy has emerged as a feasible therapeutic approach for the treatment of neurodegenerative diseases and may be effective in alleviating and/or halting the pathophysiological mechanisms underlying HD. Several pre-clinical studies have used stem cells in animal models of HD. Here, we performed a systematic review of preclinical studies to estimate the treatment efficacy of stem cells in animal models of HD. Based on our systematic review, treatment with stem cells significantly improves neurological and behavioral outcomes in animal models of HD. Although promising results were found, the design of animal studies, the types of transplanted cells and the route of administration are poorly standardized and this greatly complicates comparative analysis.

Gene Expression Profiling in Huntington's Disease: Does Comorbidity with Depressive Symptoms Matter?

Huntington's disease (HD) is an inherited neurodegenerative disease. Besides the well-characterized motor symptoms, HD is marked by cognitive impairment and behavioral changes. In this study, we analyzed the blood of HD gene carries using RNA-sequencing techniques. We evaluated samples from HD gene carriers with (n = 8) and without clinically meaningful depressive symptoms (n = 8) compared with healthy controls (n = 8). Groups were age- and sex-matched. Preprocessing of data and between-group comparisons were calculated using DESeq2. The Wald test was used to generate p-values and log2 fold changes. We found 60 genes differently expressed in HD and healthy controls, of which 21 were upregulated and 39 downregulated. Within HD group, nineteen genes were differently expressed between patients with and without depression, being 6 upregulated and 13 downregulated. Several of the top differentially expressed genes are involved in nervous system development. Although preliminary, our findings corroborate the emerging view that in addition to neurodegenerative mechanisms, HD has a neurodevelopmental component. Importantly, the emergence of depression in HD might be related to these mechanisms.

Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease.

Huntington disease (HD) is the most common inherited neurodegenerative disorder. It has no cure. The protein huntingtin causes HD, and mutations to it confer toxic functions to the protein that lead to neurodegeneration. Thus, identifying modifiers of mutant huntingtin-mediated neurotoxicity might be a therapeutic strategy for HD. Sphingosine kinases 1 (SK1) and 2 (SK2) synthesize sphingosine-1-phosphate (S1P), a bioactive lipid messenger critically involved in many vital cellular processes, such as cell survival. In the nucleus, SK2 binds to and inhibits histone deacetylases 1 and 2 (HDAC1/2). Inhibiting both HDACs has been suggested as a potential therapy in HD. Here, we found that SK2 is nuclear in primary neurons and, unexpectedly, overexpressed SK2 is neurotoxic in a dose-dependent manner. SK2 promotes DNA double-strand breaks in cultured primary neurons. We also found that SK2 is hyperphosphorylated in the brain samples from a model of HD, the BACHD mice. These data suggest that the SK2 pathway may be a part of a pathogenic pathway in HD. ABC294640, an inhibitor of SK2, reduces DNA damage in neurons and increases survival in two neuron models of HD. Our results identify a novel regulator of mutant huntingtin-mediated neurotoxicity and provide a new target for developing therapies for HD.

Does the Use of Intraoperative Microelectrode Recording Influence the Final Location of Lead Implants in the Ventral Intermediate Nucleus for Deep Brain Stimulation?

To determine if the use of intraoperative microelectrode recording (MER) influences the final location of lead implant in deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM), and to evaluate the incidence of associated complications. The usefulness of intraoperative MER in DBS is debated, some centers suggesting it increases complications without additional benefit. We conducted a retrospective chart review of all patients who underwent VIM DBS with MER at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013. Initial (MRI determined) and final (intraoperative MER determined) coordinates of implant were compared. To assess incidences of hemorrhagic and infectious complications, we reviewed postoperative CT scans and follow-up notes. Forty-five lead implants on 24 patients were reviewed. The mean age at implantation was 62.42 years (range 18-83). The average duration from diagnosis to surgery was 21.5 years (range 1-52). A statistically significant mean difference was observed in the superior-inferior plane (0.52 ± 0.80 mm inferiorly, p < 0.05) and the anterior-posterior plane (0.45 ± 0.86 mm posteriorly, p < 0.05). A non-statistically significant difference was also observed in the medial-lateral plane (0.02± 0.15 mm, p > 0.05). One patient developed an infectious complication (4.2 %) that required removal of leads; two patients had minimal asymptomatic intra-ventricular bleeding (8.3 %). In our DBS center, intraoperative MER in VIM DBS implant does not seem to have a higher rate of surgical complications compared to historical series not using MER, and might also be useful in determining the final lead location.

Procedure-Oriented Torsional Anatomy of the Hand for Spasticity Injection.

OBJECTIVES: To provide musculoskeletal ultrasound (MSKUS) images of hand anatomy in the position of hemiparetic flexion as a reference for spasticity injections. After a stroke, spasticity can result in anatomic distortion of the hand. Spasticity may require treatment with botulinum toxin or phenol injections. Anatomic distortion may decrease the accuracy of injections. Standard anatomic references are of limited utility because they are not in this spastic hemiparetic position. There presently is no anatomic reference in the literature for these spastic postures. This study is part three of a series examining torsional anatomy of the body. DESIGN: Ultrasound (US) images were obtained in a healthy subject. The muscles examined included the lumbricals and the flexor pollicis brevis. A marker dot was placed at each dorsal and palmar anatomic injection site for these muscles. The US probe was placed on these dots to obtain a cross-sectional view. A pair of US images was recorded with and without power Doppler imaging: the first in anatomic neutral and second in hemiparetic spastic positions. In addition, a video recording of the movement of the muscles during this rotation was made at each site. RESULTS: On the palmar view, the lumbricals rotated medially. On dorsal view, the lumbricals can be seen deep to the dorsal interossei muscles, with spastic position, and they become difficult to identify. The flexor pollicis brevis (FPB) muscle contracts with torsion, making abductor pollicis brevis (APB) predominately in view. DISCUSSION: The anatomic location of the lumbrical muscles makes them difficult to inject even with ultrasound guidance. However, recognizing the nearby digital vasculature allows for improved identification of the musculature for injection purposes. The FPB muscle also can be identified by its adjacent radial artery lateral to the flexor pollicus longus tendon. CONCLUSION: Normal anatomy of hand can become distorted in spastic hemiparesis. Diagnostic ultrasound is able to discern these anatomic locations if the sonographer is competent in recognizing the appearance of normal anatomy and is skilled in resolving the visual changes that occur in spastic hemiparesis. The authors hope this series of images will increase the accuracy, safety, and efficacy of spasticity injections in the hand.

Neuroimmunology of Huntington's Disease: Revisiting Evidence from Human Studies.

Huntington's disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described-HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3-the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

Procedure Oriented Torsional Anatomy of the Forearm for Spasticity Injection.

UNLABELLED: : This is the second in a series of articles related to the concept of "torsional" anatomy. The objective of this article is to provide musculoskeletal ultrasound (MSKUS) anatomy of the forearm in the position of hemispastic flexion as a reference relevant to needle procedures. METHODS: The MSKUS images were obtained in a healthy human subject. Marker dots were placed over common injection sites in the forearm for spasticity. The MSKUS probe was centered over each dot to obtain a cross-sectional view. A pair of MSKUS images was recorded for each site: the first in anatomic neutral and second in hemiparetic spastic position. The images were compared side to side. In addition, a video recording was made at each site to track the movement of the muscles and nerves during internal rotation. RESULTS: The pronator teres (PT) rotated medially and the brachialis and biceps tendon rotated in view. In addition, the median nerve became more superficial. The flexor carpi radialis rotated medially and was replaced by PT and the median nerve. The flexor carpi ulnaris and flexor digitorum profundus rotated medially and were replaced by the flexor carpi radialis, PT and median nerve. The flexor digitorum superficialis was replaced by the brachioradialis, extensor carpi radialis brevis, and radial nerve. The brachioradialis was replaced by the extensor carpi radialis brevis and extensor digitorum communis. DISCUSSION: Intended muscle targets rotate out of view and injection range. These are replaced by other muscles and nerves that could inadvertently be injected. This potentially could result in both increased complications and decreased efficacy of the procedure. CONCLUSIONS: It is hoped that this series of images will increase the accuracy and safety of needle placement for spasticity injections in the forearm.

Procedure-oriented torsional anatomy of the proximal arm for spasticity injection.

UNLABELLED: This is the first in a series of papers related to the new concept of "torsional" anatomy. The objective of this article is to provide musculoskeletal ultrasound (MSKUS) anatomy of the upper arm in the position of hemispastic flexion as a reference relevant to needle procedures. METHODS: The MSKUS images were obtained in a healthy human subject. A pair of MSKUS images was recorded for each level: the first in anatomic neutral and second in hemispastic position. RESULTS: At the proximal 1/3 level of the upper arm, the pectoralis major rotated out of view. At the middle of the upper arm, the biceps rotated medially, and the brachialis rotated from far lateral to the middle of the screen. At the distal 1/3 level of the upper arm, the radial nerve rotated more anteriorly. At the distal 1/6 level of the upper arm, the biceps shifted and was replaced by the brachialis and brachioradialis. The radial nerve also rotated more anteriorly and superficially. DISCUSSION: With torsion, it is possible that intended muscle targets, such as the pectoralis, are missed, and unintended targets, such as the radial nerve, are accidentally injected in the upper arm. CONCLUSIONS: It is hoped that this series of images will increase the accuracy and safety of needle placement for spasticity and nerve block injections in the proximal upper arm.

Procedure-oriented sectional anatomy of the foot.

This is the seventh and last in a series of studies related to procedure-oriented joint anatomy. This article reviews the anatomy of the foot and its relationship to procedures in the clinical setting with or without ultrasound guidance. Anatomically correct axial schematics allow injections to be envisioned relative to clinically important anatomy for common forefoot procedures. Cross-sectional schematics for the ankle were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped that these schematics allow for safer and more accurate needle procedures in the foot area.

Spasticity and intrathecal baclofen.

Severe spastic tone and/or spastic hypertonia can be the most disabling consequences of a neurologic insult, resulting from an excess of muscle tone. Baclofen, a GABA-B agonist, is one of the most widely used drugs in treating abnormal or disabling spastic tone. However, the effectiveness of baclofen taken orally is often limited by its systemic side effects, including sedation, confusion, and lethargy. Intrathecal baclofen (ITB) delivered by an implanted catheter can work directly at the spinal cord level to reduce spastic tone through presynaptic inhibition. Several decades after Penn and Kroin (1984) proved that continuous infusion of intrathecal baclofen reduced spinal cord spasticity, numerous studies have demonstrated the benefits of ITB therapy and proven its effectiveness in modulating and reducing spastic tone. In this article the authors review current methods of management with ITB therapy; summarize the current knowledge, controversies, and available scientific literature; illustrate through different clinical cases treatment strategies and their outcomes; and lastly, provide a synopsis of current clinical practice in ITB therapy with insights into new therapeutic developments.

Procedure-oriented sectional anatomy of the knee.

This is the fifth in a series of articles related to procedure-oriented joint anatomy. This article reviews the anatomy of the knee and its relationship to procedures in the clinical setting with or without ultrasound/electromyographic guidance. Anatomically correct axial schematics allow injections to be envisioned relative to clinically important anatomy for common knee procedures. Cross-sectional schematics for the knee were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped that these schematics allow for safer and more accurate needle procedures in the knee area.

Procedure-oriented sectional anatomy of the ankle.

This is the sixth in a series of articles related to procedure-oriented joint anatomy. This article reviews the anatomy of the ankle and its relationship to procedures in the clinical setting with or without ultrasound guidance. Anatomically correct axial and oblique axial schematics allow injections to be envisioned relative to clinically important anatomy for common ankle procedures. Cross-sectional schematics for the ankle were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped these schematics allow for safer and more accurate needle procedures in the ankle area.

Procedure-oriented sectional anatomy of the hip.

This is the fourth in a series of articles related to procedure-oriented joint anatomy. This article reviews the anatomy of the hip and its relationship to procedures in the clinical setting with or without imaging guidance. Anatomically correct axial and coronal schematics allow injections to be envisioned relative to clinically important anatomy for common hip procedures. Cross-sectional schematics for the hip were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped that these schematics allow for safer and more accurate needle procedures in the knee area.

Obsessive-compulsive and perseverative behaviors in Huntington's disease.

Obsessive-compulsive and perseverative behaviors (OCBs/PBs) are characteristic features of Huntington's Disease (HD). Although a few recent research have attempted to discriminate between OCBs and PBs, most of the available evidence on OCBs does not consistently make this distinction. In this article, we aimed to explore the current inconsistencies in assessing and reporting OCBs/PBs and map the body of existing evidence. Up to half of the patients with motor manifest HD can experience OCBs. Separate reporting of PBs in HD patients has been uncommon among the studies and was frequently reported as a part of obsessive-compulsive symptoms. The structural limitation of the currently used rating scales and the overlaps in neuropathology and definition of OCBs and PBs are among the main reasons for the mixed reporting of OCBs/PBs. Perseverative thinking or behavior as a separate item is found in a few assessment tools, such as the Problem Behaviors Assessment - Short form (PBA-s). Even when the item exists, it is commonly reported as a composite score in combination with the obsessive-compulsive item. In addition to the significant psychological burden in individuals with HD, PBs are associated with somatic effects (e.g., cardiovascular symptoms) and high-risk behaviors (e.g., suicide). Recognition and monitoring of PBs in HD can aid in early detection of concerning symptoms and differentiating overlapping illnesses.

An Exploratory Pilot Study of Neuropsychological Performance in Two Huntington Disease Centers of Excellence Clinics.

OBJECTIVES: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations). METHOD: Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables. RESULTS: Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency. CONCLUSIONS: This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted.