Huntingtin Lowering Strategies

Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients

Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study

Objective: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). Methods: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. Results: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. Conclusion: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP

G3 Hedonic olfaction in huntington’s disease

Background Huntington’s disease (HD) features a broad range of neuropsychiatric symptoms. In particular depression, apathy, and anhedonia are frequently present in HD. Anhedonia and apathy are observed as core symptoms of depression in HD but also as distinct features of HD independent from major depression. Therefore, methods helping to dissociate these symptoms are an important need for a precise diagnostic workup. Assessing anhedonia by focusing on hedonic perception of a sensory stimulus may be particularly helpful in HD. Aims In this study, we examine anhedonia by measuring the perception of pleasantness of odours in HD patients compared to controls. Methods By using the “Sniffin’Sticks®” odour identification test we assess hyposmia. In order to dissociate hedonia and olfaction we use additional olfactory sticks with 22 odours assessing intensity and pleasantness of odours. Pleasantness of odours is measured on a visual 9-point scale. For the assessment of hedonia and apathy the Snaith-Hamilton-Pleasure-Scale (SHAPS) and the Starkstein scale are applied respectively. Depression is measured using the Zung Self-Rating Depression Scale and the Beck Depression Inventory II. Perspective The hypothesis of this study is that the assessment of hedonic olfaction in HD allows discriminating anhedonia and apathy from depression. To test our hypothesis we will compare the hedonic perception of odours between HD patients and age and gender matched controls. Furthermore, we will correlate hedonic olfaction with the questionnaire-based assessment of depression, apathy and anhedonia. These data will be compared to our previously published findings that have shown reduced hedonic olfaction in Parkinson’s disease

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration

Factors influencing the reliability of intraoperative testing in deep brain stimulation for Parkinson’s disease

Background Several meta-analyses comparing the outcome of awake versus asleep deep brain stimulation procedures could not reveal significant differences concerning the postoperative improvement of motor symptoms. Only rarely information on the procedural details is provided for awake operations and how often somnolence and disorientation occurred, which might hamper the reliability of intraoperative clinical testing. The aim of our study was to investigate possible influencing factors on the occurrence of somnolence and disorientation in awake DBS procedures. Methods We retrospectively analyzed 122 patients with Parkinson's disease having received implantation of a DBS system at our centre. Correlation analyses were performed for the duration of disease prior to surgery, number of microelectrode trajectories, AC-PC-coordinates of the planned target, UPDRS-scores, intraoperative application of sedative drugs, duration of the surgical procedure, perioperative application of apomorphine, and the preoperative L-DOPA equivalence dosage with the occurrence of intraoperative somnolence and disorientation. Results Patients with intraoperative somnolence were significantly older (p=0.039). Increased duration of the DBS procedure (p=0.020), delayed start of the surgery (p=0.049), higher number of MER trajectories (p=0.041), and the patients’ % UPDRS improvement (p=0.046) also correlated with the incidence of intraoperative somnolence. We identified the main contributing factor to intraoperative somnolence as the use of sedative drugs applied during skin incision and burr hole trepanation (p=0.019). Perioperatively applied apomorphine could reduce the occurrence of somnolent phases during the operation (p=0.026). Conclusion Several influencing factors were found to seemingly increase the risk of intraoperative somnolence and disorientation, while the use of sedative drugs seems to be the main contributing factor. We argue that awake DBS procedures should omit the use of sedatives for best clinical outcome. When reporting on awake DBS surgery these factors should be considered and adjusted for, to permit reliable interpretation and comparison of DBS study results

Early remission in multiple sclerosis is linked to altered coherence of the Cerebellar Network

Background The development of permanent disability in multiple sclerosis (MS) is highly variable among patients, and the exact mechanisms that contribute to this disability remain unknown. Methods Following the idea that the brain has intrinsic network organization, we investigated changes of functional networks in MS patients to identify possible links between network reorganization and remission from clinical episodes in MS. Eighteen relapsing–remitting MS patients (RRMS) in their first clinical manifestation underwent resting-state functional MRI and again during remission. We used ten template networks, identified from independent component analysis, to compare changes in network coherence for each patient compared to those of 44 healthy controls from the Human Connectome Project test–retest dataset (two-sample t-test of pre-post differences). Combining a binomial test with Monte Carlo procedures, we tested four models of how functional coherence might change between the first clinical episode and remission: a network can change its coherence (a) with itself (“one-with-self”), (b) with another network (“one-with-other”), or (c) with a set of other networks (“one-with-many”), or (d) multiple networks can change their coherence with respect to one common network (“many-with-one”). Results We found evidence supporting two of these hypotheses: coherence decreased between the Executive Control Network and several other networks (“one-with-many” hypothesis), and a set of networks altered their coherence with the Cerebellar Network (“many-with-one” hypothesis). Conclusion Given the unexpected commonality of the Cerebellar Network’s altered coherence with other networks (a finding present in more than 70% of the patients, despite their clinical heterogeneity), we conclude that remission in MS may result from learning processes mediated by the Cerebellar Network

Amelioration of Parkinsonian tremor evoked by DBS: which role play cerebello-(sub)thalamic fiber tracts?

Background Current pathophysiological models of Parkinson’s disease (PD) assume a malfunctioning network being adjusted by the DBS signal. As various authors showed a main involvement of the cerebellum within this network, cerebello-cerebral fiber tracts are gaining special interest regarding the mediation of DBS effects. Objectives The crossing and non-decussating fibers of the dentato-rubro-thalamic tract (c-DRTT/nd-DRTT) and the subthalamo-ponto-cerebellar tract (SPCT) are thought to build up an integrated network enabling a bidimensional communication between the cerebellum and the basal ganglia. The aim of this study was to investigate the influence of these tracts on clinical control of Parkinsonian tremor evoked by DBS. Methods We analyzed 120 electrode contacts from a cohort of 14 patients with tremor-dominant or equivalence-type PD having received bilateral STN-DBS. Probabilistic tractography was performed to depict the c-DRTT, nd-DRTT, and SPCT. Distance maps were calculated for the tracts and correlated to clinical tremor control for each electrode pole. Results A significant difference between “effective” and “less-effective” contacts was only found for the c-DRTT (p = 0.039), but not for the SPCT, nor the nd-DRTT. In logistic and linear regressions, significant results were also found for the c-DRTT only (pmodel logistic = 0.035, ptract logistic = 0,044; plinear = 0.027). Conclusions We found a significant correlation between the distance of the DBS electrode pole to the c-DRTT and the clinical efficacy regarding tremor reduction. The c-DRTT might therefore play a major role in the mechanisms of alleviation of Parkinsonian tremor and could eventually serve as a possible DBS target for tremor-dominant PD in future

Gait variability as digital biomarker of disease severity in Huntington’s disease

Abstract Background Impaired gait plays an important role for quality of life in patients with Huntington’s disease (HD). Measuring objective gait parameters in HD might provide an unbiased assessment of motor deficits in order to determine potential beneficial effects of future treatments. Objective To objectively identify characteristic features of gait in HD patients using sensor-based gait analysis. Particularly, gait parameters were correlated to the Unified Huntington’s Disease Rating Scale, total motor score (TMS), and total functional capacity (TFC). Methods Patients with manifest HD at two German sites (n = 43) were included and clinically assessed during their annual ENROLL-HD visit. In addition, patients with HD and a cohort of age- and gender-matched controls performed a defined gait test (4 × 10 m walk). Gait patterns were recorded by inertial sensors attached to both shoes. Machine learning algorithms were applied to calculate spatio-temporal gait parameters and gait variability expressed as coefficient of variance (CV). Results Stride length (− 15%) and gait velocity (− 19%) were reduced, while stride (+ 7%) and stance time (+ 2%) were increased in patients with HD. However, parameters reflecting gait variability were substantially altered in HD patients (+ 17% stride length CV up to + 41% stride time CV with largest effect size) and showed strong correlations to TMS and TFC (0.416 ≤ rSp ≤ 0.690). Objective gait variability parameters correlated with disease stage based upon TFC. Conclusions Sensor-based gait variability parameters were identified as clinically most relevant digital biomarker for gait impairment in HD. Altered gait variability represents characteristic irregularity of gait in HD and reflects disease severity

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers’ Lives

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required

Leucine-Rich Repeat Kinase 2 Modulates Retinoic Acid-Induced Neuronal Differentiation of Murine Embryonic Stem Cells

Background: Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson’s disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment. Methodology/Principal Findings: In the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/2 cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2deficient stem cells in culture. Conclusion/Significance: Parkinson’s disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in othe