Symptomatic treatment options for Huntington's disease (guidelines of the German Neurological Society).

INTRODUCTION: Ameliorating symptoms and signs of Huntington's disease (HD) is essential to care but can be challenging and hard to achieve. The pharmacological treatment of motor signs (e.g. chorea) may favorably or unfavorably impact other facets of the disease phenotype (such as mood and cognition). Similarly, pharmacotherapy for behavioral issues may modify the motor phenotype. Sometimes synergistic effects can be achieved. In patients undergoing pragmatic polypharmacological therapy, emerging complaints may stem from the employed medications' side effects, a possibility that needs to be considered. It is recommended to clearly and precisely delineate the targeted signs and symptoms (e.g., chorea, myoclonus, bradykinesia, Parkinsonism, or dystonia). Evidence from randomized controlled trials (RCTs) is limited. Therefore, the guidelines prepared for the German Neurological Society (DGN) for German-speaking countries intentionally extend beyond evidence from RCTs and aim to synthesize evidence from RCTs and recommendations of experienced clinicians. RECOMMENDATIONS: First-line treatment for chorea is critically discussed, and a preference in prescription practice for using tiapride instead of tetrabenazine is noted. In severe chorea, combining two antidopaminergic drugs with a postsynaptic (e.g., tiapride) and presynaptic mode of action (e.g., tetrabenazine) is discussed as a potentially helpful strategy. Sedative side effects of both classes of compounds can be used to improve sleep if the highest dosage of the day is given at night. Risperidone, in some cases, may ameliorate irritability but also chorea and sleep disorders. Olanzapine can be helpful in the treatment of weight loss and chorea, and quetiapine as a mood stabilizer with an antidepressant effect. CONCLUSIONS: Since most HD patients simultaneously suffer from distinct motor signs and distinct psychiatric/behavioral symptoms, treatment should be individually adapted.

The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.

BACKGROUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.

ConvNets for automatic detection of polyglutamine SCAs from brain MRIs: state of the art applications.

Polyglutamine spinocerebellar ataxias (polyQ SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its connections. The diagnosis of each type of polyQ SCA, alongside with genetic tests, includes medical images analysis, and its automation may help specialists to distinguish between each type. Convolutional neural networks (ConvNets or CNNs) have been recently used for medical image processing, with outstanding results. In this work, we present the main clinical and imaging features of polyglutamine SCAs, and the basics of CNNs. Finally, we review studies that have used this approach to automatically process brain medical images and may be applied to SCAs detection. We conclude by discussing the possible limitations and opportunities of using ConvNets for SCAs diagnose in the future.

The Role of Vascular Risk Factors in Biomarker-Based AT(N) Groups: A German-Dutch Memory Clinic Study.

BACKGROUND: The relation between vascular risk factors (VRFs) and Alzheimer's disease (AD) is important due to possible pathophysiological association. OBJECTIVE: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context. METHODS: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site. RESULTS: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aß42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition. CONCLUSION: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia.

Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.

BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

BACKGROUND: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. OBJECTIVE: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). METHODS: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. RESULTS: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. CONCLUSIONS: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of gender and genetics on emotion processing in Parkinson's disease - A multimodal study.

•Understanding of the phenotypic heterogeneity of Parkinson's disease is needed.•Gender and genetics determine manifestation and progression of Parkinson's disease.•Altered emotion processing in Parkinson's disease is specific to male patients.•This is influenced by endocrinal and genetic factors in both genders.•This finding may impact the diagnosis and treatment of emerging clinical features.

Reduced intraepidermal nerve fiber density in patients with REM sleep behavior disorder.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) has been increasingly acknowledged to be an initial specific manifestation of alpha-synucleinopathies such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Recent findings suggest that cutaneous abnormalities like small fiber neuropathy and alpha-synuclein deposition might reflect brain pathology and might function as early biomarkers in PD. This is the first study to elucidate whether iRBD patients already suffer from distinctive cutaneous features. METHODS: We examined skin punch biopsies from the distal leg of 18 iRBD patients and 22 age- and sex-matched controls using immunohistochemistry and microscopy. Further clinical evaluation included structured interviews, clinical motor and non-motor questionnaires and rating scales (e.g. Unified Parkinson's disease rating scale [UPDRS], non-motor symptoms questionnaire [NMS-Quest] and Beck Depression Inventory, Epworth Sleepiness Scale, evaluation of cognitive and olfactory functioning as well as blood samples. RESULTS: Intraepidermal nerve fiber density (IEFND) was reduced in iRBD patients compared to controls (p = 0.037), whereas the axon swelling ratio did not differ between groups. Patients with iRBD reported non-motor symptoms more frequently than controls (UPDRS I, NMS-Quest). Olfaction and daytime sleepiness differed between both groups, whereas there were no differences regarding cognition. CONCLUSIONS: These in vivo findings demonstrate small fiber neuropathy in iRBD patients that are associated with non-motor symptoms indicating that peripheral abnormalities may occur early in iRBD. However, the prognostic value has to be further investigated in longitudinal studies.

Cognitive effects of deep brain stimulation for essential tremor: evaluation at 1 and 6 years.

Only a few studies have explored cognitive changes with deep brain stimulation (DBS) in patients with essential tremor (ET). Furthermore, the cognitive effects after years of electrical stimulation are unknown. Assessing the impact of stereotactic electrode implantation and the actual electrical stimulation on cognition in patients with ET in the short and long term is of interest, because DBS is increasingly applied and can offer deeper insight into human brain functions. We examined nine ET patients before surgery (PRE-SURGERY), and 1 and 6 years thereafter with DBS switched on (DBS-ON) and off (DBS-OFF). Standardized neuropsychological tests and reaction time tests were applied. There were no differences in tasks of verbal fluency, memory, and executive and intellectual functions comparing PRE-SURGERY, DBS-ON, and DBS-OFF at 1 and 6 years post-surgery. Imaging data revealed that the dorsolateral prefrontal cortex and mamillo-thalamic tracts crucial for cognitive functioning were spared by electrode implantation. Additionally, with electrodes targeting the thalamus and adjacent subthalamic area, the actual electrical stimulation did not affect neuropsychological functioning. However, lesions caused by electrode implantation led to an increase in simple reaction time, while the actual electrical stimulation restored impaired reaction time. This is the second largest study of neuropsychological functioning in patients with ET treated with DBS, and the first covering a neuropsychological long-term follow-up over 6 years. Neither stereotactic surgery nor electrical stimulation affected higher cognitive processes. This study proposes that cerebello-thalamo-cortical pathways in humans are involved in tasks of simple reaction time.

Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis.

BACKGROUND: The neuropathological hallmark of Huntington's disease (HD) is progressive striatal loss starting several years prior to clinical onset. In the past decade, whole-brain magnetic resonance imaging (MRI) studies have provided accumulating evidence for widely distributed cortical and subcortical atrophy in the early course of the disease. OBJECTIVE: In order to synthesize current morphometric MRI findings and to investigate the impact of clinical and genetic features on structural changes, we performed a coordinate-based meta-analysis of voxel-based morphometry (VBM) studies in HD. METHODS: Twenty HD samples derived from 17 studies were integrated in the analysis comparing a total of 685 HD mutation carriers [345 presymptomatic (pre-HD) and 340 symptomatic (symp-HD) subjects] and 507 controls. Convergent findings across studies were delineated using the anatomical likelihood estimation approach. Effects of genetic and clinical parameters on the likelihood of observing VBM findings were calculated by means of correlation analyses. RESULTS: Pre-HD studies featured convergent evidence for neurodegeneration in the basal ganglia, amygdala, thalamus, insula and occipital regions. In symp-HD, cerebral atrophy was more pronounced and spread to cortical regions (i.e., inferior frontal, premotor, sensorimotor, midcingulate, frontoparietal and temporoparietal cortices). Higher cytosine-adenosine-guanosine repeats were associated with striatal degeneration, while parameters of disease progression and motor impairment additionally correlated with cortical atrophy, especially in sensorimotor areas. CONCLUSION: This first quantitative meta-analysis in HD demonstrates the extent of striatal atrophy and further consistent extrastriatal degeneration before clinical conversion. Sensorimotor areas seem to be core regions affected in symp-HD and, along with widespread cortical atrophy, may account for the clinical heterogeneity in HD.

Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype.

OBJECTIVE: To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. DESIGN: Prospective multimodal clinical and neuroimaging study. SETTING: University of Lübeck, Lübeck, Germany. PARTICIPANTS: Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). INTERVENTIONS: Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). MAIN OUTCOME MEASURES: Frequency of parkinsonian signs, brain structure, and functional alterations. RESULTS: The only available patient with compound heterozygous KRS showed a markedly reduced striatal DAT density bilaterally. Magnetic resonance imaging revealed severe global brain atrophy as well as iron deposition in the basal ganglia. The heterozygous mother had definite parkinsonism with reduced DAT density in both putamina. While all asymptomatic heterozygous siblings displayed subtle extrapyramidal signs, DAT imaging revealed striatal tracer uptake within physiological levels. Voxel-based morphometry revealed an increase in gray matter volume in the right putamen and a decrease in the cerebellum of the heterozygous carriers. In all mutation carriers, the substantia nigra had a normal appearance on TCS. CONCLUSIONS: Single ATP13A2 heterozygous mutations may be associated with clinical signs of parkinsonism and contribute to structural and functional brain changes. Lack of hyperechogenicity in the substantia nigra may be a distinctive feature of this form of genetic parkinsonism. This, along with the finding of iron in the basal ganglia in our patient with KRS, implies a different underlying pathophysiology compared with other monogenic forms of parkinsonism and idiopathic PD and may place KRS among the syndromes of neurodegeneration with brain iron accumulation (NBIA).

Structural imaging in the presymptomatic stage of genetically determined parkinsonism.

Several genes associated with monogenic forms of Parkinson's disease (PD) have been discovered, opening up new avenues for the investigation of presymptomatic stages of PD. Using voxel-based morphometry in 30 asymptomatic mutation carriers (MC) with mutations in four different genes for PD and 100 healthy controls, we identified an increase in gray matter volume (GMV) in the striatum in asymptomatic Parkin, PINK1, ATP13A2 and, to a much lesser extent, in LRRK2 MC. Moreover, an increase in GMV was found in the parieto-temporo-occipital association cortex in asymptomatic Parkin and ATP13A2 MC. The observed striatal GMV increase might be the common structural correlate of compensatory mechanisms due to the latent dopaminergic deficit, reflecting the different, but probably interrelated pathogenic pathways resulting in nigral cell death. Asymptomatic PINK1 and LRRK2 MC also revealed smaller GMV in the hippocampal region, which might play a role in the observed psychiatric disorders.

ATP13A2 variants in early-onset Parkinson's disease patients and controls.

Four genes responsible for recessively inherited forms of Parkinson's disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exons of the ATP13A2 coding region in 112 patients with early-onset PD (EOPD; <40 years) of mostly European ethnic origin and of 55 controls. We identified four carriers (3.6%) of novel single heterozygous ATP13A2 missense changes that were absent in controls. Interestingly, the carrier of one of these variants also harbored two mutations in the Parkin gene. None of the carriers had atypical features previously described in patients with two mutated ATP13A2 alleles (Kufor-Rakeb syndrome). Our data suggest that two mutated ATP13A2 alleles are not a common cause of PD. Although heterozygous variants are present in a considerable number of patients, they are-based on this relatively small sample-not significantly more frequent in patients compared to controls.