Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors

Исследование теплопереноса при воспламенении типичного лесного горючего материала (ветвь хвойного дерева) при воздействии высокотемпературной среды

Объект исследования – ветвь хвойного дерева. Предмет исследования – моделирование теплопереноса в слоистой структуре ветви хвойного дерева при тепловом воздействии от фронта лесного пожара. Исходные данные – теплофизические характеристики хвойного дерева.The object of study is a branch of a coniferous tree. The subject of the study is the modeling of heat transfer in a layered structure of a branch of a coniferous tree under thermal effects from the front of a forest fire. Baseline data - thermophysical characteristics of coniferous wood

Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease

Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha(+) thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5–11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 × 10(−5), locus-specific heritability of 37.7%; 95% confidence interval, 15.7%–59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria

Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

Abstract: Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA

Long-term effects of cerebellar anodal transcranial direct current stimulation (tDCS) on the acquisition and extinction of conditioned eyeblink responses

Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)–US (unconditioned stimulus) trials were applied. During the first 50 paired CS–US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS–US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer)

Cerebellar patients do not benefit from cerebellar or M1 transcranial direct current stimulation during force-field reaching adaptation

Several studies have identified transcranial direct current stimulation (tDCS) as a potential tool in the rehabilitation of cerebellar disease. Here, we tested whether tDCS could alleviate motor impairments of subjects with cerebellar degeneration. Three groups took part in this study: 20 individuals with cerebellar degeneration, 20 age-matched controls, and 30 young controls. A standard reaching task with force-field perturbations was used to compare motor adaptation among groups and to measure the effect of stimulation of the cerebellum or primary motor cortex (M1). Cerebellar subjects and age-matched controls were tested during each stimulation type (cerebellum, M1, and sham) with a break of 1 wk among each of the three sessions. Young controls were tested during one session under one of three stimulation types (anodal cerebellum, cathodal cerebellum, or sham). As expected, individuals with cerebellar degeneration had a reduced ability to adapt to motor perturbations. Importantly, cerebellar patients did not benefit from anodal stimulation of the cerebellum or M1. Furthermore, no stimulation effects could be detected in aging and young controls. The present null results cannot exclude more subtle tDCS effects in larger subject populations and between-subject designs. Moreover, it is still possible that tDCS affects motor adaptation in cerebellar subjects and control subjects under a different task or with alternative stimulation parameters. However, for tDCS to become a valuable tool in the neurorehabilitation of cerebellar disease, stimulation effects should be present in group sizes commonly used in this rare patient population and be more consistent and predictable across subjects and tasks. NEW & NOTEWORTHY Transcranial direct current stimulation (tDCS) has been identified as a potential tool in the rehabilitation of cerebellar disease. We investigated whether tDCS of the cerebellum and primary motor cortex could alleviate motor impairments of subjects with cerebellar degeneration. The present study did not find stimulation effects of tDCS in young controls, aging controls, and individuals with cerebellar degeneration during reach adaptation. Our results require a re-evaluation of the clinical potential of tDCS in cerebellar patients