Progression of Clinical and Eye Movement Markers in Preataxic Carriers of Machado-Joseph Disease.

BACKGROUND: Little is known about preclinical stages of Machado-Joseph disease, a polyglutamine disorder characterized by progressive adult-onset ataxia. OBJECTIVE: We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease. METHODS: Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score < 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time. RESULTS: A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The "TimeToAfterOnset" timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non-Ataxia Symptoms (INAS0.07), and the vestibulo-ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2-year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate. CONCLUSIONS: NESSCA, INAS, vestibulo-ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The "TimeToAfterOnset" timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society.

Quality of Life since Pre-Ataxic Phases of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

Although health-related quality of life (HRQoL) has been increasingly valued in healthcare and in clinical trials, there is scarce information about it in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). This study describes the HRQoL results obtained from ataxic SCA3/MJD subjects, and their non-ataxic offspring included in the BIGPRO (Biomarkers and genetic modifiers in a study of presymptomatic and symptomatic SCA3/MJD carriers) study. Demographic data, clinical scales, and HRQoL instruments EQ-5D-3L and SF-36 were collected. Subjects at 50% risk were genotyped in a double-blind manner. The time left until the onset of the disease was estimated for mutation carriers with a SARA < 3 and combined with disease duration of ataxic subjects (TimeToAfterOnset). Analyses were performed using PASW Statistics version 18.0, R version 4.0.0, and G*Power 3.1, and p < 0.05 was considered statistically significant. Twenty-three ataxic carriers, 33 pre-ataxic carriers, and 21 controls were enrolled. Significant differences between ataxic carriers and controls were seen in EQ-VAS, EQ-5D Index, and in some domains of EQ-5D-3L and SF-36. EQ-5D Index showed the best effect size between ataxic and controls (Cohen's d = 2.423). Stepwise changes were seen in pre-ataxic subjects, although not statistically significant. TimeToAfterOnset correlated with EQ-5D Index, EQ-VAS, and SF-36 Physical functioning, Role Physical, Pain, and General Health. EQ-5D Index and EQ-VAS correlated with clinical scales in the ataxic group. These results suggest that HRQoL worsens among carriers since pre-ataxic stages and that they might encompass the underlying disease process. In this cohort, SF-36 Physical Functioning, SF-36 General health, and especially EQ-5D Index and EQ-VAS were the best HRQoL instruments to be used as ancillary evidence to support biological and social meanings for future interventions.

Pre-ataxic Changes of Clinical Scales and Eye Movement in Machado-Joseph Disease: BIGPRO Study.

BACKGROUND: The pathological burden of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), accumulates before the beginning of symptoms. Our study aims at validating biomarkers for disease progression since pre-ataxic periods. We report on baseline findings of clinical scales and oculomotor neurophysiology. METHODS: Ataxic (Scale for the Assessment and Rating of Ataxia > 2.5) and at 50% risk subjects were included. The latter were subdivided into noncarriers, pre-ataxic carriers near (PAN), or pre-ataxic carriers far from (PAFF) ataxia onset (AO), with 4 years from the predicted age at onset being the cutoff. The subjects were assessed by Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), International Cooperative Ataxia Rating Scale (ICARS), Inventory of Non-Ataxic Signs (INAScount), Composite Cerebellar Functions Score and SCA Functional Index, and video-oculography, including the regression slope of vestibulo-ocular reflex gain (VORr), main sequence of volitional and reflexive vertical saccades, slow-phase velocity of central and gaze-evoked (SPV-GE) nystagmus, and vertical pursuit gain. Correction for multiple comparisons was performed; the threshold for statistical significance was P < 0.05. RESULTS: A total of 35 ataxic, 14 PAN, 24 PAFF, and 22 noncarriers were included. All variables showed significant differences between groups and correlated to time to onset or time after onset, among all 73 SCA3/MJD carriers; none significantly changed with age in controls. NESSCA, ICARS, INAScount, VORr, main sequence of volitional saccades, and SPV-GE not only distinguished PAN from controls but also correlated with time left to AO. CONCLUSIONS: Clinical scales and video-oculography variables were already altered in pre-ataxic SCA3/MJD carriers and worsened with time. NESSCA, ICARS, INAScount, VORr, main sequence of vertical volitional saccades, and SPV-GE are good candidates to measure preclinical changes in SCA3/MJD. © 2021 International Parkinson and Movement Disorder Society.

Alterations in neuromuscular junctions and oxidative stress of the soleus muscle of obese Wistar rats caused by vibratory platform training.

OBJECTIVES: evaluate the effects that whole-body vibration (WBV) causes on the neuromuscular junctions and oxidative stress of the soleus muscle of obese Wistar rats. METHODS: 32 male Wistar rats were used, 16 of which were obesity induced by monosodium glutamate, randomized into four groups: control (GC), control with WBV (GCP), obese (GO) and obese with WBV (GOP). At the 70 days old, the training on WBV was started, performed 3 times a week, during 8 consecutive weeks. At the 130 days old, the animals were euthanized and the soleus muscles were collected. RESULTS: Regarding the analysis of the neuromuscular junctions, the obese groups had lower mean size when compared to the control groups. On the other hand, the WBV presented higher averages when compared to the groups that did not perform the training. Regarding the oxidative stress, for the lipid peroxidation there was a significant difference between obese and non-obese animals, however, there was no difference between the animals WBV and those who did not. CONCLUSION: WBV promotes beneficial changes such as increased measurements of the structures of the neuromuscular junctions, but is not able to promote changes in the concentration of the cholinesterase enzyme in the synaptic cleft.

The longitudinal progression of MRI changes in pre-ataxic carriers of SCA3/MJD.

BACKGROUND: The natural history of magnetic resonance imaging (MRI) in pre-ataxic stages of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is not well known. We report cross-sectional and longitudinal data obtained at this stage. METHODS: Baseline (follow-up) observations included 32 (17) pre-ataxic carriers (SARA < 3) and 20 (12) related controls. The mutation length was used to estimate the time to onset (TimeTo) of gait ataxia. Clinical scales and MRIs were performed at baseline and after a median (IQR) of 30 (7) months. Cerebellar volumetries (ACAPULCO), deep gray-matter (T1-Multiatlas), cortical thickness (FreeSurfer), cervical spinal cord area (SCT) and white matter (DTI-Multiatlas) were assessed. Baseline differences between groups were described; variables that presented a p < 0.1 after Bonferroni correction were assessed longitudinally, using TimeTo and study time. For TimeTo strategy, corrections for age, sex and intracranial volume were done with Z-score progression. A significance level of 5% was adopted. RESULTS: SCT at C1 level distinguished pre-ataxic carriers from controls. DTI measures of the right inferior cerebellar peduncle (ICP), bilateral middle cerebellar peduncles (MCP) and bilateral medial lemniscus (ML), also distinguished pre-ataxic carriers from controls, and progressed over TimeTo, with effect sizes varying from 0.11 to 0.20, larger than those of the clinical scales. No MRI variable showed progression over study time. DISCUSSION: DTI parameters of the right ICP, left MCP and right ML were the best biomarkers for the pre-ataxic stage of SCA3/MJD. TimeTo is an interesting timescale, since it captured the longitudinal worsening of these structures.

Whole-body vibration promotes lipid mobilization in hypothalamic obesity rat.

OBJECTIVES: This study aimed to analyze the effect of whole-body vibration (WBV) on metabolic parameters using the monosodium l-glutamate (MSG) model of obesity. METHOD: MSG-obese rats that were exposed to WBV on a vibrating platform with 60 Hz frequency, 2 mm amplitude, three times/week, 10 min/day, during eight weeks (from postnatal day (PN) 80 to PN136). Blood glucose, creatine kinases (CK and CK-MB) and lipid profile through plasma and liver levels of lipids and lipoproteins were evaluated. Morphology and oxidative stress of adipose and hepatic tissues were further evaluated. RESULTS: When performing a WBV exercise, animals showed contrasting metabolic responses. Vibration Control group (CTL-WBV) presented a reduction in CK and liver triacylglycerol, an increase in glucose, lactate, total cholesterol, liver cholesterol, and LDL while MSG Vibration group (MSG-WBV) showed an increase in total triacylglycerol, VLDL, lactate, CK, liver cholesterol, additional liver lipid peroxidation and LDL, total cholesterol and CKMB reduction. CONCLUSION: Even although the MSG is a model of impacting injury, the metabolic demand of WBV exercise was able to induce mobilization of substrates, highlighting the lipid mobilization in obese animals, it should be used as a metabolic rehabilitation tool in patients with metabolic diseases, such as obesity and diabetes.

Short-term effects of whole-body vibration on the soleus of ooforectomized rats: Histomorphometric analysis and oxidative stress in an animal model.

PURPOSE: The aim of this study was to analyze the effects of mechanical vibration on the histomorphometry and oxidative stress of oophorectomized rats. METHOD: Seventy-two Wistar rats were randomized to Pseudoophorectomy (P) and Oophorectomy (O) and subdivided into untreated animals and euthanized after four (P4 and O4) and eight (P8 and O8) weeks and animals treated during four (PT4 and OT4) and eight (PT8 and OT8) weeks. The treatment consisted of use of whole-body vibration for 10 min, three times a week. After euthanasia, the soleus muscle was collected. The general morphological analysis was performed in the right soleus muscle and then the cross-sectional area, the largest and the smallest diameter of the muscle fiber in 100 fibers per muscle, also the nuclei and capillary/fiber ratios, and percentage of connective tissue were measured. The left soleous was used for oxidative stress analysis. RESULTS: PT4 presented higher values in cross-sectional area than P4 and PT8, while O8 was lower than O4, P8 and OT8; for the fiber diameters, the oophorectomized animals had lower values than the pseudo-oophorectomized animals and the treatments values higher than the ones that had no treatment. In oxidative stress, O8 and OT8 presented higher lipoperoxidation, without any alterations to the activities of superoxide dismutase, catalase and cholinesterase. CONCLUSION: Whole-body vibration induced muscle hypertrophy in the pseudo-oophorectomized rats after four weeks, as well as being able to reverse the changes caused by the surgery in eight weeks in that variable.

Dropped head syndrome as a manifestation of Charcot-Marie-Tooth disease type 4C.

Charcot Marie Tooth disease type 4C (CMT4C) is considered the most frequent autosomal recessive form of CMT worldwide, being described as an early-onset disorder with marked clinical heterogeneity. We report a CMT4C case associated with dropped head syndrome and predominant involvement of proximal muscles. An 11-year-old boy born to consanguineous parents presented with predominantly proximal muscle weakness with facial involvement, associated with dropped head and severe scoliosis. Symptoms started at the age of 3 years-old with frequent falls. Nerve conduction studies showed a sensorimotor demyelinating polyneuropathy. A comprehensive multigene next-generation sequencing panel for CMT revealed the homozygous pathogenic missense variant c.1969G > A (p.E657K) in SH3TC2 gene, confirming CMT4C diagnosis. The present report broadens the phenotype associated with CMT4C and raises the importance of considering early-onset inherited polyneuropathies in the differential diagnosis of patients with proximal muscle wasting associated with dropped head syndrome.

Antioxidant Systems as a Response to Midgut Cellular of Bombyx mori Lineu, 1758 (Lepidoptera: Bombycidae) Infection for Baculoviruses.

Bombyx mori nucleopolyhedrovirus (BmNPV) is a DNA virus that infects different tissues in Bombyx mori at immature stage. Caterpillars become infected after ingesting polyhedral occlusion bodies (POB) present in contaminated mulberry leaves and spread through the body after passing the epithelium of the midgut. As this organ is responsible for digestion, most absorption of nutrients requires an intact epithelium to maintain gastrointestinal physiology. Considering the importance of this organ in the feeding of caterpillars and in the production of quality silk threads, and because it is also the first barrier faced by the BmNPV, the study analyzed details of cytopathological events in the intestinal cells as well as evaluated the action of the antioxidant systems as a response to cellular infection. For this purpose, B. mori hybrid caterpillars of fifth instar were inoculated with a suspension of 7.8 × 107 POB ml-1 and, from the first to the eighth day post-inoculation (dpi), segments of the midgut were collected and processed for light and electronic microscopy. The nuclei of columnar cells showed polyhedric occlusion bodies in the seventh dpi and fragmentation of those cells, with peritrophic matrix disorganization. Analysis of antioxidant systems shows some moments of changes of the catalase enzymes and superoxide dismutase. Analysis of the cholinergic system revealed changes only at the beginning of the infection. Thus, the article acknowledges the antioxidant system as a barrier to stop viral infection, albeit it cannot stop infection from occurring, once a coevolutionary bond is maintained between virus and host.