A Novel Multisystem Proteinopathy Caused by a Missense ANXA11 Variant.

OBJECTIVE: Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). METHODS: We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. RESULTS: Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). INTERPRETATION: These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239-252.

Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI.

INTRODUCTION: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA. METHODS: We enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging in a 3 T device; three-dimensional high-resolution T1-weighted images and diffusion tensor images were used to assess gray and white matter, respectively. We used T1 multiatlas approach to assess deep gray matter and cortical thickness measures to evaluate cerebral cortex and DTI multiatlas approach to assess white matter. All analyses were corrected for multiple comparisons. RESULTS: Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = -0.552, P = 0.012) and severity (R = -0.783, P < 0.001). CONCLUSION: The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA. Hum Brain Mapp 38:4157-4168, 2017. © 2017 Wiley Periodicals, Inc.

Structural brain and spinal cord damage in symptomatic and pre-symptomatic VAPB-related ALS.

INTRODUCTION: The VAPB gene is associated with fALS (fALS 8). This disease presents a variable phenotype and no study sought to characterize its neuroanatomical abnormalities until now. This study aims to evaluate structural brain and spinal cord abnormalities in symptomatic and pre-symptomatic VAPB-related ALS. METHODS: This cohort included 10 presymptomatic and 20 symptomatic carriers of the Pro56Ser VAPB variant as well as 30 matched controls and 20 individuals with sporadic ALS. They underwent detailed clinical evaluation and MRI in a 3 T scanner. Using volumetric T1 sequence, we computed cerebral cortical thickness (FreeSurfer), basal ganglia volumetry (T1 Multi-atlas) and SC morphometry (SpineSeg). DTI was used to assess white matter integrity (DTI Multi-atlas). Groups were compared using a generalized linear model with Bonferroni-corrected p values<0.05. We also plotted VAPB brain expression map using Allen Human Brain Atlas to compare with imaging findings. RESULTS: Mean age of presymptomatic and symptomatic subjects were 43.2 and 51.9 years, respectively. Most patients had a predominant lower motor neuron phenotype (16/20). Sleep complaints and tremor were the most frequent additional manifestations. Compared to controls, symptomatic subjects had pallidal, brainstem and SC atrophy, whereas presymptomatic only had SC atrophy. This pattern also contrasted with the sALS group that presented motor cortex and corticospinal abnormalities. Brain structural damage and VAPB expression maps were highly overlapping. CONCLUSION: VAPB-related ALS has a distinctive structural signature that targets the basal ganglia, brainstem and SC, which are regions with high VAPB expression. Neuroanatomical SC changes are evident before clinical onset of the disease.

Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia.

OBJECTIVES: To evaluate autonomic symptoms and function in Friedreich's Ataxia (FRDA). METHODS: Twenty-eight FRDA patients and 24 controls underwent clinical/electrophysiological testing. We employed the Friedreich's Ataxia Rating Scale (FARS) and the Scales for Outcomes in Parkinson's Disease: Autonomic Questionnaire-SCOPA-AUT to estimate the intensity of ataxia and autonomic complaints, respectively. Cardiovagal tests and the quantitative sudomotor axonal reflex, Q-SART, were then assessed in both groups. RESULTS: In the patient group, there were 11 men with mean age of 31.5 ±â€¯11.1 years. Mean SCOPA-AUT score was 15.1 ±â€¯8.1. Minimum RR interval at rest was shorter in the FRDA group (Median 831.3 × 724.0 ms, p < 0.001). The 30:15 ratio, Valsalva index, E:I ratio, low and high frequency power presented no differences between patients and controls (p > 0.05). Sweat responses were significantly reduced in patients for all sites tested (forearm 0.389 × 1.309 µL; proximal leg 0.406 × 1.107 µL; distal leg 0.491 × 1.232 µL; foot 0.265 × 0.708 µL; p value < 0.05). Sweat volumes correlated with FARS scores. CONCLUSIONS: We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease. SIGNIFICANCE: Quantification of sudomotor function might be a biomarker for FRDA.

Longitudinal evaluation of cerebral and spinal cord damage in Amyotrophic Lateral Sclerosis.

OBJECTIVE: To evaluate MRI-based parameters as biomarkers of Amyotrophic Lateral Sclerosis (ALS) progression. METHODS: Twenty-seven patients and 27 controls performed two clinical and MRI acquisitions 8 months apart. ALSFRS-R scale was used to quantify disease severity at both time points. Multimodal analyses of MRI included cortical thickness measurements (FreeSurfer software), analysis of white matter integrity using diffusion-tensor imaging (tract-based spatial statistics-TBSS) and measurement of cervical spinal cord cross-sectional area (SpineSeg software). All analyses were corrected for multiple comparisons. The standardized response mean (SRM = mean score change / standard deviation of score change) was calculated for all methods herein employed and used for comparison purposes. RESULTS: There were 18 men and mean age at first examination was 51.9 years. Mean ALSFRS-R scores at baseline and follow-up were 34.0 and 29.0, respectively. There was no region with progressive cortical thinning, but there was significant brainstem volumetric reduction (p = 0.001). TBSS analyses revealed progressive increase of AD (axial diffusivity) and MD (mean diffusivity) at the corpus callosum (p < 0.05), whereas SpineSeg showed progressive cord area reduction (p = 0.002). Cervical spinal cord cross-sectional area reduction was the only MRI parameter that correlated with ALSFRS-R change (r = 0.309, p = 0.038). SRM for ALSFRS-R was 0.95, for cord area 0.95, for corpus callosum AD 0.62 and MD 0.65, and for brainstem volume 0.002. CONCLUSIONS: Structural MRI is able to detect short term longitudinal changes in ALS. Cervical spinal cord morphometry is a promising neuroimaging marker to assess ALS course.

Dystonia in Machado-Joseph disease: Clinical profile, therapy and anatomical basis.

INTRODUCTION: Dystonia is frequent in Machado-Joseph disease, but several important aspects are not yet defined, such as the detailed clinical profile, response to treatment and anatomical substrate. METHODS: We screened 75 consecutive patients and identified those with dystonia. The Burke-Marsden-Fahn Dystonia Rating Scale was employed to quantify dystonia severity. Patients with dystonia received levodopa 600 mg/day for 2 months and were videotaped before and after treatment. A blinded evaluator rated dystonia in the videos. Patients with disabling dystonia who failed to respond to levodopa treatment received botulinum toxin. Finally, volumetric T1 and diffusion tensor imaging sequences were obtained in the dystonic group using a 3T-MRI scanner to identify areas of gray and white matter that were selectively damaged. RESULTS: There were 21 patients with dystonia (28%): 9 classified as generalized and 12 as focal/segmental. Patients with dystonia had earlier onset and larger (CAG) expansions (28.9 ± 11.7 vs 40.6 ± 11.4; p < 0.001 and 75 vs 70; p < 0.001, respectively). Although group analyses failed to show benefit on levodopa (p = 0.07), some patients had objective improvement. In addition, ten patients received botulinum toxin resulting in a significant change in dystonia scores after 4 weeks (p = 0.03). Patients with dystonia had atrophy at pre- and paracentral cortices; whereas, non-dystonic patients had occipital atrophy. Basal ganglia volume was reduced in both groups, but atrophy at the thalami, cerebellar white matter and ventral diencephali was disproportionately higher in the dystonic group. CONCLUSION: Dystonia in Machado-Joseph disease is frequent and often disabling, but may respond to levodopa. It is associated predominantly with structural abnormalities around the motor cortices and in the thalami.