26 research outputs found

    Case report: Chorea and cognitive decline in a young woman: instrumental and genetic assessment of a case originally diagnosed as multiple sclerosis

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    We describe the case of a young woman affected by debilitating chorea and rapidly progressive cognitive decline. While her original diagnosis was multiple sclerosis, we performed a full instrumental and genetic assessement, though which we identified multiple genetic variants, including a novel variant of the APP gene. We propose some possible mechanisms by which such variants may contribute to neuroinflammation and ultimately lead to this devastating clinical course

    Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

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    Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability

    Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

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    Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy

    Rasagiline for sleep disorders in patients with Parkinson’s disease: A prospective observational study

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    Introduction: Rasagiline is a selective, irreversible monoamine oxidase B inhibitor that ameliorates the symptoms of Parkinson’s disease (PD) by inhibiting striatal dopamine metabolism. There is also evidence that monoamine oxidase B inhibitors increase melatonin levels in the pineal gland and may have a beneficial effect on sleep disorders, which are a common feature in patients with PD. Methods: This single-center, prospective, observational, 12-week study compared the effect of combination therapy with levodopa 200-300 mg/d + rasagiline 1 mg/d (n=19) with levodopa 200-300 mg/d alone (n=19) in the treatment of sleep disorders in patients with idiopathic PD. Results: After 12 weeks’ treatment, mean sleep latency was significantly (P<0.001) lower and the improvement in sleep latency from baseline was significantly (P=0.001) greater in patients receiving levodopa + rasagiline than in patients receiving levodopa alone. Similarly, at the end of the study, the mean total sleep time was significantly (P=0.002) longer and the improvement from baseline in mean total sleep time was significantly (P=0.026) greater in patients receiving levodopa + rasagiline than levodopa alone. There were no significant differences between treatment groups for the mean number of awakenings reported at week 12 nor the change from baseline to week 12 in mean number of awakenings. Conclusion: Adding rasagiline to levodopa improved sleep outcomes and may be an appropriate option for patients with PD experiencing sleep disorders

    Verapamil Inhibits Ser202/Thr205 Phosphorylation of Tau by Blocking TXNIP/ROS/p38 MAPK Pathway

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    Purpose Oxidative stress is a hallmark of Alzheimer’s Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects. Methods We analyzed TXNIP expression and tau phosphorylation in the hippocampus of the 5xFAD mice in the absence and presence of a pharmacological treatment with Verapamil. Using SH-SY5Y cells, we verified the causative role of TXNIP in promoting tau phosphorylation atSer202/Thr205, by inducing TXNIP silencing. Results The amyloid beta peptide (Aβ1–42) leads to TXNIP over-expression in SH-SY5Y cells, which in turns induces oxidative stress and the activation of p38 MAPK, promoting tau phosphorylation at Ser202/Thr205. Silencing of TXNIP abolishes Aβ1–42-induced tau phosphorylation, p38 MAPK phosphorylation and subsequent tau phosphorylation. Verapamil prevents TXNIP expression as well as p38 MAPK and tau phosphorylation at Ser202/Thr205 in the hippocampus of the 5xFAD mice. Conclusions Our study unveil a novel pathway involved in AD progression that is inhibited by Verapamil, shedding new light on the understanding of the therapeutic potential of Verapamil in AD

    Effects of recombinant BDNF treatment on striatal atrophy in R6/2 mice.

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    <p>Transmitted light microscope images showing representative Nissl-stained coronal sections of a wild-type mouse, a vehicle treated R6/2 mouse and a BDNF-treated R6/2 mouse, (A), left to right, respectively. Marked gross atrophy and enlarged lateral ventricles are present in the sections from the vehicle treated R6/2 mouse compared the wild type mouse. These differences are largely absence from the sections of the R6/2 mouse treated with BDNF. (B) Quantification of differences in striatal volume from wild type and vehicle- or BDNF-treated R6/2 mice. Post hoc analysis indicated that R6/2 mice treated with vehicle had a significantly reduced striatal volume compared to the wild type group. The striatal volume of R6/2 mice treated with BDNF was significantly greater than that of the vehicle treated R6/2. <i>Effects of BDNF treatment on reactive microglia in the striatum of R6/2 mice (C–E).</i> Representative photomicrographs of single label immunofluorescence for the marker of activated microglia, CD68, in the striatum of (C) wild type, (D) vehicle treated R6/2, or (E) R6/2 mice treated with BDNF. In the sample from the vehicle treated R6/2 mouse, an intense microglial reaction is observed, while in the sample from a BDNF treated R6/2 mouse there were fewer reactive cells, along with quiescent cells. <i>Effects of BDNF treatment on the density of NIIs in the striatum of R6/2 mice. (</i>F–H). Confocal laser scanning microscopy images of single-label immunofluorescence for NII marker (EM48). Single-label immunostaining was employed in the striata of vehicle-treated wild-type (WT) mice (F), vehicle-treated R6/2 mice (G) and BNF-treated R6/2 mice (4 µg/day) (H) at 13 weeks of age. Of note, is the lower density of EM48-positive NIIs in the BDNF-treated R6/2 mice (H). (I) Quantification of NIIs in vehicle- or BDNF treated R6/2 mice. There were no NIIs detected in striatum of wild type mice, so this group was not included in the statistical analysis. One Way Anova indicated that the density of NIIs in striatum of R6/2 mice treated with BDNF was lower than that in R6/2 mice treated with vehicle (p<0.0001). (J) Histogram showing the quantification of CD68 immunostained total surface in vehicle or BDNF treated wild-type and vehicle or BDNF treated R6/2 mice. Data are presented as the mean values of CD68 positive areas ± SEM. Microglia reactivity was significantly decreased in the striatum of R6/2 mice after treatment with BDNF (*P<0.001).</p
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