JAMA neurology
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Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. ⋯ Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.
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Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers. ⋯ This study suggests that the TMEM106B polymorphism modulates brain connectivity in aGRN+ individuals, with additional damage of the ventral salience network and left frontoparietal network observed. Genotyping TMEM106B is of importance in aGRN+ individuals for prognostic purposes and to assess early brain damage.
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Review Meta Analysis
Effect and reporting bias of RhoA/ROCK-blockade intervention on locomotor recovery after spinal cord injury: a systematic review and meta-analysis.
Blockade of small GTPase-RhoA signaling pathway is considered a candidate translational strategy to improve functional outcome after spinal cord injury (SCI) in humans. Pooling preclinical evidence by orthodox meta-analysis is confounded by missing data (publication bias). ⋯ Taking into account publication bias, RhoA/ROCK inhibition improves functional outcome in experimental SCI by 15%. This is a plausible strategy for the pharmacological augmentation of neurorehabilitation after human SCI. These findings support the necessity of a systematic analysis to identify preclinical bias before embarking on a clinical trial.
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Multicenter Study Comparative Study
Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping.
In Duchenne muscular dystrophy (DMD), the reading frame of an out-of-frame DMD deletion can be repaired by antisense oligonucleotide (AO)-mediated exon skipping. This creates a shorter dystrophin protein, similar to those expressed in the milder Becker muscular dystrophy (BMD). The skipping of some exons may be more efficacious than others. Patients with exon 44 or 45 skippable deletions (AOs in clinical development) have a less predictable phenotype than those skippable for exon 51, a group in advanced clinical trials. A way to predict the potential of AOs is the study of patients with BMD who have deletions that naturally mimic those that would be achieved by exon skipping. ⋯ Exon 44 or 45 skipping will likely yield lower levels of dystrophin than exon 51 skipping, although the resulting protein is functional enough to often maintain a mild BMD phenotype. Dystrophin transcript stability is an important indicator of dystrophin expression, and transcript instability in DMD compared with BMD should be explored as a potential biomarker of response to AOs. This study is beneficial for the planning, execution, and analysis of clinical trials for exon 44 and 45 skipping.