Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterised by TDP-43 pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here, we have created a novel TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed leading to a gain of TDP-43 function, and altered splicing of Mapt, another pivotal dementia gene. Furthermore, a novel approach to stratify transcriptomic data by phenotype in differentially affected mutant mice reveals 471 changes linked with improved behaviour. These changes include downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD, and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

Decision making in both animals and humans is influenced by the anticipation of reward and/or punishment. Little is known about how reward and punishment interact in the context of decision making. The Avoidance-Reward Conflict (ARC) Task is a new paradigm that varies the degree of reward and the probability of punishment in a single paradigm that can be used in both non-human primates (NHPs) and humans. This study examined the behavioral pattern in the ARC task in both NHPs and humans. Two adult male NHPs (macaca mulatta) and 20 healthy human volunteers (12 females) participated in the ARC task. NHPs and humans perform similarly on the ARC task. With a high probability of punishment (an aversive air puff to the eye), both NHPs and humans are more likely to forgo reward if it is small or medium magnitude than when it is large. Both NHPs and humans perform similarly on the same behavioral task suggesting the reliability of animal models in predicting human behavior.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that has significant overlap with frontotemporal dementia (FTD). Mutations in specific genes have been identified that can cause and/or predispose patients to ALS. However, the clinical variability seen in ALS patients suggests that additional genes impact pathology, susceptibility, severity, and/or progression of the disease. To identify molecular pathways involved in ALS, we undertook a meta-analysis of published genetic modifiers both in patients and in model organisms, and undertook bioinformatic pathway analysis. From 72 published studies, we generated a list of 946 genes whose perturbation (1) impacted ALS in patient populations, (2) altered defects in laboratory models, or (3) modified defects caused by ALS gene ortholog loss of function. Herein, these are all called modifier genes. We found 727 modifier genes that encode proteins with human orthologs. Of these, 43 modifier genes were identified as modifiers of more than one ALS gene/model, consistent with the hypothesis that shared genes and pathways may underlie ALS. Further, we used a gene ontology-based bioinformatic analysis to identify pathways and associated genes that may be important in ALS. To our knowledge this is the first comprehensive survey of ALS modifier genes. This work suggests that shared molecular mechanisms may underlie pathology caused by different ALS disease genes. Surprisingly, few ALS modifier genes have been tested in more than one disease model. Understanding genes that modify ALS-associated defects will help to elucidate the molecular pathways that underlie ALS and provide additional targets for therapeutic intervention.

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Background:This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV).Methods:Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale.Results:For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P<.05) on clinician- and self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n=7) satisfied full medication response criteria. Intention-to-treat analyses (n=20) showed similar improvements (P<.05) on primary and secondary study outcome measures.Conclusion:The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder.ClinicalTrials.gov NCT00464698; .

If, after being in the dark for many minutes, one views an extended surface under dim (scotopic) illumination, one fails to see any hint of the dark spot at the center of gaze that might be expected from the absence of rods in the fovea. Here we report that, if the surface is suddenly completely darkened, one sees for a few seconds a relatively bright spot, about 2 deg in size, at the point of fixation. If the surface is now restored to its original brightness, a dark spot of similar size appears where one fixates, that again lasts for several seconds. All this can be observed with no elaborate apparatus.

In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the article.

Background: Studies of movement of the upper extremity for stroke patients currently require assessments with special equipment and trained assessors, limiting the accessibility. Hevelius is an experimental online platform designed to study human interaction with technology at a large scale. Our aim was to demonstrate the feasibility of using Hevelius for testing arm kinematics in stroke patients. Methods: Stroke patients (time from stroke 6 weeks to 1 year) with upper extremity weakness with an NIH Stroke Scale contralesional arm motor (5A or 5B) score of 2 or less were tested on Hevelius. Participants engaged in a Point-And-Click task. Thirty-two kinematic features of movement from continuous, target-driven mouse movement were collected in the arms contralesional and ipsilesional to stroke and compared to data from with health controls. Upper extremity Fugl-Meyer (UE-FM), NIH Stroke Scale (NIHSS), 9-Hole-Peg as well as patient reported outcomes (via Stroke Impact Scale) were collected during the same research visits. Results: In a total sample of N = 19 patients with upper extremity weakness after stroke who performed Hevelius testing, the median age was 66 (range 47 - 81) with 70% male participants. Nine participants had strokes affecting their dominant arm. LASSO method was used for regression to simultaneously performs feature selection and fitting of a linear model. Score estimates on Hevelius platform correlated strongly on linear regression modeling with clinical scores (from r=0.675 for arm portion of NIHSS ). There was also correlation with 9-Hole-Peg (r=0.581) and no clear correlation with UE-FM, modified Rankin score and Stroke Impact Scale. Five of the 9 patients with dominant arm affected by stroke had NIHSS of 0 and UE-FM of 66. Abnormal movement kinematics were detected in both the contralesional and ipsilesional arms when compared to healthy controls. Conclusions: Characteristics of arm movement are essential to the understanding of motor recovery after stroke. Our study demonstrates subtle deficits of arm movement in task-directed testing that were not captured with traditional measures of stroke recovery.