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TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g. , STMN2 ), as well as being able to modify disease progression (e.g. , UNC13A ). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.

Many neuropsychiatric illnesses are associated with psychosis, i.e., hallucinations (perceptions in the absence of causative stimuli) and delusions (irrational, often bizarre beliefs). Current models of brain function view perception as a combination of two distinct sources of information: bottom-up sensory input and top-down influences from prior knowledge. This framework may explain hallucinations and delusions. Here, we characterized the balance between visual bottom-up and top-down processing in people with early psychosis (study 1) and in psychosis-prone, healthy individuals (study 2) to elucidate the mechanisms that might contribute to the emergence of psychotic experiences. Through a specialized mental-health service, we identified unmedicated individuals who experience early psychotic symptoms but fall below the threshold for a categorical diagnosis. We observed that, in early psychosis, there was a shift in information processing favoring prior knowledge over incoming sensory evidence. In the complementary study, we capitalized on subtle variations in perception and belief in the general population that exhibit graded similarity with psychotic experiences (schizotypy). We observed that the degree of psychosis proneness in healthy individuals, and, specifically, the presence of subtle perceptual alterations, is also associated with stronger reliance on prior knowledge. Although, in the current experimental studies, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Overall, we show that early psychosis and psychosis proneness both entail a basic shift in visual information processing, favoring prior knowledge over incoming sensory evidence. The studies provide complementary insights to a mechanism by which psychotic symptoms may emerge.

ObjectiveAmyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis.MethodsSamples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS.ResultsThere were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10−5, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097).ConclusionsPeople with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias.

Perception can prime action (visuomotor priming), and action can prime perception (motorvisual priming). According to ideomotor theory both effects rely on the overlap of mental representations between perception and action. This implies that both effects get more pronounced the more features they share. We tested this hypothesis by employing in a motorvisual (Exp. 1) and in a visuomotor (Exp. 2) setting, three different pairs of left/right target stimuli (hand pictures, arrows, and words) varying in how strongly they overlap with the pair of left/right responses. For two stimulus pairs (hands and words) the hypothesis was confirmed: hand pictures share more features with the responses than words, consequently hand pictures produced a stronger visuomotor and a stronger motorvisual priming effect than words. However, arrow stimuli showed a different pattern: the temporal dynamics of both priming effects, as well as the direction of the effect seen in motorvisual priming, were significant but opposite to that of the hand and word stimuli. This suggests that the arrows’ representations were not involved in ideomotor processes, and we propose instead that they were represented in a spatial or scalar fashion, outside the representations assumed in ideomotor theory. The results are discussed in the context of ideomotor theory, and the planning and control model of motorvisual priming.

We describe a non-smoker who presented with a persistent cough, weight loss and general malaise, and had a medical history of bladder carcinoma that had been successfully treated with intravesical BCG immunotherapy. Radiology revealed hilar lymphadenopathy, a predominantly mid-zone and lower-zone lung parenchymal nodular pattern with a perilymphatic distribution, a few thickened interlobular septae, and small pleural effusions bilaterally. The T-SPOT.TB blood test was negative. Video-assisted thoracoscopic surgery showed multiple pleural nodules, the histopathology of which showed multiple well-defined non-caseating granulomata. The patient was started on antituberculosis medication for presumed BCGosis—a systemic complication of previous BCG immunotherapy—and the patient showed an excellent clinical and radiological response. This case further adds to previous reports and reinforces the recommendation that all patients should be made fully aware of the potential systemic and delayed complications of BCG immunotherapy when they are consented for treatment.

Cryptic splicing caused by TDP-43 proteinopathy is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, which cryptic splicing events (CEs) are the most sensitive to TDP-43 depletion, where CEs localise within cells, and how specific CEs are in human tissues is poorly defined. Analyses of TDP-43 knockdowns and postmortem RNA-seq datasets revealed that a small subset out of thousands of CEs are specific markers for TDP-43 proteinopathy . Nonsense-mediated decay (NMD) masked a portion of CEs, influencing their subcellular localization and detectability in tissue. Dose-dependent TDP-43 depletion identified \"early-responsive\" CEs, which possess stronger splice sites and denser, more canonical TDP 43 binding motifs. Finally, we developed a composite cryptic burden score that effectively captured TDP-43 pathology across heterogeneous tissues and correlated with regional vulnerability and genetic background. Our work identifies robust biomarkers and offers new insights into TDP-43-mediated splicing dysregulation in neurodegeneration.

We describe a 62-year-old smoker, presenting with a 6-week evolving history of progressive weakness of his legs and right hand, with sphincter disturbance. Past medical history included latent tuberculosis aged 25, which was treated. MRI whole-spine revealed longitudinally extensive transverse myelitis (LETM) spanning C4-T1. CSF examination revealed WCC 43 (93% lymphocytes), protein 844 mg/L, normal paired glucose, unmatched CSF oligoclonal bands, negative viral PCR, AFB, and mycobacterial culture, and cytology in keeping with chronic inflammation. He was treated with intravenous steroids with an oral taper; however, he made no improvement. Aquaporin-4 and anti-MOG antibodies were negative. Anti-Hu antibodies were strongly positive. CT thorax revealed a right hilar mass with mediastinal lymph node enlargement. Whole-body FDG PET-CT was in keeping with a primary lung malignancy. EBUS-guided fine needle aspiration confirmed a histological diagnosis of small-cell lung cancer. Oncology MDT deemed the tumour to be inoperable and he was treated with palliative chemotherapy. To our knowledge, this is the first reported case of paraneoplastic LETM, secondary to small-cell lung cancer, associated with positive anti-Hu antibodies. This case highlights that a paraneoplastic work-up should be considered early in LETM, particularly in older patients and those with risk factors for cancer.

TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including and , disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement , positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1 -ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1 -ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1 -ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability. Analysis of age of onset and disease duration in a large, international cohort of people with SOD1 -ALS shows that there is a distinct phenotype and that onset and progression are decoupled.