Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia ...contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.
Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of ...lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain.
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•NSCs in multiple states of activation coexist in the adult SVZ•Dormancy is associated with high glycolytic and lipid metabolism•Activation is associated with high protein synthesis and differentiation priming•IFN-γ activates a state-dependent response to acute ischemic injury in NSCs
Llorens-Bobadilla et al. perform single-cell RNA sequencing of acutely isolated neural stem cells (NSCs) from the adult SVZ, identifying lineage-primed NSCs residing along a continuum of co-existing states between dormancy and activation. NSCs in different states possess unique molecular features and exhibit differential responses to acute ischemic brain injury.
Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system-resident microglia and infiltrating immune cells contribute to the degeneration of ...dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease.
Many studies having shown significant improvements in non-social and social cognitive performance in smoking FEP patients compared to non-smoking FEP patients. The findings are controversial. This ...study analyzed the effects of tobacco use on non-social and social cognitive function in a large group of FEP patients and a matched healthy control group.
A sample of 335 patients with FEP and 253 healthy controls was divided into four subgroups: control tobacco users (CTU), control non-tobacco users (CNTU), patient tobacco users (PTU) and patient non-tobacco users (PNTU). Demographic variables, tobacco use variables (presence or absence, frequency and duration of tobacco use), neurocognitive (non-social) performance and social cognition were assessed.
Comparison of 4 subgroups in non-social cognitive function revealed significant differences after controlling for covariables in executive functions (F=13.45; p≤0.001) and working memory domains (F=4.30; p=0.005). CTU and CNTU subgroups scored higher in all the domains compared to the PTU and the PNTU subgroups respectively. Social cognitive function was also significantly different within the four subgroups, with control subgroups showing better social cognition than patient subgroups. Significant differences in the executive functions domain were observed when comparing PTU and CTU groups (F=19.60; p≤0.001). No significant differences were revealed in the comparison between the patient groups.
This large study suggests that tobacco use in FEP patients is not related to better non-social or social cognitive performance.
Few randomised clinical trials have examined the efficacy of an intervention aimed at improving psychosocial functioning in bipolar disorder.
To examine changes in psychosocial functioning in a group ...that has been enrolled in a functional remediation programme 1 year after baseline.
This was a multicentre, randomised, rater-masked clinical trial comparing three patient groups: functional remediation, psychoeducation and treatment as usual over 1-year follow-up. The primary outcome was change in psychosocial functioning measured by means of the Functioning Assessment Short Test (FAST). Group×time effects for overall psychosocial functioning were examined using repeated-measures ANOVA (trial registration NCT01370668).
There was a significant group×time interaction for overall psychosocial functioning, favouring patients in the functional remediation group (F = 3.071, d.f. = 2, P = 0.049).
Improvement in psychosocial functioning is maintained after 1-year follow-up in patients with bipolar disorder receiving functional remediation.
Abstract We analyzed the efficacy of functional remediation, in a sample of patients with bipolar disorder who presented with subsyndromal symptoms. From a total sample of 239 patients with bipolar I ...and II disorder, according to DSM-IV-TR diagnostic criteria, entering a randomized clinical trial, those patients who presented with subsyndromal symptoms were selected based on a method already described by Berk and colleagues was applied. It consists of using the Clinical Global Impression-Bipolar version (CGI-BP) to establish the scores of the Hamilton Depression Rating Scale (HAM-D) and of the Young Mania Rating Scale (YMRS) that correspond with 1 in the CGI-BP. Functional outcome and mood symptoms were assessed at 6 and at 12-month follow-up. A total of 99 patients were selected for this post-hoc analysis, allocated as follows: functional remediation ( n =33); psychoeducation ( n =37) and treatment as usual (TAU, n =29). The repeated-measures analyses at 12-month follow-up revealed a significant group x time interaction in favour of the patients who received functional remediation when compared to psychoeducation and TAU ( F =2.93; p =0.02) at improving psychosocial functioning. Finally, mood symptoms did not significantly change in any of the three groups at any time of follow-up, as shown by the non-significant group x time interaction effect in HAM-D scores ( F =1.57; p =0.18) and YMRS scores ( F =1.51; p =0.20). Bipolar patients with subsyndromal symptoms improve their functional outcome when exposed to functional remediation regardless of the persistence of mood symptomatology.
Abstract
Background
The most efficient procedures to engage and guide healthcare professionals in collaborative processes that seek to optimize practice are unknown. The PREDIAPS project aims to ...assess the effectiveness and feasibility of different procedures to perform a facilitated interprofessional collaborative process to optimize type 2 diabetes prevention in routine primary care.
Methods
A type II hybrid cluster randomized implementation trial was conducted in nine primary care centers of the Basque Health Service. All centers received training on effective healthy lifestyle promotion. Headed by a local leader and an external facilitator, centers conducted a collaborative structured process—the PVS-PREDIAPS implementation strategy—to adapt the intervention and its implementation to their specific context. The centers were randomly allocated to one of two groups: one group applied the implementation strategy globally, promoting the cooperation of all health professionals from the beginning, and the other performed it sequentially, centered first on nurses, who later sought the pragmatic cooperation of physicians. The following patients were eligible for inclusion: all those aged ≥ 30 years old with at least one known cardiovascular risk factor and an impaired fasting glucose level (≥ 110-125 mg/dl) but without diabetes who attended centers during the study period. The main outcome measures concerned changes in type 2 diabetes prevention practice indicators after 12 months.
Results
After 12 months, 3273 eligible patients at risk of type 2 diabetes had attended their family physician at least once, and of these, 490 (15%) have been addressed by assessing their healthy lifestyles in both comparison groups. The proportion of at-risk patients receiving a personalized prescription of lifestyle change was slightly higher (8.6%; range 13.5-5.9% vs 6.8%; range 7.2-5.8%) and 2.3 times more likely (95% CI for adjusted hazard ratio, 1.38-3.94) in the sequential than in the global centers, after 8 months of the intervention program implementation period. The probability of meeting the recommended levels of physical activity and fruit and vegetable intake were four- and threefold higher after the prescription of lifestyle change than only assessment and provision of advice. The procedure of engagement in and execution of the implementation strategy does not modify the effect of prescribing healthy habits (p interaction component of intervention by group, p > 0.05).
Discussion
Our results show that the PVS-PREDIAPS implementation strategy manages to integrate interventions with proven efficacy in the prevention of type 2 diabetes in clinical practice in primary care. Further, they suggest that implementation outcomes were somewhat better with a sequential facilitated collaborative process focused on enhancing the autonomy and responsibility of nurses who subsequently seek a pragmatic cooperation of GPs.
Trial registration
Clinicaltrials.gov identifier:
NCT03254979
. Registered 16 August 2017—retrospectively registered.
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