https://www.pnas.org/topic/558

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Abstract

Background: Tbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density. However, an understanding of Tbr1’s function in the adult mouse brain remains elusive.

Methods: We used conditional mutagenesis to interrogate Tbr1’s function in cortical layers 5 and 6 of the adult mouse cortex.

Results: Adult Tbr1 CKO mutants have dendritic spine and synaptic deficits as well as reduced frequency of mEPSCs and mIPSCs. LiCl, a WNT signaling agonist, robustly rescues the dendritic spine maturation, synaptic defects, and excitatory and inhibitory synaptic transmission deficits.

Conclusions: LiCl treatment could be used as a therapeutic approach for some cases of ASD with deficits in synaptic transmission.

Fazel Darbandi S, Nelson AD, Pai EL, Bender KJ, Rubenstein JLR. LiCl treatment leads to long-term restoration of spine maturation and synaptogenesis in adult Tbr1 mutants. J Neurodev Disord. 2022 Feb 5;14(1):11. doi: 10.1186/s11689-022-09421-5. PMID: 35123407; PMCID: PMC8903688.

https://pubmed.ncbi.nlm.nih.gov/35123407/

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Abstract: Sigma-1 receptor (SIG1R) is a chaperone that modulates inositol 1,4,5-trisphosphate receptor type1 (IP3R1) calcium (Ca2+) channels on the endoplasmic reticulum. Therefore, SIG1R functions as an indirect regulator of Ca2+ and acts as an apoptosis modulator. Increased expression of SIG1R is associated with poor prognosis in breast cancers (BC), and SIG1R antagonists like BD1047 induce apoptosis. As a heavy metal, cadmium (Cd2+) is competitive with Ca2+ due to its physicochemical similarities and may trigger apoptosis at low concentrations. Our study investigated the SIG1R protein expression in 74 BC patients and found a significant increase in SIG1R expression in the triple-negative BC subtype. We also examined the apoptotic and anti-cancer effects of BD1047 in combination with CdCl2 in MCF7 and MDA-MB-213 cells. Cells were treated with CdCl2 at doses of 1 μM, 25 μM, and 50 μM, along with BD1047. Higher doses of CdCl2 were cytotoxic on both cancer cells and significantly increased DNA breaks. However, low-dose CdCl2 with BD1047 increased cell death and the apoptotic index in BC cells, although it did not exhibit cytotoxic effects on HUVEC cells. Co-administration of low-dose CdCl2 with BD1047 also reduced the migration and colony-forming ability of BC cells. Moreover, the expression of SIG1R protein in these groups decreased significantly compared to groups treated with BD1047 or low-dose CdCl2 alone. In conclusion, low-dose CdCl2 is thought to increase the apoptotic ability of BD1047 in BC cells by reducing SIG1R expression.

 

Yıldız B, Demirel R, Havadar HB, Yıldız G, Öziç C, Kamiloğlu NN, Özden Ö. Blocking SIG1R Along with Low Cadmium Exposure Display Anti-cancer Qualities in Both MCF7 and MDA-MB-231 Cells. Biol Trace Elem Res. 2023 Nov 9. doi: 10.1007/s12011-023-03947-y. Epub ahead of print. PMID: 37940833.

https://pubmed.ncbi.nlm.nih.gov/37940833/

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Abstract

Importance: Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested.

Objective: To examine the association between adult ADHD and the risk of dementia.

Design, setting, and participants: This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023.

Exposure: Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent.

Main outcome and measures: Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented.

Results: At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild.

Conclusions and relevance: In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.

Levine SZ, Rotstein A, Kodesh A, Sandin S, Lee BK, Weinstein G, Schnaider Beeri M, Reichenberg A. Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia. JAMA Netw Open. 2023 Oct 2;6(10):e2338088. doi: 10.1001/jamanetworkopen.2023.38088. PMID: 37847497; PMCID: PMC10582792.

https://pubmed.ncbi.nlm.nih.gov/37847497/

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Abstract: Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission. As such, it represents a druggable target to treat neuropathic pain. This study aims at investigating the therapeutic potential of the novel compound (+)-2R/S-LP2, a σ1R antagonist, in reducing painful behaviour and modulating the neuroinflammatory environment. We showed that repeated administration of the compound significantly inhibited mechanical allodynia in neuropathic rats, increasing the withdrawal threshold as compared to CCI-vehicle rats. Moreover, we found that (+)-2R/S-LP2-mediated effects resolve the neuroinflammatory microenvironment by reducing central gliosis and pro-inflammatory cytokines expression levels. This effect was coupled with a significant reduction of connexin 43 (Cx43) expression levels and gap junctions/hemichannels mediated microglia-to-astrocyte communication. These results suggest that inhibition of σ1R significantly attenuates neuropathic pain chronicization, thus representing a viable effective strategy.

Denaro S, Pasquinucci L, Turnaturi R, Alberghina C, Longhitano L, Giallongo S, Costanzo G, Spoto S, Grasso M, Zappalà A, Li Volti G, Tibullo D, Vicario N, Parenti R, Parenti C. Sigma-1 Receptor Inhibition Reduces Mechanical Allodynia and Modulate Neuroinflammation in Chronic Neuropathic Pain. Mol Neurobiol. 2023 Nov 3. doi: 10.1007/s12035-023-03717-w. Epub ahead of print. PMID: 37922065.

https://pubmed.ncbi.nlm.nih.gov/37922065/

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Summary

Background

There is a paucity of data on the natural trajectory of outcomes in survivors of COVID-19 beyond 2 years after symptom onset, and no evidence exists on the effect of re-infection in people with long COVID symptoms. We aimed to investigate the 3-year health outcomes of COVID-19 survivors and the effect of omicron re-infection.

Methods

In this single-centre, longitudinal cohort study, we recruited participants with confirmed COVID-19 who were discharged from the Jin Yin-tan hospital in Wuhan, China, between Jan 7 and May 29, 2020. Participants completed three follow-up visits at 6 months (June 16 to Sept 13, 2020), 1 year (Dec 16, 2020, to Feb 7, 2021), and 2 years (Nov 16, 2021, to Jan 10, 2022) since symptom onset (reported previously). At 1-year follow-up, community controls without a history of SARS-CoV-2 infection were recruited from two communities in Wuhan and at 2 years were matched (1:1) with survivors of COVID-19 who underwent pulmonary function tests. We did a 3-year follow-up from Feb 23, 2023, to April 20, 2023, after the omicron (B.1.1.529) wave in winter, 2022. All eligible survivors of COVID-19 and community controls matched at 2-year follow-up were invited to the outpatient clinic at the hospital to complete several face-to-face questionnaires, a 6-min walking test (6MWT), and laboratory tests. A subgroup of survivors of COVID-19 identified by stratified sampling on the basis of disease severity scale score during hospitalisation and community controls underwent pulmonary function tests. Survivors of COVID-19 who received high-resolution CT and showed abnormal lung images at 2-year follow-up were invited for another assessment. We identified participants with and without long COVID at 2 years. The primary outcomes were sequelae symptoms, omicron infection, lung function, and chest imaging at the 3-year follow-up.

Findings

Of 1359 COVID-19 survivors who completed 2-year and 3-year follow-up, 728 (54%) had at least one sequelae symptom at 3 years after symptom onset and before omicron infection, mainly mild to moderate severity. During the omicron wave, participants with long COVID at 2 years had a significantly higher proportion of re-infection (573 [76%] of 753 vs 409 [67%] of 606 without long COVID; p=0·0004), pneumonia (27 [5%] of 568 vs seven [2%] of 403; p=0·012). 3 months after omicron infection, 126 (62%) of 204 survivors with long COVID at 2 years had newly occurring or worse symptoms, which was significantly higher than the proportion in the non-long COVID group (85 [41%] of 205; p<0·0001) and community controls (81 [40%] of 205; p<0·0001), and not significantly different between COVID-19 survivors without long COVID and matched community controls (85 [41%] of 205 vs 81 [39%] of 206; p=0·66). Re-infection was a risk factor for dyspnoea (odds ratio 1·36 [95% CI 1·04 to 1·77]; p=0·023), anxiety or depression (OR 1·65 [1·24 to 2·20]; p=0·0007), EuroQol visual analogue scale score (β –4·51 [–6·08 to –2·95]; p<0·0001), but not for reduced daily activity (0·72 [0·38 to 1·37]; p=0·32) at 3 years. Lung function of survivors at 3 years was similar to that of matched community controls. We found irregular line, traction bronchiectasis, subpleural lines and ground glass opacity at 3 years, but the volume ratio of lung lesion to total lung was only 0·2–0·3%.

Interpretation

Most long COVID symptoms at 3 years were mild to moderate, with lung function recovering to levels of matched controls. Survivors with long COVID had a higher proportion of participants with re-infection and newly occurring or worse symptoms 3 months after omicron infection than those without long COVID. Re-infection had increased symptom occurrence but not increased reduced daily activity. Although the organ function of survivors of COVID-19 recovered over time, those with severe long COVID symptoms, abnormal organ function, or limited mobility require urgent attention in future clinical practice and research.
Zhang H et al., 3-year outcomes of discharged survivors of COVID-19 following the SARS-CoV-2 omicron (B.1.1.529) wave in 2022 in China: a longitudinal cohort study. Lancet Respiratory Medicine  (publ. Nov.21,2023) DOI: https://doi.org/10.1016/S2213-2600(23)00387-9

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00387-9/fulltext

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https://www.societyforscience.org/isef/forms/

 

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https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00005-5

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Abstract:

Objective:

Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge.

Methods:

Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci.

Results:

Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells.

Conclusions:

These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidi

https://doi.org/10.1176/appi.ajp.20220660

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.20220660

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The COVID-19 pandemic has left an indelible mark on every facet of our existence. In this issue of Acta Neuropsychiatrica, we embark on a comprehensive exploration of the pandemic’s multifaceted impact, drawing on the insights gleaned from four recent research papers. These studies illuminate critical dimensions, including the pivotal role of inflammation management in shaping COVID-19 outcomes, the unexpected neurological manifestations it incites, the potential risk of obsessive-compulsive disorder (OCD), and the pandemic’s toll on the mental health of undergraduate students. Collectively, these findings offer a holistic perspective on the profound and far-reaching effects of COVID-19, providing essential guidance as we continue to navigate this global crisis.

Inflammation Management in COVID-19 Our evolving understanding of COVID-19 has brought the role of inflammation into sharp focus, as underscored by the work of Tang and coworkers (Tang et al., Reference Tang, Helmeste and Leonard2023). This research emphasises the intricate interplay of various factors in COVID-19, highlighting the host’s inflammatory response as a key determinant of disease severity, symptoms, and prognosis. Genetic factors, age, immune status, health, and disease stage all influence this inflammatory response. Effectively managing inflammation has emerged as a vital strategy for reducing morbidity and mortality across all stages of COVID-19.

OCD and Gender Disparities The pandemic’s impact extends to the realm of mental health, including a potential risk of OCD, as elucidated in a systematic review (Jalalifar et al., Reference Jalalifar, Arad, Rastkar and Beheshti2023). This analysis reveals that COVID-19 and its containment measures may heighten the risk of OCD, with females appearing particularly susceptible. Notably, under-18 students, hospital staff, and individuals in the Middle East are among the groups most affected. This insight can inform targeted support and resource allocation to address these vulnerabilities.

Psychological Suffering Among Undergraduate Students One poignant revelation is the psychological toll exacted on undergraduate students during remote learning (Silva et al., 2023). Despite a relatively low prevalence of COVID-19 fear, an alarming 83.0% of students reported symptoms of depression, and 76.1% experienced anxiety. These findings underscore the profound impact of the pandemic on the mental health of young individuals. Vulnerable groups, including female students, those in poor health, and those who lost family members to COVID-19, are particularly affected. Targeted interventions, such as physical activity programmes, hold promise for enhancing students’ well-being.

Surprising Neurological Manifestations in Post-COVID-19 Patients A fourth paper explores the unexpected neurological sequelae in post-COVID-19 patients, revealing marked impairments in fine motor skills, balance, memory, attention, and concentration (Chiminazzo and Kirsten, Reference Chiminazzo and Kirsten2023). This study challenges initial assumptions about COVID-19, which primarily targets the respiratory system. Instead, it unveils a range of neurological manifestations even among young and healthy individuals. These findings underscore the urgency of developing rehabilitation protocols to address the neurological deficits stemming from COVID-19 infection.

Collectively, these research papers offer a comprehensive view of the multifaceted and profound impact of COVID-19. From the critical role of inflammation management to potential OCD risk disparities, surprising neurological consequences, and the psychological toll on students, our understanding of this pandemic continues to evolve. As we navigate the ongoing challenges, these insights must guide our response, offering hope and evidence-based strategies to mitigate COVID-19’s extensive effects on individuals and society as a whole.

Wegener, G. (2023). Navigating the complexity of COVID-19: A multifaceted examination. Acta Neuropsychiatrica, 35(5), 247-247. doi:10.1017/neu.2023.50

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/navigating-the-complexity-of-covid19-a-multifaceted-examination/CCD0997DDCA5E1B26DEB74D974112844

 

 

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