Download: Paranoid Thinking as a Function of Minority Group Status and Intersectionality: An International Examination of the Role of Negative Beliefs –

Using cross-sectional, survey design, with a large (n = 2510) international sample, moderation analyses (PROCESS) examined whether self and other beliefs, and perceived social rank, operate similarly or differently in minority vs majority group participants. Specifically, we tested whether beliefs moderated the influence of minority group, and intersecting aspects of difference, on paranoia.

Paranoia was consistently higher in participants from minority vs majority groups and level of paranoid thinking was significantly higher at each level of the intersectionality index. Negative self/other beliefs were associated with elevated paranoia in all participants. However, in support of the notion of healthy cultural mistrust, low social rank, and low positive self/other beliefs were significantly associated with paranoia in majority group participants but unrelated to paranoia in respective minority group members.

Although mixed, our findings signal the need to consider healthy cultural mistrust when examining paranoia in minority groups and bring into question whether “paranoia” accurately describes the experiences of marginalized individuals, at least at low levels of severity. Further research on paranoia in minority groups is crucial to developing culturally appropriate ways of understanding people’s experiences in the context of victimization, discrimination, and difference.

minority group; negative beliefs; paranoia; positive beliefs; social rank.

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Download: Self-reported Gesture Interpretation and Performance Deficits in Individuals at Clinical High Risk for Psychosis –

This study examined self-reported gesture interpretation (SRGI) and performance (SRGP) in those at clinical high risk for psychosis (CHR; N = 88), those with internalizing disorders (INT; N = 51), and healthy controls (HC; N = 53). Participants completed questionnaires, clinical interviews, and neurocognitive tasks.

Results indicated that the CHR group was characterized by significantly lower SRGI scores than the HC or INT groups (d = 0.41); there were no differences among groups in SRGP. Within CHR participants, greater deficits in SRGP were associated with lower verbal learning and memory (r = -.33), but not general intelligence or processing speed. Furthermore, gesture deficits were associated with higher cross-sectional risk for conversion to a full psychotic disorder in the CHR group.

Overall, these findings suggest that specific subdomains of gesture may reflect unique vulnerability for psychosis, self-report may be a viable assessment tool in understanding these phenomena, and gesture dysfunction may signal risk for transition to psychosis.

CHR; cognition; gesture; prodrome; working memory.

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Download: Evolutionarily conserved regulators of tau identify targets for new therapies – PubMed

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.

RNF130; RNF149; USP7; genetic screens; modifier; neurodegeneration; tau levels; ubiquitination.

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Download: Dorsomedial prefrontal hypoexcitability underlies lost empathy in frontotemporal dementia – PubMed

Empathic function is essential for the well-being of social species. Empathy loss is associated with various brain disorders and represents arguably the most distressing feature of frontotemporal dementia (FTD), a leading form of presenile dementia. The neural mechanisms are unknown. We established an FTD mouse model deficient in empathy and observed that aged somatic transgenic mice expressing GGGGCC repeat expansions in C9orf72, a common genetic cause of FTD, exhibited blunted affect sharing and failed to console distressed conspecifics by affiliative contact. Distress-induced consoling behavior activated the dorsomedial prefrontal cortex (dmPFC), which developed profound pyramidal neuron hypoexcitability in aged mutant mice. Optogenetic dmPFC inhibition attenuated affect sharing and other-directed consolation in wild-type mice, whereas chemogenetically enhancing dmPFC excitability rescued empathy deficits in mutant mice, even at advanced ages when substantial cortical atrophy had occurred. These results establish cortical hypoexcitability as a pathophysiological basis of empathy loss in FTD and suggest a therapeutic strategy.

C9orf72; affiliative behavior; behavioral variant FTD; consolation; dorsomedial prefrontal cortex; empathy; frontotemporal dementia; hypoexcitability; observational fear.

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Download: Neurodegeneration cell per cell – PubMed

The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical symptomatology are themselves preceded by clinically mostly silent, slowly progressing multicellular processes that trigger or are triggered by the accumulation of abnormally folded proteins such as Aβ, Tau, TDP-43, and α-synuclein, among others. Methodological advances in single-cell omics, combined with complex genetics and novel ways to model complex cellular interactions using induced pluripotent stem (iPS) cells, make it possible to analyze the early cellular phase of neurodegenerative disorders. This will revolutionize the way we study those diseases and will translate into novel diagnostics and cell-specific therapeutic targets, stopping these disorders in their early track before they cause difficult-to-reverse damage to the brain.

Alzheimer’s disease; Parkinson’s disease; neurodegeneration; single-cell sequencing.

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Download: Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management – PubMed

Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.

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Download: EMBER multidimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains – PubMed

In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains in vitro, as well as amyloid-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ and tau deposits from Down syndrome, sporadic and familial Alzheimer’s disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick’s disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.

conformational strain; fluorescent excitation/emission; machine learning; neurodegenerative diseases; proteins fold.

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Download: Benefits of the PRISM Shelter-Based Program for Attainment of Stable Housing and Functional Outcomes by People Experiencing Homelessness and Mental Illness: A Quantitative Analysis –

Housing status, psychiatric follow-up trajectory, personal recovery (Canadian Personal Recovery Outcome Measure), functional level (Multnomah Community Ability Scale), and quality of life (Lehman Quality of Life Interview) were assessed at program entry, at program discharge and 1 year later.

Of the 50 clients who participated in the study from May 31, 2018, to December 31, 2019, 43 completed the program. Of these, 76.7% were discharged to housing modalities and 78% were engaged with psychiatric follow-up at the program’s end. Housing stability, defined as residing at the same permanent address since discharge, was achieved for 62.5% of participants at 1-year follow-up. Functional level and quality of life scores improved significantly both at discharge and at 1-year follow-up from baseline.

Admission to PRISM helped clients secure long-term stable housing and appropriate psychiatric follow-up. Stable housing was maintained for most clients at 1-year follow-up, and they benefited from sustained functional and quality of life outcomes in long-term follow-up.

emergency shelter; homeless persons; housing; mental disorders; mental health services; quality of life.; severe; urban health services.

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Download: Socioenvironmental Adversity and Adolescent Psychotic Experiences: Exploring Potential Mechanisms in a UK Longitudinal Cohort –

Data were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994-1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences.

Higher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses.

Cognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.

disadvantage; intelligence; mediation; neighborhood; psychosis; urban.

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Download: Healthy choices, healthy changes: A randomized trial of incentives to promote healthy eating and exercise in people with schizophrenia and other serious mental illnesses –

From 2012 to 2015, 1348 overweight or obese adults with SMI enrolled in a study using equipoise stratified randomization. Participants were randomly assigned to intervention, then to cash incentives, or not, for participation (gym and/or Weight Watchers), with baseline and quarterly assessments for 12 months. We examined effects of the interventions, key covariates, and incentives, using generalized linear models.

Main effects of randomization to receive cash incentives was not significant for any outcome; whereas total amount of incentives was significantly associated with all three primary outcomes (weight loss, cardiovascular endurance, mortality risk), mainly for participants in the InSHAPE+WW group who received additional cash incentives.

Incentives may be effective at preventing CVD and improving health outcomes for people with SMI, especially in the context of intensive support for healthy lifestyle behaviors. Policy changes are required to increase access to healthy lifestyle programming and more research is needed to establish the optimal amount of incentives for people with SMI.

ClinicalTrials.gov identifier: NCT02515981.

Fitness; Healthy lifestyle; Incentives; Schizophrenia; Weight management.

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