Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and nonpsychiatric comparison participants.

STUDY OBJECTIVES: People living with schizophrenia (PLWS) have increased physical comorbidities and premature mortality which may be linked to dysregulated rest-activity rhythms (RARs). This study aimed to compare RARs between PLWS and nonpsychiatric comparison participants (NCs) and to examine the relationships of RARs with age, sleep, metabolic, and physical health outcomes and, among PLWS, relationships of RARs with illness-related factors. METHODS: The study sample included 26 PLWS and 36 NCs, assessed with wrist-worn actigraphy to compute RAR variables and general sleep variables. Participants completed assessments for clinical symptoms, physical health, sleep quality, medication use, and assays for fasting glycosylated hemoglobin (hemoglobin A1c) levels. We examined group differences in RAR and sleep variables, relationships of RAR variables with metabolic and physical health measures, and, among PLWS, relationships between RAR variables and illness-related measures. RESULTS: PLWS had significantly shorter active periods, lower relative amplitude, and lower mean activity during their most active 10 hours compared to the NCs (Cohen's d = 0.79, 0.58, and 0.62, respectively). PLWS had poorer sleep quality, greater mean percent sleep, less wake after sleep onset, and higher total sleep time variability compared to NCs. PLWS had higher rates of antidepressant, anxiolytic, and antipsychotic medication use compared to NCs, which may have impacted sleep quality and objective sleep measures. Across both groups, more fragmented and variable RARs were associated with higher HbA1c levels (ηp2 = .10) and worse physical health (ηp2 = .21). Among PLWS, RARs were correlated with total sleep time (rs = .789, P < .01) and percent sleep (rs = .509, P < .05), but not with age, sleep quality, or other illness-related factors. CONCLUSIONS: RARs provide unique information about sleep and activity for PLWS and have the potential for targeted interventions to improve metabolic health and mortality. CITATION: Mahmood Z, Ramsey A, Kidambi N, et al. Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and nonpsychiatric comparison participants. J Clin Sleep Med. 2024;20(9):1505-1516.

Self-compassion, but not compassion toward others, is associated with better physical health: A cross-sectional study.

Compassion is a modifiable construct that is associated with better physical health outcomes but, to our knowledge, has seldom been studied in people with schizophrenia (PwS) despite its applicability to counteract widespread depression in this community that might prevent positive health behaviors. We hypothesized that, compared to non-psychiatric comparison subjects (NCs), PwS would have lower compassion toward self (CTS), lower compassion toward others (CTO), and a positive association between compassion and health outcomes, such as physical wellbeing, comorbidities, and plasma hs-CRP. This cross-sectional study examined differences in physical health, CTS, and CTO in 189 PwS and 166 NCs. We used general linear models to analyze the relationship between compassion and health. As hypothesized, PwS had lower levels of CTS and CTO, worse physical well-being, more comorbidities, and higher levels of plasma hs-CRP than NCs. In the combined sample, higher CTS was significantly associated with better physical well-being and fewer comorbidities, while higher CTO was significantly associated with more comorbidities. In PwS alone, higher CTS was significantly associated with better physical well-being and lower levels of hs-CRP. CTS seemed to have a larger positive association with physical health than CTO, with depression acting as a potential mediator for CTS. Exploring effects of CTS interventions on physical health and health behaviors could be a promising next step.

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.

Plastin 3 rescues BDNF-TrkB signaling in spinal muscular atrophy.

In this issue, Hennlein and colleagues (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202204113) show that F-actin-bundling protein Plastin 3 is drastically reduced in motor neurons with spinal muscular atrophy, whereas virus-mediated overexpression of Plastin 3 restores actin cytoskeleton and promotes BDNF-TrkB signaling in the growth cones of spinal motor neurons.

Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations.

Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN.