Cell autonomous microglia defects in a stem cell model of frontotemporal dementia.

Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the MAPT IVS10+16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that MAPT IVS10+16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from MAPT IVS10+16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed in vitro were recapitulated in human brain tissue and cerebrospinal fluid from MAPT mutations carriers. Together, our findings that MAPT IVS10+16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutic strategies.

Mapping consent practices for outpatient psychiatric use of ketamine.

BACKGROUND: Given increasing community-based and off-label use of ketamine for psychiatric indications, we examined current informed consent processes from a convenience sample of outpatient ketamine clinics to identify areas of congruence with current evidence and opportunities for growth. METHODS: Using a rubric developed from existing practice guidelines, we conducted an exploratory analysis of informed consent documents (IC-Docs) from 23 American clinics offering ketamine as a psychiatric treatment. Domains assessed included clinical content, procedures, and syntax. RESULTS: Participating clinics (23/288) varied widely in their constitution, training, and services provided. We found that IC-Docs addressed a majority of consent elements, though did so variably on an item-level. Areas for improvement included communication around long-term adverse effects, treatment alternatives, medical/psychiatric evaluation prior to treatment, medical/psychological support during treatment, adjunctive psychological interventions, and subjective/dissociative-type effects. All forms were limited by poor readability. LIMITATIONS: Our study was limited by convenience sampling along with possible underestimation of verbal consent processes. CONCLUSIONS: As ketamine continues to emerge as a psychiatric intervention, both patients and providers will benefit from a deliberate consent process informed by scientific, ethical, and pragmatic factors toward the goal of shared decision-making regarding treatment.

National Institutes of Mental Health Data Archive: Privacy, Consent, and Diversity Considerations and Options for Improvement.

Data sharing is essential to further advance the field of neuropsychiatry. However, it raises significant ethical issues in the domains of privacy, consent, and diversity. We begin by considering the sensitive nature of much neuropsychiatric data. Next, we review relevant policies of the National Institutes of Mental Health (NIMH), a prominent funder in this field. Because data sharing in neuropsychiatry is in its infancy and rapidly evolving, the NIMH policies serve as a helpful starting point for examining ethical considerations related to the collection and distribution of neuropsychiatric data. However, we find gaps in their guidance in each of the three key ethical domains. Finally, we illustrate how examination of lessons and strategies from other contexts where sustained attention has already been given to these ethical issues may add value by suggesting specific opportunities for improvement. In particular, we highlight approaches including a three-tiered data access scheme, use of technology to enhance the data sharing component of the informed consent process, and evidence-based, targeted recruitment of underrepresented populations to support diverse data resources. Assessment of current policy and potentially helpful innovations in other fields is a necessary step in moving the field forward in an ethically responsible manner.

Loss of Quaking RNA binding protein disrupts the expression of genes associated with astrocyte maturation in mouse brain.

Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3'UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation.

Relevance of ANCA positivity at the time of renal transplantation in ANCA associated vasculitis.

BACKGROUND: Renal transplantation (RTx) is the modality of choice for ESRD due to ANCA associated vasculitis (AAV). The significance of ANCA positivity (ANCA+) at the time of RTx on recurrent disease is controversial. METHODS: We evaluated clinical outcomes and predictors of vasculitis relapse in sixteen transplanted AAV patients who were ANCA+ at RTx at a single University Medical Center. Allograft function, vasculitis relapse, and predictors of vasculitis relapse were assessed using descriptive statistics and logistic regression analysis. RESULTS: Our cohort had a median age of 64 years, 88 % Caucasians, 63 % males, 50 % PR3+. All patients were in remission at the time of RTx. Twelve received induction therapy and all were on mycophenolate mofetil, prednisone and tacrolimus. The mean (SD) serum creatinine was 1.2 (0.3) mg/dl at 1 year and 1.8 (1.7) mg/dl at last follow up. Six developed vasculitis relapse at post-transplant. All relapses were treated with escalation in immunosuppression. One non-compliant patient suffered graft loss while the remaining patients achieved remission. In adjusted logistic regression analysis, PR3 ANCA+ patients were two times (OR 2.19, p = 0.71) more likely to experience a relapse compared to MPO ANCA+ patients. CONCLUSIONS: This study demonstrates that PR3 ANCA+ patients may be more likely to experience relapse post-transplant. Further investigation of the predictors of vasculitis relapse among AAV patients who are ANCA+ at the time of RTx needs to be pursued.

Dapsone induced hemolysis in a patient with ANCA associated glomerulonephritis and normal G6PD level and implications for clinical practice: case report and review of the literature.

Dapsone is a commonly used second line drug for prophylaxis of pneumocystis jirovecii pneumonia (PJP) in immunocompromised patients. Oxidant hemolysis, caused by dapsone's metabolite hydroxylamine, is a common side effect, and screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency is recommended before the drug is started in order to prevent potential hemolytic reactions. We report a case of dapsone induced hemolytic anemia in a patient with ANCA associated glomerulonephritis and normal G6PD level. Her anemia improved after cessation of therapy with dapsone. We review the literature of dapsone induced hemolysis in patients who have normal G6PD level and discuss potential pathways leading to hemolytic anemia and its implications for clinical practice.