Citations

Abstract Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnC) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivoderived senescence signature using a foreign body response (FBR) fibrosis model in a SnC reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell typespecific senescence associated secretory phenotypes (SASP). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single cell RNAseq (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34- CSF1R-TGFßR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify transcriptional profiles and SASP factors produced by SnCs that regulate tissue structure and pathology.

Abstract Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

Purpose of review Does neuroinflammation promote neurodegeneration? Does neurodegeneration promote neuroinflammation? Or, is the answer to both questions, yes? These questions have proven challenging to answer in patients with typical age-related neurodegenerative diseases in whom the onset of neuroinflammation and neurodegeneration are largely unknown. Patients recovering from diseases associated with abrupt-onset neuroinflammation, including rare forms of antibody-mediated encephalitis (AME) and common complications of novel coronavirus disease 2019 (COVID-19), provide a unique opportunity to untangle the relationship between neuroinflammation and neurodegeneration. This review explores the lessons learned from patients with AME and COVID-19. Recent findings Persistent cognitive impairment is increasingly recognized in patients recovering from AME or COVID-19, yet the drivers of impairment remain largely unknown. Clinical observations, neuroimaging and biofluid biomarkers, and pathological studies imply a link between the severity of acute neuroinflammation, subsequent neurodegeneration, and disease-associated morbidity. Summary Data from patients with AME and COVID-19 inform key hypotheses that may be evaluated through future studies incorporating longitudinal biomarkers of neuroinflammation and neurodegeneration in larger numbers of recovering patients. The results of these studies may inform the contributors to cognitive impairment in patients with AME and COVID-19, with potential diagnostic and therapeutic applications in patients with age-related neurodegenerative diseases.

AbstractObjectivesTo assess and compare the associations between socioeconomic status (SES) measures from two sources (claims vs. survey data) and the type of post‐acute care (PAC) locations following hospital discharge.MethodsThis observational study included Medicare Fee‐for‐Service (FFS) beneficiaries age 65.5 years or older who participated in the Medicare Current Beneficiary Survey (MCBS) and were hospitalized in 2006–2011. Multiple data sets were used including: Area Deprivation Index; Medicare Cost Reports, Provider of Services files, and Area Health Resource File. Multinomial regression models estimated associations between beneficiary's SES and PAC type. SES measures came from surveys (income and education) and administrative records (dual enrollment and area deprivation). PAC types included home with self‐care, home health agency, skilled nursing facility (SNF), or inpatient rehabilitation facility.ResultsLow income and dual enrollment were associated with higher SNF use while living in a deprived area was associated with lower SNF use and higher use of home with self‐care. Dual enrollment and area deprivation were associated with the largest differences.ConclusionsIf policies to modify payment based on SES are considered, administrative measures (dual enrollment and area deprivation) rather than survey measures (education and income) may be sufficient.

Abstract Aims Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF. Methods and results Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator‐dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume (‘euvolaemia’) (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e′ velocity, r = −0.44), and left atrial strain (r = −0.47). In multivariable regression TBV, left ventricular e′, and left atrial strain were independently associated with PCWP (all P < 0.05). Conclusions While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

Abstract Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.

Aim Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. Methods A “two-hit” hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone, a transient receptor potential ankyrin 1 (TRPA1) activator, in uninjured female and male C57BL/6 mice. Priming (i.e. the first hit) was induced by three consecutive daily episodes of restraint stress; repeated umbellulone was also evaluated for potential priming effects. Sixteen days after the first restraint stress, mice received inhalational umbellulone (i.e. the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1 B/D agonist), as well as olcegepant, an experimental calcitonin gene related peptide (CGRP) receptor antagonist and nor-Binaltorphimine (nor-BNI), an experimental long-acting kappa opioid receptor (KOR) antagonist, were investigated for their efficacy to block priming and prevent or reverse umbellulone-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia was determined by responses to periorbital or hindpaw probing with von Frey filaments. Results Repeated restraint stress, but not umbellulone exposure, produced transient cutaneous allodynia that resolved within 16 d. Restraint stress produced long-lasting priming that persisted beyond 16 d, as demonstrated by reinstatement of cutaneous allodynia following inhalational umbellulone challenge. Pretreatment with propranolol or nor-BNI prior to restraint stress prevented both transient cutaneous allodynia and priming, demonstrated by a lack of umbellulone-induced cutaneous allodynia. Following establishment of restraint stress priming, olcegepant, but not propranolol or nor-BNI, prevented umbellulone-induced cutaneous allodynia. When administered 1 h after umbellulone, sumatriptan, but not olcegepant, reversed umbellulone-induced cutaneous allodynia in restraint stress-primed rats. Conclusion We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. Restraint stress priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as “latent sensitization”. The development of latent sensitization could be prevented by blockade of stress pathways with propranolol or with a kappa opioid receptor antagonist. Following establishment of latent sensitization, subthreshold stimulation with umbellulone reinstated cutaneous allodynia, likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in restraint stress-primed animals, sumatriptan reversed umbellulone-induced cutaneous allodynia, supporting peripheral sites of action, while propranolol and nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with latent sensitization when given prior to, but not after, umbellulone challenge, suggesting time-dependent contributions of calcitonin gene-related peptide receptor signaling in promoting migraine-like pain in this model. Activation of the calcitonin gene-related peptide receptor participates in initiating, but has a more limited role in maintaining, pain responses, supporting the efficacy of small molecule calcitonin gene-related peptide antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-calcitonin gene-related peptide receptor-mediated nociceptive mechanisms. Kappa opioid receptor antagonists may represent a novel preventive therapy for stress-related migraine.