Context Chronic psychological distress has deleterious effects on many of the body’s physiological systems. In experimental animal models, chronic stress leads to neuroanatomic changes in the hippocampus, in particular a decrease in the length and branching of dendrites as well as a decrease in the number of dendritic spines. Objectives To examine whether analogous distress-related neuroanatomic changes occur in humans and whether such changes might also be related to cognitive dysfunction observed in older people who report greater psychological distress. Design Postmortem study of brain tissues from participants of the Religious Orders Study, an ongoing population-based clinicopathological study of aging and cognition. Setting The Rush University Religious Orders Study and the University of Pennsylvania Cellular and Molecular Neuropathology Program. Participants Seventy-two deceased participants of the Religious Orders Study. Main Outcome Measures Densities of microtubule-associated protein 2–immunolabeled dendrites and synaptopodin-immunolabeled dendritic spines in the CA3 subfield of the hippocampus, quantified using semiautomated image acquisition and analysis. Results Higher levels of trait anxiety and longitudinal depression scores were associated with decreased densities of dendrites and spines in CA3. Dendrite and spine densities did not correlate with an index of global cognition or with densities of common age-related pathological changes. Conclusions Regressive neuronal changes occur in humans who experience greater psychological distress. These changes are analogous to neuronal changes in animal models of chronic stress.

Background and Purpose: We sought to determine if biomarkers of inflammation and coagulation can help define coronavirus disease 2019 (COVID-19)–associated ischemic stroke as a novel acute ischemic stroke (AIS) subtype. Methods: We performed a machine learning cluster analysis of common biomarkers in patients admitted with severe acute respiratory syndrome coronavirus 2 to determine if any were associated with AIS. Findings were validated using aggregate data from 3 large healthcare systems. Results: Clustering grouped 2908 unique patient encounters into 4 unique biomarker phenotypes based on levels of c-reactive protein, D-dimer, lactate dehydrogenase, white blood cell count, and partial thromboplastin time. The most severe cluster phenotype had the highest prevalence of AIS (3.6%, P <0.001), in-hospital AIS (53%, P <0.002), severe AIS (31%, P =0.004), and cryptogenic AIS (73%, P <0.001). D-dimer was the only biomarker independently associated with prevalent AIS with quartile 4 having an 8-fold higher risk of AIS compared to quartile 1 ( P =0.005), a finding that was further corroborated in a separate cohort of 157 patients hospitalized with COVID-19 and AIS. Conclusions: COVID-19–associated ischemic stroke may be related to COVID-19 illness severity and associated coagulopathy as defined by increasing D-dimer burden.

We present a radiology-pathology case series of 3 patients with coronavirus disease 2019 (COVID-19) with acute ischemic stroke due to fulminant carotid thrombosis overlying mild atherosclerotic plaque and propose a novel stroke mechanism: COVID-associated carotid atherothrombosis. ABBREVIATIONS: ACE2 ¼ angiotensin-converting enzyme 2; CCA ¼ common carotid artery; COVID-19 ¼ coronavirus disease 2019; RT-PCR ¼ reverse-transcriptase polymerase chain reaction; SARS-CoV-2 ¼ Severe Acute Respiratory Syndrome coronavirus 2

Introduction: While coronavirus disease 2019 (COVID-19) has been associated with acute ischemic stroke (AIS), the causal relationship has yet to be elucidated. Factors that likely confer increased stroke risk are COVID-19-associated coagulopathy and hyperinflammatory response. Studying clinical features of patients with otherwise undetermined cause of AIS could help better define COVID-19-associated stroke. Methods: We performed a multicenter cross-sectional study of consecutive patients presenting with AIS and COVID-19 to one of two large healthcare systems in New York City during the local COVID-19 surge from March 1, 2020 to May 31, 2020. In-hospital stroke cases were excluded. We compared demographic and clinical features of patients with COVID-19 and a cryptogenic AIS subtype to patients with COVID-19 and a determined subtype. Baseline characteristics and clinical variables were compared using chi-squared and Fisher exact tests. Results: A total of 62 patients with AIS and COVID-19 at the time of hospital arrival were identified. Of these, 30 were classified as having a cryptogenic subtype (80% after complete diagnotics evaluation), and 32 had an identifiable stroke mechanism. Patients with cryptogenic AIS were significantly younger (p=0.011) and less likely to have co-morbid hypertension (p=0.019), coronary artery disease (p=0.024), heart failure (p=0.039), atrial fibrillation (<0.0001), and prior stroke or TIA (p=0.033) compared to those with defined mechanisms. Further, d-dimer, but not C-reactive protein, was significantly higher in patients with cryptogenic stroke compared to those with defined causes (p=0.009). Conclusion: Patients with AIS in the setting of COVID-19 and no other determined stroke mechanism were younger, less likely to have classic risk factors, and had higher d-dimer levels when compared to those with a determined mechanism. Further study of COVID-19-associated hypercoagulability as a mechanism of stroke is warranted.

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