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Macrophages are important players for the maintenance of tissue homeostasis(1). Perivascular and leptomeningeal macrophages reside in close proximity to the central nervous system (CNS) parenchyma(2), and their role in CNS physiology has not been well enough studied to date. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here, we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs expressing high levels of CD163 and Lyve1 (scavenger receptor proteins), located in close proximity to the brain arterial tree, and show that Lyve1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces hence impairing CNS perfusion and clearance. Aging-associated alterations in PBMs and impairment of CSF dynamics were restored upon intracisternal injection of macrophage colony-stimulating growth factor (M-CSF). Human single-nuclei RNA sequencing data obtained from Alzheimer’s disease (AD) patients and healthy controls point to changes in phagocytosis/endocytosis and interferon-gamma (IFNγ) signaling on PBMs, pathways that are corroborated in a mouse AD model. Collectively, our results identify PBMs as novel cellular regulators of CSF flow dynamics, which could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and AD.

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Background Coronavirus disease 2019 (COVID-19) has infected more than 4.4 million people and caused more than 300,000 deaths partly through acute respiratory distress syndrome with propensity to affect African American and Hispanic communities disproportionately. Patients with worse outcomes have exhibited higher blood plasma levels of proinflammatory cytokines. Activation of the vitamin D receptor expressed on immune cells has been shown to directly reduce the secretion of inflammatory cytokines, such as interleukin-6, and indirectly affect C-reactive protein. Areas of uncertainty The significance of the vitamin D pathway in patients diagnosed with COVID-19. Therapeutic innovation Vitamin D supplementation in patients after diagnosis of COVID-19. Patients and pharmacological interventions We report 4 vitamin D deficient patients diagnosed with COVID-19 in April 2020 who were provided with either cholecalciferol of 1000 IU daily (standard dose) or ergocalciferol 50,000 IU daily for 5 days (high dose) as part of supplementation. Clinical outcomes Patients that received a high dose of vitamin D supplementation achieved normalization of vitamin D levels and improved clinical recovery evidenced by shorter lengths of stay, lower oxygen requirements, and a reduction in inflammatory marker status. Conclusions Vitamin D supplementation may serve as a viable alternative for curtailing acute respiratory distress syndrome in patients in underserved communities where resources to expensive and sought-after medications may be scarce. Randomized clinical trials will serve as an appropriate vessel to validate the efficacy of the therapeutic regimen and dissection of the pathway.

The inefficiencies in the healthcare supply chain are well documented, with a 2001 study stating that lack of data synchronization and visibility in purchasing data results in considerable errors and rework. A 1996 report also identified billions of dollars in potential savings through process improvements.

Because of its relative rarity and a wide variety of clinical manifestations, peripheral nerve tumors (PNTs) often present to specialists from widely different disciplines, thus often resulting in delayed diagnosis and a non-cohesive pattern of management. Critical appraisal of the history and physical examination followed by radiological investigations, by experienced medical personnel, ultimately suggests that the extremity mass is perhaps a PNT, rather than the wide variety and more common soft tissue tumors. Included in this appraisal is a search for a pre-disposition syndrome, the most common of which are neurofibromatosis-1 and -2 (NF1, NF2) and schwannomatosis, which may require life-long careful follow up. Intra-operative and post-operative management decisions in a multidisciplinary manner with knowledge of the biological, pathological and clinical behavior of the PNT, is of utmost importance. In the context of pre-disposition syndromes, where multiple tumors may exist along with other nervous system lesions, molecular biological insights and hopefully the biological therapies that stem from this knowledge are of interest. In this article the spectrum of PNTs and their management protocols, including the algorithm for treatment of malignant PNTs advocated by our institute, are presented and currently available genetic insights and probable role of experimental therapies are briefly reviewed.

Introduction: Mutism after posterior fossa tumour resection is generally said to be transient. Our experience suggested that speech did not usually normalise, and that mutism was associated with neurologic deficits that did not recover fully. Methods: Children with mutism after posterior fossa tumour resection, and alive more than 2 years post-operatively, were reviewed retrospectively. Charts were reviewed and parents contacted to ascertain details about mutism, associated neurologic deficits, and the most recent speech and neurologic status. Results: There were 7 children, with follow-up ranging from 2.5 to 13.1 years (mean 6.8 years). Tumours were midline, with 4 astrocytomas and 3 medulloblastomas. Mutism was noted immediately after post-operative extubation in all patients. Speech reappeared 1–15 weeks post-operatively, except for 1 patient, who remained mute at 2.5 years. Speech returned to normal in only 1 patient. Mutism was always accompanied by new or worsened cerebellar ataxia, which resolved incompletely in the long term. Sixth nerve palsies occurred in 3 and recovered incompletely. Seventh nerve paresis occurred in 2 and recovered completely. Conclusion: Mutism after posterior fossa tumour resection is associated with other neurologic deficits, particularly ataxia. Whereas speech usually returns, contrary to general opinion, speech rarely normalises. Other associated deficits rarely resolve completely. These findings have significant implications for counselling of family and patients.

International audience; Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.