The World Neurosurgery Global Champions Program: First-Year Experience of a Model Initiative for Reducing Disparities in Global Neurosurgical Literature.

OBJECTIVE: Most surgical journals are published in English, representing a challenge for researchers from non-Anglophone countries. We describe the implementation, workflow, outcomes, and lessons learned from the WORLD NEUROSURGERY Global Champions Program (GCP), a novel journal-specific English language editing program for articles rejected because of poor English grammar or usage. METHODS: The GCP was advertised via the journal website and social media. Applicants were selected to be a reviewer for the GCP if they demonstrated English proficiency on writing samples supplied in their application. The demographics of GCP members and characteristics and outcomes of articles edited by the GCP during its first year were reviewed. Surveys of GCP members and authors who used the service were conducted. RESULTS: Twenty-one individuals became part of the GCP, representing 8 countries and 16 languages apart from English. A total of 380 manuscripts were peer reviewed by the editor-in-chief, who determined these manuscripts to have potentially worthwhile content but needed to be rejected due to poor language. The authors of these manuscripts were informed of the existence of this language assistance program. Forty-nine articles (12.9%) were edited by the GCP in 41.6 ± 22.8 days. Of 40 articles resubmitted to WORLD NEUROSURGERY, 24 (60.0%) were accepted. GCP members and authors understood the purpose and workflow of the program and recognized improvements in article quality and the probability of acceptance through their participation. CONCLUSIONS: The WORLD NEUROSURGERY Global Champions Program mitigated a critical barrier to publication in an English language journal for authors from non-Anglophone countries. This program promotes research equity by providing a free, largely medical student and trainee operated, English language editing service. This model or a similar service can be replicated by other journals.

Rift Valley fever during the COVID-19 pandemic in Africa: A double burden for Africa's healthcare system.

A new rising incidence of Rift Valley fever (RVF) among livestock and humans in the African continent during the COVID-19 pandemic has become of increasing concern. We analyzed the different ways COVID-19 has contributed to the increase in RVF cases and how it has impacted the interventions allocated to the disease by comparing it with the status of the disease before the pandemic. There is enough evidence to conclude that the COVID-19 pandemic has impacted the efforts being taken to prevent outbreaks of RVF. Therefore, with no definitive treatment in place and inadequate preventive measures and disease control, RVF may potentially lead to a future epidemic unless addressed urgently.

Retinal Venular Tortuosity Jointly with Retinal Amyloid Burden Correlates with Verbal Memory Loss: A Pilot Study.

INTRODUCTION: Retinal imaging is a non-invasive tool to study both retinal vasculature and neurodegeneration. In this exploratory retinal curcumin-fluorescence imaging (RFI) study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status. METHODS: We used quantitative RFI in a cohort of patients with cognitive impairment to automatically compute retinal amyloid burden. Retinal blood vessels were segmented, and the vessel tortuosity index (VTI), inflection index, and branching angle were quantified. We assessed the correlations between retinal vascular and amyloid parameters, and cognitive domain Z-scores using linear regression models. RESULTS: Thirty-four subjects were enrolled and twenty-nine (55% female, mean age 64 ± 6 years) were included in the combined retinal amyloid and vascular analysis. Eleven subjects had normal cognition and 18 had impaired cognition. Retinal VTI was discriminated among cognitive scores. The combined proximal mid-periphery amyloid count and venous VTI index exhibited significant differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs. 0.91 ± 1.4, p = 0.006), and correlated with both the Wechsler Memory Scale-IV and SF-36 mental component score Z-scores (p < 0.05). CONCLUSION: This pilot study showed that retinal venular VTI combined with the proximal mid-periphery amyloid count could predict verbal memory loss. Future research is needed to finesse the clinical application of this retinal imaging-based technology.

Effects of IL-34 on Macrophage Immunological Profile in Response to Alzheimer's-Related Aß42 Assemblies.

Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid ß-protein (Aß). Aß42 forms are especially neurotoxic and highly associated with Alzheimer's disease (AD). As a ligand of CSF1R, IL-34 may be relevant to innate immune responses in AD. To investigate how IL-34 affects macrophage phenotype in response to structurally defined and stabilized Aß42 oligomers and preformed fibrils, we characterized murine BMMO cultured in media containing M-CSF, IL-34, or regimens involving both cytokines. We found that the immunological profile and activation phenotype of IL-34-stimulated BMMO differed significantly from those cultured with M-CSF alone. Specifically, macrophage uptake of fibrillar or oligomeric Aß42 was markedly reduced following exposure to IL-34 compared to M-CSF. Surface expression of type B scavenger receptor CD36, known to facilitate Aß recognition and uptake, was modified following treatment with IL-34. Similarly, IL-34 macrophages expressed lower levels of proteins involved in both Aß uptake (triggering receptor expressed on myeloid cells 2, TREM2) as well as Aß-degradation (matrix metallopeptidase 9, MMP-9). Interestingly, intracellular compartmentalization of Aß visualized by staining of early endosome antigen 1 (EEA1) was not affected by IL-34. Macrophage characteristics associated with an anti-inflammatory and pro-wound healing phenotype, including processes length and morphology, were also quantified, and macrophages stimulated with IL-34 alone displayed less process elongation in response to Aß42 compared to those cultured with M-CSF. Further, monocytes treated with IL-34 alone yielded fewer mature macrophages than those treated with M-CSF alone or in combination with IL-34. Our data indicate that IL-34 impairs monocyte differentiation into macrophages and reduces their ability to uptake pathological forms of Aß. Given the critical role of macrophage-mediated Aß clearance in both murine models and patients with AD, future work should investigate the therapeutic potential of modulating IL-34 in vivo to increase macrophage-mediated Aß clearance and prevent disease development.

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aß42 Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid ß-protein (Aß42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aß42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aß-phagocytic macrophages. We found that cortical neurons were more susceptible to Aß42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aß42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aß42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aß42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.

Sectoral segmentation of retinal amyloid imaging in subjects with cognitive decline.

INTRODUCTION: Despite advances in imaging retinal amyloidosis, a quantitative and topographical investigation of retinal amyloid beta burden in patients with cognitive decline has never been reported. METHODS: We used the specific amyloid-binding fluorophore curcumin and laser ophthalmoscopy to assess retinal amyloid imaging (RAI) in 34 patients with cognitive decline. We automatically quantified retinal amyloid count (RAC) and area in the superotemporal retinal sub-regions and performed correlation analyses with cognitive and brain volumetric parameters. RESULTS: RAC significantly and inversely correlated with hippocampal volume (HV; r = -0.39, P = .04). The proximal mid-periphery (PMP) RAC and RA areas were significantly greater in patients with Montreal Cognitive Assessment (MOCA) score < 26 (P = .01; Cohen d = 0.83 and 0.81, respectively). PMP showed significantly more RAC and area in subjects with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal (P = .04; Cohen d = 0.83). CONCLUSION: Quantitative RAI is a feasible technique and PMP RAC may predict HV. Future larger studies should determine RAI's potential as a biomarker of early AD.

Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina-brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APPSWE/PS1∆E9; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre- and early-symptomatic disease stages. Here, we explored the link between retinal and cerebral AD-related biomarkers, including response to GA immunization, in cohorts of old, late-stage ADtg mice. This aged model is considered more clinically relevant to the age-dependent disease. Levels of synaptotoxic amyloid ß-protein (Aß)1-42, angiopathic Aß1-40, non-amyloidogenic Aß1-38, and Aß42/Aß40 ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of Aß burden, with one-side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aß levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal Aß deposits, especially of large, dense-core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino-cerebral AD-related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation-guided CNS repair in old AD model mice, while shedding light onto similar retino-cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.

Optical Coherence Tomography in Alzheimer's Disease and Other Neurodegenerative Diseases.

Over the past decade, a surge of evidence has documented various pathological processes in the retina of patients suffering from mild cognitive impairment, Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative diseases. Numerous studies have shown that the retina, a central nervous system tissue formed as a developmental outgrowth of the brain, is profoundly affected by AD. Harboring the earliest detectable disease-specific signs, amyloid ß-protein (Aß) plaques, the retina of AD patients undergoes substantial ganglion cell degeneration, thinning of the retinal nerve fiber layer, and loss of axonal projections in the optic nerve, among other abnormalities. More recent investigations described Aß plaques in the retina located within sites of neuronal degeneration and occurring in clusters in the mid- and far-periphery of the superior and inferior quadrants, regions that had been previously overlooked. Diverse structural and/or disease-specific changes were also identified in the retina of PD, Huntington's disease, and multiple sclerosis patients. The pathological relationship between the retina and brain prompted the development of imaging tools designed to noninvasively detect and monitor these signs in living patients. One such tool is optical coherence tomography (OCT), uniquely providing high-resolution two-dimensional cross-sectional imaging and three-dimensional volumetric measurements. As such, OCT emerged as a prominent approach for assessing retinal abnormalities in vivo, and indeed provided multiple parameters that allowed for the distinction between normal aged individuals and patients with neurodegenerative diseases. Beyond the use of retinal optical fundus imaging, which recently allowed for the detection and quantification of amyloid plaques in living AD patients via a wide-field view of the peripheral retina, a major advantage of OCT has been the ability to measure the volumetric changes in specified retinal layers. OCT has proven to be particularly useful in analyzing retinal structural abnormalities consistent with disease pathogenesis. In this review, we provide a summary of OCT findings in the retina of patients with AD and other neurodegenerative diseases. Future studies should explore the combination of imaging early hallmark signs together with structural-functional biomarkers in the accessible retina as a practical means of assessing risk, disease progression, and therapeutic efficacy in these patients.