Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Differences in Age-related Retinal and Cortical Atrophy Rates in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course. METHODS: We analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models. RESULTS: The rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years). DISCUSSION: An age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss.

Complete Genome Sequence of Finnry, a Subcluster L3 Mycobacteriophage from Charleston, South Carolina.

Subcluster L3 bacteriophage Finnry was isolated from soil collected in Charleston, South Carolina, using Mycobacterium smegmatis mc2155 as a host. The genome of this temperate siphovirus is 75,632 bp long (130 predicted protein-coding genes, 9 tRNAs, and no transfer-messenger RNAs), and BLASTn alignment revealed 99.86% identity with the genome of L3 mycobacteriophage Samty.

Retinal imaging demonstrates reduced capillary density in clinically unimpaired APOE ε4 gene carriers.

INTRODUCTION: Apolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries. METHODS: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations. RESULTS: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature. DISCUSSION: These results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.

Computed tomography angiography is associated with low added utility for detecting clinically relevant vascular injuries among patients with extremity trauma.

BACKGROUND: Extremity CT angiography (CTA) is frequently used to assess for vascular injury among patients with extremity trauma. The injured extremity index (IEI), defined as the ratio of systolic occlusion pressure between injured and uninjured extremities, has been implemented to screen patients being considered for CTA. Physical examination together with IEI is extremely sensitive for significant extremity vascular injury. Unfortunately, IEI cannot always be calculated. This study aimed to determine whether patients with normal pulse examinations and no hard signs of vascular injury benefitted from further imaging with CTA. We hypothesized that CTA has become overused among patients with extremity trauma, as determined by the outcome of vascular abnormalities that underwent vascular intervention but were missed by physical examination. METHODS: The charts of traumatically injured patients who underwent extremity CTA were retrospectively reviewed. This study was performed at a level 1 trauma center for patients who presented as trauma activations from September 1, 2019 to September 1, 2020. RESULTS: One hundred and thirty-six patients with 167 injured limbs were included. Eight limbs (4.8%) underwent an open vascular operation, whereas five limbs (3.0%) underwent an endovascular procedure. One of the 167 limbs (0.6%) had a vascular injury seen on CTA and underwent intervention that was not associated with a pulse abnormality or hard signs of vascular injury. This patient presented in a delayed fashion after an initially normal IEI and examination. Proximity injuries and fractures alone were not highly associated with vascular injuries. DISCUSSION: Many patients with normal pulse examination and no hard signs of vascular injury underwent CTA; the vast majority of these patients did not then have a vascular intervention. Given the consequences of missed vascular injuries, further work is required to prospectively assess the utility of CTA among patients with extremity trauma. LEVEL OF EVIDENCE: III.

Imaging correlates of visual function in multiple sclerosis.

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.

Stress-Induced Hyperglycemia in White-Throated and White-Crowned Sparrows: A New Technique for Rapid Glucose Measurement in the Field.

Organisms experience stressors, and the physiological response to these stressors is highly conserved. Acute stress activates both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, increasing epinephrine, norepinephrine, and glucocorticoids, collectively promoting glucose mobilization. While this is well characterized in mammals, the hyperglycemic response to stress in avian and nonavian reptiles has received less attention. A number of factors, ranging from time of day to blood loss, are reported to influence the extent to which acute stress leads to hyperglycemia in birds. Here we characterized the glycemic response to acute handling stress in two species of free-living sparrows: white-throated sparrows (WTSPs: Zonotrichia albicollis) in St. Mary's County, Maryland, and white-crowned sparrows (WCSPs: Zonotrichia leucophrys) in Tioga Pass Meadow, California. We validated a novel technique for rapid field measurement of glucose using a human blood glucose meter, FreeStyle Lite. As expected, acute handling stress elevated blood glucose at both 15 and 30 min postcapture as compared to baseline for both WTSPs and WCSPs. In addition, handling for 30 min without bleeding had the same hyperglycemic effect as handling with serial bleeds in WCSPs. Finally, body condition that was measured as abdominal fat score predicted stress-induced blood glucose in WTSPs but not in WCSPs. Our results are consistent with the mammalian literature on acute stress and energy mobilization, and we introduce a new field technique for avian field biologists.

Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness.

Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5-encoded protein, Lebercilin, is essential for the trafficking of proteins and vesicles to the photoreceptor outer segment. Using the AAV serotype AAV7m8 to deliver a human LCA5 cDNA into an Lca5 null mouse model of LCA5, we show partial rescue of retinal structure and visual function. Specifically, we observed restoration of rod-and-cone-driven electroretinograms in about 25% of injected eyes, restoration of pupillary light responses in the majority of treated eyes, an ∼20-fold decrease in target luminance necessary for visually guided behavior, and improved retinal architecture following gene transfer. Using LCA5 patient-derived iPSC-RPEs, we show that delivery of the LCA5 cDNA restores lebercilin protein and rescues cilia quantity. The results presented in this study support a path forward aiming to develop safety and efficacy trials for gene augmentation therapy in human subjects with LCA5 mutations. They also provide the framework for measuring the effects of intervention in ciliopathies and other severe, early-onset blinding conditions.

A new species of Quexua from southeastern Peru (Hymenoptera, Crabronidae).

A distinctive new species of the crabronine wasp genus Quexua Pate is described and figured from a single male collected from lowland Amazonian rain forest in southeastern Peru. Quexua cicrasp. n. is the only species in the genus known with a sessile metasoma.