Stuart L. Graham

Magnetic resonance imaging (MRI) is frequently used to monitor disease progression in multiple sclerosis (MS). This study aims to systematically evaluate the correlation between MRI measures and histopathological changes, including demyelination, axonal loss, and gliosis, in the central nervous system of MS patients. We systematically reviewed post-mortem histological studies evaluating myelin density, axonal loss, and gliosis using quantitative imaging in MS. Relevant studies were identified through searches in PubMed, EMBASE, and Web of Science. A total of 38 studies involving 1782 regions of interest from 229 subjects were included. Pooled random-effects models were used to calculate the correlation between demyelination, axonal loss, gliosis, and various MRI parameters, including magnetization transfer ratio (MTR), T1 and T2 relaxation times, myelin water fraction (MWF), proton density (PD), and diffusivities. Pair-wise analyses compared results between lesioned and non-lesioned tissues. Our results demonstrated moderate to strong correlations between MRI parameters and myelin density in MS, with correlation coefficients: T1 (0.72), T2 (0.72), MTR (-0.73), FA (-0.73), RD (0.70), MD (0.70), MWF (-0.82), and PD (0.73). Interestingly, stronger correlations were found in lesioned tissues compared to non-lesioned tissues (P < 0.001). Moderate correlations were found between MRI parameters and axonal loss and gliosis. Our study reveals significant correlations between MRI techniques and histological assessments of myelin, axonal damage, and gliosis in MS. MRI metrics exhibited a more robust association with demyelination in lesioned areas than in non-lesioned brain tissue, highlighting the pronounced degree of myelin degradation in MS lesions. Further investigation is warranted to corroborate these results and refine MRI-based monitoring of MS pathology.

Remyelination therapies are advancing for multiple sclerosis, focusing on visual pathways and using visual evoked potentials (VEPs) for de/remyelination processes. While the cuprizone (CZ) model and VEPs are core tools in preclinical trials, many overlook the posterior visual pathway. This study aimed to assess functional and structural changes across the murine visual pathway during de/remyelination. One group of C57BL/6 mice underwent a CZ diet for 6 weeks to simulate demyelination, with a subset returning to a regular diet to induce remyelination. An additional group was fed a protracted CZ diet for 12 weeks to maintain chronic demyelination. Visual function was evaluated using electrophysiological recordings, including scotopic threshold responses (STRs) and electroretinograms (ERGs), with VEPs serving as a key biomarker for overall pathway health. Tissues from eyes, brains, and optic nerves (ONs) were collected at different time points for structural analysis. Our results demonstrated significant effects on VEPs, including increased N1 latencies and reduced amplitudes in the CZ mouse model. However, retinal function remained unaffected, as evidenced by unchanged STRs, ERGs, and retinal ganglion cell counts. Analysis of ONs revealed morphological changes, characterized by a significantly decreased axon diameter in the core region compared to the subpial region. Additionally, there was a significant increase in the g-ratio of the core region at 12 weeks CZ compared to controls. Immunofluorescence further demonstrated a decrease in myelin basic protein levels at 6 and 12 weeks in CZ animals. Interestingly, the dorsal lateral geniculate nucleus and primary visual cortex (V1) exhibited similar myelin changes, correlating with VEP latency alterations. These data reveal that interpreting VEP latency solely as a marker for ON demyelination is incomplete. Previous preclinical studies have overlooked the posterior visual pathways, necessitating a broader interpretation of VEP latency to cover the entire visual pathway.

Objective: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR) can stratify individuals with pseudoexfoliation for the risk of glaucoma development. Methods: Retrospective multicohort study of 2 glaucoma registries and 1 population-based cohort. Methods: For the primary analysis, participants (n = 828) were classified as having PEX with glaucoma, PEX with suspected glaucoma, or PEX with no glaucoma. For the secondary analysis, a cohort of participants (n = 2460) were classified as having PEX with glaucoma, having PEX with no glaucoma, and being unaffected, and an independent cohort of participants (n = 3372) were classified as having primary open-angle glaucoma (POAG) or suspected POAG. Methods: Previously published and validated PRSs for open-angle glaucoma, IOP, and VCDR were expressed as a percentile, decile, or tertile of an ancestrally matched healthy population. Multivariable logistic and linear regressions and survival analyses were performed. Methods: The main outcome measures were odds of pseudoexfoliative glaucoma (PEX-G) and odds of clinically relevant outcomes. Results: Participants in the top tertile of the glaucoma PRS showed greater odds of receiving a PEX-G diagnosis (adjusted odds ratio [aOR], 4.22; 95% confidence interval [CI], 2.62-6.88; P < 0.001), greater odds of bilateral central vision loss (aOR, 3.43; 95% CI, 1.49-8.99; P = 0.007), and greater odds of bilateral incisional surgery (aOR, 3.35; 95% CI, 1.33-10.24; P = 0.018). Age at PEX-G diagnosis was 1 year younger with each increasing glaucoma PRS decile (1.06 years; 95% CI, 0.59-1.53 years; P < 0.001). Participants with manifest glaucoma and pseudoexfoliation showed a comparatively lower glaucoma PRS than counterparts with POAG. Conclusions: The PRSs for open-angle glaucoma, IOP, and VCDR stratify risk of glaucoma development and disease severity among individuals with PEX.

Neurodegenerative and demyelinating disease, such as multiple sclerosis (MS) are at the forefront of medical research and the discovery of new drugs and therapeutics. One phenomenon of degeneration seen in these diseases is transsynaptic degeneration (TSD), where damage from one axon spreads to the other axons that are connected to it synaptically. It has previously been found that demyelination occurs prior to neuronal loss in an experimental form of induced TSD. Retinoid-x receptor (RXR) agonists have been shown to promote remyelination. Therefore, this study aimed to reveal the effects of a novel endogenous RXR-γ agonist, 9-cis-13,14-dihydroretinoic acid (9CDHRA), on preventing or restoring the effects of TSD. 9CDHRA was administered to mice following optic nerve crush (ONC) procedures, and electrophysiology (visual evoked potential, VEP) and histological (immunofluorescent) assessments were performed. It was found that 9CDHRA treatment effectively delayed glial activation and reduced the presence of apoptosis at the site of injury and further anterogradely in the visual system, including the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Most notably, 9CDHRA was able to maintain myelin levels following ONC, and effectively protected from demyelination. This was corroborated by VEP recordings with improved P1 latency. The promising findings regarding the injury attenuating and myelin protecting properties of 9CDHRA necessitates further investigations into the potential therapeutic uses of this compound.

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.