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Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide 1 . Both IOP and POAG are highly heritable 2 . We report a combined analysis of participants from the UK Biobank ( n  = 103,914) and previously published data from the International Glaucoma Genetic Consortium ( n  = 29,578) 3 , 4 that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported 4 – 12 . We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1–7.6) of glaucoma relative to the bottom decile. A combined analysis of participants from the UK Biobank and the International Glaucoma Genetic Consortium identifies 85 new loci for intraocular pressure (IOP). Pathway analysis uncovers new pathways associated with both IOP and glaucoma.

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by inflammation, demyelination, neuro-axonal loss, and gliosis. Inflammatory demyelinating lesions are a hallmark of the disease. Spontaneous remyelination, however, is often incomplete and strategies that promote remyelination are needed. As a result, accurate and sensitive in vivo measures of remyelination are necessary. The visual pathway provides a unique opportunity for in vivo assessment of myelin damage and repair in the MS-affected brain since it is highly susceptible to damage in MS and is a very frequent site of MS lesions. The visually evoked potential (VEP), an event-related potential generated by the striate cortex in response to visual stimulation, is uniquely placed to serve as a biomarker of the myelination along the visual pathway. The multifocal VEP (mfVEP) represents a most recent addition to the array of VEP stimulations. This article provides a current view on the role of mfVEP as a biomarker of demyelination, spontaneous remyelination, and myelin repair in MS.

Objectives Recent studies suggested that the expansion of long‐standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing‐remitting MS. Methods Pre‐ and post‐gadolinium 3D‐T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients. Choroid plexus (CP) volume (normalised by Total Intracranial Volume, TIV) and lesion activity were analysed between baseline and 48 months. In addition, plexus volume was measured in 40 healthy controls of similar age and gender. Results Baseline CP/TIV ratio was significantly larger in RRMS patients compared to normal controls (p < 0.001). CP/TIV ratio remained stable in RRMS patients during follow‐up period. There was a strong correlation between baseline CP/TIV ratio and subsequent rate of chronic lesion expansion (p < 0.001), which was stronger in close proximity to CSF. A cut‐off of 98 × 10−5 CP/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. CP/TIV ratio larger than a cut‐off was associated with >8‐fold increased risk of chronic lesion expansion. Baseline CP/TIV ratio was also associated with change in Mean Diffusivity (MD) inside of chronic lesions. Furthermore, baseline CP/TIV ratio significantly correlated with central brain atrophy. There was, however, no correlation between CP/TIV ratio and volume of new lesions. Interpretation Our data demonstrate that baseline CP/TIV ratio predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage within and outside of chronic lesions.

It is reported that glaucoma may be associated with vascular dysregulation. Normal tension glaucoma (NTG) and primary open angle glaucoma (POAG), which feature different intraocular pressure levels, may manifest differential features of systemic autonomic dysregulation. We investigated autonomic regulation to carbohydrate ingestion and postural change in 37 glaucoma patients (19 NTG and 18 POAG) and 36 controls. Subjects were age and gender-matched, normotensive, and had normal comparable insulin sensitivity. Continuous finger arterial pressure and ECG was recorded in supine and standing positions before and after carbohydrate ingestion. Low frequency (LF, 0.04-0.15Hz) and high frequency (HF, 0.15-0.4Hz) spectral power of heart rate and systolic blood pressure variability (HRV and SBPV) were calculated to estimate sympathovagal function. Overall comparison glaucoma (N = 37) and controls (N = 36) showed an increased sympathetic excitation, vagal withdrawal and unstable mean arterial pressure after carbohydrate ingestion in glaucoma patients. Glaucoma severity by retinal nerve fibre layer (RNFL) thickness is positively correlated to autonomic responses (HRV LF power and HF power in normalised units (nu), and HRV LF/HF ratio) after carbohydrate ingestion. Early (30 minutes) following carbohydrate ingestion, SBP LF power and HRV parameters remained unchanged in controls; while POAG showed abnormal autonomic responses, with a paradoxical vagal enhancement (increased HRV HF power in nu) and sympathetic inhibition (decreased HRV LF power nu and HRV LF/HF ratio), and associated hypotension. Later (60-120 minutes) following carbohydrate ingestion, HRV parameters remained unaltered in controls; whereas NTG manifested vagal withdrawal (reduced HRV HF power nu) and sympathetic hyper-responsiveness (increased HRV LF power nu and HRV LF/HF ratio), despite increased SBP LF power in both controls and NTG. Both NTG and POAG exhibited attenuated autonomic responses to postural stress. NTG and POAG both manifest some systemic autonomic cardiovascular dysregulation. However, the two forms of glaucoma respond differentially to carbohydrate ingestion, irrespective of insulin resistance.

Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina. Siponimod is an immunomodulatory drug for multiple sclerosis and is a selective modulator of S1PR subtypes 1 and 5 and has been shown to have beneficial effects on the central nervous system (CNS) in degenerative conditions. Our previous study showed that mice administered orally with siponimod protected inner retinal structure and function against acute NMDA excitotoxicity. To elucidate the molecular mechanisms behind these protective effects, we investigated the inflammatory pathways affected by siponimod treatment in NMDA excitotoxicity model. NMDA excitotoxicity resulted in the activation of glial cells coupled with upregulation of the inflammatory NF-kB pathway and increased expression of TNFα, IL1-β, and IL-6. Siponimod treatment significantly reduced glial activation and suppressed the pro-inflammatory pathways. Furthermore, NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) were significantly diminished with siponimod treatment. Our data demonstrated that siponimod induces anti-inflammatory effects via suppression of glial activation and inflammatory singling pathways that could protect the retina against acute excitotoxicity conditions. These findings provide insights into the anti-inflammatory effects of siponimod in the CNS and suggest a potential therapeutic strategy for neuroinflammatory conditions.

Retinoid X-receptors (RXRs) are members of the ligand-dependent transcription factor family of nuclear receptors that have gained recent research focus as potential targets for neurodegenerative disorders. Bexarotene is an RXR pharmacological agonist that is shown to be neuroprotective through its effects in promoting amyloid beta (Aβ) uptake by the glial cells in the brain. This study aimed to evaluate the dose-dependent effects of bexarotene on RXR expression in SH-SY5Y neuroblastoma cells and validate the drug effects in the brain in vivo. The protein expression studies were carried out using a combination of various drug treatment paradigms followed by expression analysis using Western blotting and immunofluorescence. Our study demonstrated that bexarotene promoted the expression of RXR α, β and γ isoforms at optimal concentrations in the cells and in the mice brain. Interestingly, a decreased RXR expression was identified in Alzheimer’s disease mouse model and in the cells that were treated with Aβ. Bexarotene treatment not only rescued the RXR expression loss caused by Aβ treatment (p < 0.05) but also protected the cells against Aβ-induced ER stress (p < 0.05) and pro-apoptotic BAD protein activation (p < 0.05). In contrast, higher concentrations of bexarotene upregulated the ER stress proteins and led to BAD activation. Our study revealed that these downstream neurotoxic effects of high drug concentrations could be prevented by pharmacological targeting of the TrkB receptor. The ER stress and BAD activation induced by high concentrations of bexarotene were rescued by the TrkB agonist, 7,8 dihydroxyflavone (p < 0.05) while TrkB inhibitor CTX-B treatment further exacerbated these effects. Together, these findings suggest a cross-talk of TrkB signalling with downstream effects of bexarotene toxicity and indicate that therapeutic targeting of RXRs could prevent the Aβ-induced molecular neurotoxic effects.

Abstarct Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis. About 5000 proteins were quantified from retinal tissue and vitreous fluid of glaucoma and control eyes. Of the differentially regulated proteins, 122 were found linked with pathophysiology of Alzheimer’s disease (AD). Pathway analyses of differentially regulated proteins indicate defects in mitochondrial oxidative phosphorylation machinery. The classical complement pathway associated proteins were activated in the glaucoma samples suggesting an innate inflammatory response. The majority of common differentially regulated proteins in both tissues were members of functional protein networks associated brain changes in AD and other chronic degenerative conditions. Identification of previously reported and novel pathways in glaucoma that overlap with other CNS neurodegenerative disorders promises to provide renewed understanding of the aetiology and pathogenesis of age related neurodegenerative diseases.

Identifying axial length growth rate as an indicator of fast progression before initiating atropine 0.01% for myopia progression in children. From baseline, axial length growth over six months was measured prospectively. Subjects were then initiated on atropine 0.01% if axial length growth was greater than 0.1mm per 6 months (fast progressors), axial length and spherical equivalent change measurements recorded every six months. The rate of change was compared to the baseline pre-treatment rate. If axial length change was below the threshold, subjects received monitoring only. 73 subjects were identified as fast progressors and commenced atropine 0.01%, (mean baseline refraction of OD -2.9±1.6, OS -2.9±1.8 and a mean baseline axial length OD 24.62 ± 1.00 mm, OS 24.53 ± 0.99 mm). At six months, the mean paired difference of axial length growth rate was significantly reduced by 50% of baseline (all 73 subjects, p<0.05). 53 subjects followed to 12 months, and 12 to 24 months maintained a reduced growth rate. Change in mean spherical equivalent was significantly reduced compared to pre-treatment refractive error (mean paired difference p<0.05) and at each subsequent visit. 91 children were slow progressors and remained untreated. Their axial length growth rate did not change significantly out to 24 months. Spherical equivalent changed less than -0.5D annually in this group. Identifying fast progressors before treatment initiation demonstrated a strong treatment effect with atropine 0.01% reducing their individual rate of myopia progression by 50%. Another large group of myopic children, slow progressors, continued without medical intervention. A baseline axial length growth rate is proposed as a guideline to identify fast progressors who are more likely to benefit from atropine 0.01%.

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 β‐protein (Aβ)1–42, angiopathic Aβ1–40, non‐amyloidogenic Aβ1–38, and Aβ42/Aβ40 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 Aβ burden, with one‐side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aβ 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 Aβ 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. In this study, Doustar et al. revealed that retinal Abeta burden predicts its brain levels in old, late‐stage murine models of Alzheimer's disease and further in response to immunotherapy. Substantial therapeutic effects are detected even at such advanced disease stage; immunomodulation effectively mitigates vascular and parenchymal amyloid‐beta deposition, diminishes neuroinflammation, as well as restores synaptic density and retino‐cerebral glutamine synthetase levels.

Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer’s disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and activated in AD dementia, evidenced by increased caspase-1, cleaved interleukin-1β, and cleaved N-terminal gasdermin-D. Chlamydia pneumoniae associates with amyloid-β 42 , inflammation, apoptosis, pyroptosis, and AD status. In neuronal cultures and APP SWE /PS1 ΔE9 model mice, infection induces amyloid-β, inflammasome activation, neuroinflammation, and neurotoxicity, and chronic infection worsens cognition. Fewer pathogen-colocalized microglia are found in AD retinas, implying impaired clearance. Machine learning detects retinal Chlamydia pneumoniae or NLRP3, combined with amyloid-β 42 , as predictors of AD diagnosis and stage. These findings support a disease-amplifying role for Chlamydia pneumoniae and propose NLRP3-attenuation or antibiotic-based early interventions. This study detects Chlamydia pneumoniae in human retina and brain, increasing with AD severity. Retinal pathogen load with Aβ 42 may predict AD stage. In models, infection drives Aβ deposition and NLRP3 activation, worsening pathology and cognition.