Michael Zhu

Background/Objectives: Characterization of individual retinal layer thicknesses in mild-to-moderate Parkinson’s disease (PD) remains limited. This study compares retinal layer thicknesses between patients with mild-to-moderate PD and controls. Methods: In this cross-sectional study, patients with PD of Hoehn and Yahr (HY) stage 1 to stage 3 and age- and sex-matched cognitively normal controls without PD underwent spectral-domain optical coherence tomography (OCT) imaging. Seven retinal layers were segmented: nerve fiber layer, ganglion cell–inner plexiform layer (GC-IPL), inner nuclear layer (INL), outer plexiform layer, outer nuclear layer (ONL), photoreceptor layer (PRL), and retinal pigment epithelium (RPE). Mean thickness for each layer and the total retina were measured within the 3 mm and 6 mm Early Treatment Diabetic Retinopathy Study rings. Results: Sixty-seven eyes from 41 patients with PD and 72 eyes from 41 controls were included. In the 6 mm ring, PD eyes had a nominally thicker GC-IPL (p = 0.01), INL (p = 0.01), RPE (p = 0.03), and total retina (p = 0.03) compared to control eyes. In the 6 mm ring, PRL was nominally thinner in HY stage 3 compared to HY stages 2–2.5 (p = 0.02). In the 6 mm ring, the ONL was nominally thinner in the eyes of PD patients in HY stage 3 compared to the eyes of PD patients in HY stages 1–1.5 (p = 0.02) and 2–2.5 (p = 0.04). However, none of these differences remained significant after False Discovery Rate adjustment (all adjusted p > 0.05). Conclusions: In this exploratory cross-sectional study, no significant differences in macular retinal layer thicknesses were found between patients with mild-to-moderate PD and controls without PD after adjusting for multiple comparisons. The nominal thickness differences observed here require larger, longitudinal cohorts to determine if true structural differences exist in mild-to-moderate PD.

Purpose: To compare retinal and choroidal structural and microvascular imaging parameters between patients with dementia with Lewy bodies and those with Alzheimer disease using optical coherence tomography (OCT) and OCT angiography (OCTA). Methods: In this cross-sectional study, patients with dementia with Lewy bodies and those with Alzheimer disease underwent imaging with the Cirrus HD-5000 AngioPlex system (Carl Zeiss Meditec). OCT metrics included central subfield thickness, ganglion cell-inner plexiform layer thickness, retinal nerve fiber layer thickness, and choroidal vascularity index. Macular OCTA metrics included perfusion density, vessel density, and foveal avascular zone area. Peripapillary OCTA metrics included capillary perfusion density and capillary flux index. Generalized estimating equations adjusted for years of education were used to account for intereye correlation. Results: A total of 36 eyes from 20 patients with dementia with Lewy bodies and 42 eyes from 21 patients with Alzheimer disease were included. Compared with eyes from patients with Alzheimer disease, eyes from patients with dementia with Lewy bodies demonstrated significantly lower perfusion density and vessel density within the 3 × 3 mm Early Treatment Diabetic Retinopathy Study circle and ring ( P = .03-.04). Structural OCT and peripapillary OCTA metrics did not differ significantly between the groups. Conclusions: Compared with Alzheimer disease, dementia with Lewy bodies was associated with reduced macular perfusion density and vessel density on OCTA. These findings suggest disease-specific differences in the retinal microvasculature between dementia with Lewy bodies and Alzheimer disease.

Précis: In a cohort of 200 veterans with glaucoma, neighborhood socioeconomic deprivation was not significantly associated with disease severity or medication adherence. These findings suggest that the integrated Veterans Health Administration system may mitigate traditional socioeconomic barriers to glaucoma care. Purpose: To evaluate the association of neighborhood socioeconomic disadvantage, measured by the Area Deprivation Index, with glaucoma severity and medication adherence in Veterans Health Administration patients. Patients and Methods: This study was a secondary data analysis of 200 veterans (100 intervention and 100 control) from the Medication Adherence in Glaucoma to Improve Care randomized controlled trial. Baseline demographics, clinical variables, and 6-month smart-bottle adherence were linked retrospectively to national Area Deprivation Index percentiles corresponding to the time of trial randomization. The primary outcomes were the associations of the Area Deprivation Index with disease severity and medication adherence. The secondary outcomes were the associations between the Area Deprivation Index and demographic/socioeconomic variables. Results: Area Deprivation Index was not significantly associated with glaucoma severity ( P =0.69). In the control arm, the Area Deprivation Index was not correlated with mean medication adherence proportion ( P =0.98). There was no interaction between the Area Deprivation Index and intervention status regarding mean medication adherence proportion ( P =0.92). Lower Area Deprivation Index (less deprivation) was observed among married participants ( P =0.003), White participants ( P P P =0.03), and those with higher income ( P =0.002). There was no significant difference in Area Deprivation Index based on sex ( P =0.24) or employment status ( P =0.17). Conclusions: In this veteran cohort, neighborhood socioeconomic deprivation was not associated with glaucoma severity or medication adherence. These findings suggest that the integrated Veterans Health Administration system may help mitigate socioeconomic barriers in glaucoma care. Larger multicenter studies are recommended to clarify how neighborhood deprivation and health system structure influence glaucoma outcomes.

Purpose: To compare systemic vascular disease risk among central and branch retinal artery occlusion (CRAO, BRAO) and central and branch retinal vein occlusion (CRVO, BRVO). Methods: This retrospective cohort study used TriNetX to compare hazard ratios (HR) for ischemic stroke (IS), ischemic heart disease (IHD), myocardial infarction (MI), atrial fibrillation (AF), and mortality among 129,468,002 patients with CRAO, CRVO, BRAO, or BRVO diagnosed between January 1, 2015, and July 5, 2026, using propensity score-matched data. Results: Retinal artery occlusions (RAO) were associated with significantly higher risks of all measured outcomes than retinal vein occlusions (RVO), including IS (HR, 1.954), IHD (HR, 1.368), MI (HR, 1.313), AF (HR, 1.530), and mortality (HR, 1.299) (all P<0.0001). BRAO carried higher risk than BRVO across all outcomes. CRAO carried higher risk than BRAO for MI and mortality only, and higher risk than CRVO across all outcomes, most strongly for IS (HR, 2.259). CRVO carried higher mortality risk than BRVO, with no significant difference in other outcomes. Conclusion: Retinal artery occlusions have a substantially greater systemic vascular risk than retinal vein occlusions. This supports urgent systemic evaluation following retinal arterial occlusion, particularly CRAO, to identify patients at highest risk for life-threatening thromboembolic events.

Background/Objectives: Evaluating noninvasive, accessible ocular and blood-based biomarkers could aid in early risk stratification and disease detection during the preclinical phase of Alzheimer’s disease. This study investigates associations between plasma biomarkers of neurodegeneration and retinal structural and microvasculature parameters in cognitively normal adults with familial or genetic risk factors for Alzheimer’s disease. Methods: Forty-one participants underwent plasma sampling for glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid-beta42 (β42), amyloid-β42/40 ratio, and phosphorylated-tau217 (p-tau217), and also underwent optical coherence tomography (OCT) and OCT angiography (OCTA) imaging. Apolipoprotein E genotyping and family history of Alzheimer’s disease were recorded. Generalized estimating equations adjusting for age, sex, race, treated hypertension, Alzheimer’s disease family history, and APOE ε4 carrier status assessed associations between plasma biomarker concentrations and OCT and OCTA measurements. Results: Higher plasma GFAP and NfL concentrations were significantly associated with reduced superficial capillary plexus perfusion density and vessel density on macular OCTA. In additional analyses restricted to participants with plasma biomarker and retinal imaging assessments obtained within 9 months, associations with GFAP remained significant, whereas NfL associations no longer remained significant after correction for multiple comparisons. Conclusions: Retinal OCTA and OCT metrics may reflect general neurovascular aging in cognitively normal individuals with familial or genetic risk factors for Alzheimer’s disease.

Purpose: To identify retinal morphologic changes associated with pregnancy in patients with diabetes and evaluate potential risk factors for disease progression. Methods: A retrospective chart and image review was performed for 35 patients (70 eyes) with type 1 or type 2 diabetes mellitus (DM) who received prenatal care and had a delivery between January 2010 and December 2022 at Duke University Health System. Multimodal retinal imaging (spectral-domain optical coherence tomography, color fundus photography, and fluorescein angiography [FA]) was assessed pre-pregnancy and post-delivery for morphologic changes, including disorganization of the retinal inner layers (DRIL), diabetic retinopathy (DR) severity (based on Early Treatment Diabetic Retinopathy Study letter level), and central subfield thickness. Clinical data were extracted via chart review. Results: DRIL prevalence increased from 75.5% of eyes (37/49) pre-pregnancy to 88.1% (52/59) post-delivery ( P < .001). Average DRIL extent nearly doubled (38.0% pre-pregnancy to 76.4% post-delivery; P < .001), and 38.6% of eyes (27/70) showed new or progressive DRIL after pregnancy. DR prevalence increased from 72.7% of eyes (40/55) pre-pregnancy to 92.1% (58/63) post-delivery, with a significant increase in proliferative DR prevalence after pregnancy ( P < .001). Overall, the severity of both proliferative and nonproliferative DR significantly increased following pregnancy (both P < .001). DRIL progression from pre-pregnancy to post-delivery correlated with DR progression ( P = .039). No significant associations were found between DR progression and baseline age, DM type, smoking, glycosylated hemoglobin level, body mass index, preeclampsia history, or hypertension treatment. New or worsening retinal ischemia (characterized as foveal avascular zone enlargement and/or peripheral nonperfusion) was identified on the longitudinal FA images available from 4 patients. Conclusions: Pregnancy is associated with the progression of DRIL and DR in diabetic women. Early identification of changes is important for timely intervention and optimizing visual outcomes.

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured (“naïve”) rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator, forskolin, induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12-24 hours later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to -45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from -69 to -66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and indications of reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, and protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. An interesting possibility is that these mechanisms can also be reactivated by re-exposure to inflammatory mediators such as serotonin during subsequent challenges to bodily integrity, “reconsolidating” the cellular memory and thereby extending the duration of persistent nociceptor hyperexcitability. Highlights Nociceptor long-term hyperexcitability (LTH) can be induced by a 5-HT4R agonist. 5-HT4R-induced LTH manifests as ongoing activity during modest depolarization. Enhanced ongoing activity is associated with long-term potentiation of DSFs. Induction of LTH depends upon PKA, CREB, transcription, and protein synthesis. Nociceptor LTH may be triggered by conserved memory-related plasticity mechanisms.