Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer's disease

BACKGROUND: Melanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body's circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer's disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD. METHODS: We performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid \u3b242 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid \u3b242 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm. RESULTS: Our results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls. CONCLUSIONS: The variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD

Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline

Background: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) A f42 (A) and tau (T) ratio. Methods: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. Results: Mean age (\ub1 standard deviation) in the CH-PAT group (n = 27; 75.2 \ub1 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 \ub1 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) \u3bcm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. Conclusions: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology

Choroidal thickness and the retinal ganglion cell complex in chronic Leberʼs hereditary optic neuropathy: a prospective study using swept-source optical coherence tomography

Background/Objectives: Choroidal thinning has been suggested in Leber�s hereditary optic neuropathy (LHON). No study has been conducted of the choroid in relation to the retinal ganglion cell-inner plexiform layer (RGC-IPL). We sought to measure choroidal thickness in chronic LHON and to correlate thickness changes with the RGC-IPL. Subjects/Methods: Chronic LHON, 11778 mitochondrial DNA (mtDNA) mutation, patients (26 eyes; mean age: 35.1 ± 16.1 years) were prospectively recruited at Doheny Eye Center, University of California Los Angeles from March 2016 to July 2017. Age-matched healthy controls (27 eyes; mean age: 32.4 ± 11.1 years) were enroled for comparison. Swept-source optical coherence tomography (SS-OCT) imaging was performed in chronic LHON patients and compared with age-matched healthy controls. Results: The macular choroid was significantly thinner in chronic LHON (250.5 ± 62.2 μm) compared with controls (313.9 ± 60.2 μm; p < 0.0001). The peripapillary choroid was also significantly thinner in chronic LHON (135.7 ± 51.4 μm) compared with controls (183.0 ± 61.8 μm, p < 0.001). Choroidal thickness strongly correlated with retinal nerve fibre layer (RNFL) thickness in both the macular (R2 = 0.72; 95 CI, 0.57�0.84) and peripapillary regions (R2 = 0.53; 95 CI, 0.31�0.70). Choroidal thickness was also significantly correlated with macular RGC-IPL thickness (R2 = 0.51; 95 CI, 0.26�0.73). Conclusions: Choroidal thinning in chronic LHON correlated strongly with both RNFL and RGC-IPL thicknesses. These findings may suggest a pathophysiological mechanism involving vascular pathology of the choroid in relation to the retinal ganglion cell complex in LHON. © 2019, The Author(s), under exclusive licence to The Royal College of Ophthalmologists

Changing Visual Defects in a Patient with Gilles de la Tourette Syndrome.

Gilles de la Tourette syndrome (GTS) is a complex disorder characterized by the presence of motor and vocal tics, as well as neuropsychiatric pathological features. Visual field defects have also been described in GTS patients by Enoch et al. in the 1980s. In the current paper, the authors discuss Enoch et al. studies showing visual field defects in patients with GTS, presenting a similar case evaluated in the context of newer structural and functional examination modalities

Leber's hereditary optic neuropathy : severe vascular pathology in a severe primary mutation

The purpose of the present article was to evaluate the previously unreported vascular alterations in Leber's Hereditary Optic Neuropathy (LHON) 3460 mitochondrial DNA (mtDNA) mutation. Among the three primary mtDNA mutations, namely 11778, 14484, and 3460, LHON 3460 is the most rare and historically recognized as having the poorest visual prognosis. Optical coherence tomography angiography (OCTA) is a novel imaging modaility providing high-resolution microcirculation maps and enhancing visualization of the optic disc and peripapillary capillary beds. We herein exploit the advantages of OCTA, for the first time, to assess the optic nerve head and peripapillary microvasculature changes in an affected patient and compare these vascular changes with an asymptomatic carrier for LHON 3460, serving as a control. Vascular changes in LHON 11778 and 14484 have classically shown microvasculature attenuation localized specifically to the temporal peripapillary quadrant. In the present case, however, OCTA in LHON 3460, the most severe of the three mutational subtypes, illustrated significant vascular attenuation involving the nasal peripapillary region in addition to the temporal peripapillary microvascular changes classically seen in LHON. Our findings suggest that vascular measures may serve useful for objectively assessing mitochondrial disease. Further OCTA studies involving the nasal peripapillary region may be warranted to further understand vascular pathogenesis in LHON

The retina in alzheimer’s disease : Histomorphometric analysis of an ophthalmologic biomarker

PURPOSE. To provide a histopathologic, morphometric analysis of the retina in Alzheimer\u2019s disease (AD). METHODS. Human postmortem retinas from eight patients with AD (mean age: 80 6 12.7 years) and from 11 age-matched controls (mean age: 78 6 16.57 years) were analyzed. The retinas were sampled from the superior quadrant on both the temporal and nasal sides with respect to the optic nerve. Thickness of the inner and outer layers involving the retinal nerve fiber layer (RNFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer nuclear layer (ONL) were measured and compared between controls and AD. A total of 16 measurements of retinal thickness were acquired for each layer. RESULTS. RNFL thinning supero-temporally was significant closest to the optic nerve (~35% thickness reduction; P < 0.001). Supero-nasally, RNFL was thinner throughout all points (~40% reduction; P < 0.001). Supero-temporally, RGCL thinning was pronounced toward the macula (~35% thickness reduction; P < 0.001). Supero-nasally, RGCL showed uniform thinning throughout (~35% reduction; P < 0.001). IPL thinning supero-temporally was statistically significant in the macula (~15% reduction; P < 0.01). Supero-nasal IPL featured uniform thinning throughout (~25% reduction; P < 0.001). Supero-temporally, INL and ONL thinning were pronounced toward the macula (~25% reduction; P < 0.01). Supero-nasally, INL and ONL were thinner throughout (~25% reduction; P < 0.01). CONCLUSIONS. Our study revealed marked thinning in both the inner and outer layers of the retina. These quantified histopathologic findings provide a more comprehensive understanding of the retina in AD than previously reported

Population-Based Assessment of Determining Predictors for Discharge Disposition in Patients with Bladder Cancer Undergoing Radical Cystectomy

Objective: To assess predictors of discharge disposition—either home or to a CRF—after undergoing RC for bladder cancer in the United States. Methods: In this retrospective, cohort study, patients were divided into two cohorts: those discharged home and those discharged to CRF. We examined patient, surgical, and hospital characteristics. Multivariable logistic regression models were used to control for selected variables. All statistical tests were two-sided. Patients were derived from the Premier Healthcare Database. International classification of disease (ICD)-9 (<2014), ICD-10 (≥2015), and Current Procedural Terminology (CPT) codes were used to identify patient diagnoses and encounters. The population consisted of 138,151 patients who underwent RC for bladder cancer between 1 January 2000 and 31 December 2019. Results: Of 138,151 patients, 24,922 (18.0%) were admitted to CRFs. Multivariate analysis revealed that older age, single/widowed marital status, female gender, increased Charlson Comorbidity Index, Medicaid, and Medicare insurance are associated with CRF discharge. Rural hospital location, self-pay status, increased annual surgeon case, and robotic surgical approach are associated with home discharge. Conclusions: Several specific patient, surgical, and facility characteristics were identified that may significantly impact discharge disposition after RC for bladder cancer

Optical Coherence Tomography of the Retinal Ganglion Cell Complex in Leber�s Hereditary Optic Neuropathy and Dominant Optic Atrophy

Background: Mitochondrial optic neuropathies such as Leber�s Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) have been shown to produce an optic neuropathy secondary to retinal ganglion cell loss with thinning of the retinal ganglion cell complex (RGCC). Methods: We performed a retrospective analysis assessing the thicknesses of the peripapillary retinal nerve fiber layer (pRNFL) along with the macular retinal ganglion cell-inner plexiform layer (RGC-IPL) using optical coherence tomography (OCT). We compared these changes among acute and chronic LHON, DOA, and normal healthy control patients. Results: Patients with chronic LHON exhibited statistically significant thinning of the RNFL in the superior, nasal, and inferior quadrants of the retina. In acute LHON, the RNFL was relatively thicker in all but the temporal quadrant when compared with respective quadrants in normal eyes; however, statistical significance was not achieved. In DOA, the RNFL was thinnest in the superior and inferior quadrants of the retina, measuring between acute and chronic LHON thickness values. In chronic LHON and DOA, both the pRNFL and RGC-IPL were significantly thinner in all four retinal quadrants relative to controls. Conclusions: This article represents the first comparative study of the RGCC between LHON and DOA. Our findings demonstrated significant thickness reductions in pRNFL and macular RGC-IPL in patients with LHON and DOA, with different specific patterns consistent with the general patterns of thinning classically observed. This study suggests the usefulness of the RGCC as a potential in vivo biomarker for assessing disease in patients with LHON and DOA. © 2019, © 2019 Taylor & Francis Group, LLC