Angiotensin-converting enzyme 2 (ACE2) is a newly discovered carboxy-peptidase responsible for the formation of vasodilatory peptides such as angiotensin-(1-7). We hypothesized that ACE2 is part of the brain renin-angiotensin system, and its expression is regulated by the other elements of this system. ACE2 immunostaining was performed in transgenic mouse brain sections from neuron-specific enolase-AT(1A) (overexpressing AT(1A) receptors), R(+)A(+) (overexpressing angiotensinogen and renin), and control (nontransgenic littermates) mice. Results show that ACE2 staining is widely distributed throughout the brain. Using cell-type-specific antibodies, we observed that ACE2 staining is present in the cytoplasm of neuronal cell bodies but not in glial cells. In the subfornical organ, an area lacking the blood-brain barrier and sensitive to blood-borne angiotensin II, ACE2 was significantly increased in transgenic mice. Interestingly, ACE2 mRNA and protein expression were inversely correlated in the nucleus of tractus solitarius/dorsal motor nucleus of the vagus and the ventrolateral medulla, when comparing transgenic to nontransgenic mice. These results suggest that ACE2 is localized to the cytoplasm of neuronal cells in the brain and that ACE2 levels appear highly regulated by other components of the renin-angiotensin system, confirming its involvement in this system. Moreover, ACE2 expression in brain structures involved in the control of cardiovascular function suggests that the carboxypeptidase may have a role in the central regulation of blood pressure and diseases involving the autonomic nervous system, such as hypertension.
Objective-Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON).Methods-Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at three centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed.Results-Among 299 patients (593 eyes) with ≥6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p<0.001; VA: p=0.005). RNFL thinning increased over time, with average losses of 2.9 μm at 2-3 years and 6.1 μm at 3-4.5 years (p<0.001 vs. 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (≥6.6 μm) increased from 11% at 0-1 year to 44% at 3-4.5 years (p<0.001).Interpretation-Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with sub-clinical axonal loss in the anterior visual pathway in MS and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.Address all correspondence to: Dr. Laura J. Balcer, Department of Neurology, 3 E. Gates, 3400 Spruce Street, Philadelphia, PA 19104, 215-349-8072, Fax 215-349-5579, lbalcer@mail.med.upenn.edu. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2011 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptVisual dysfunction is a common cause of disability and reduced quality of life in multiple sclerosis (MS). 1 The anterior visual pathway is a frequent site for inflammation and demyelination, and axonal degeneration is likely to be a final common pathway to permanent visual loss. [2][3][4][5] Recognized by MS experts as a critical dimension for outcomes assessment, 6 vision has been an important area of investigation. The findings of many studies have supported low-contrast letter acuity as a candidate clinical trial outcome measure. It can capture subtle visual impairment, treatment effects, MRI lesion burden, prolonged visual evoked potential latencies, and quality of life. 1,[7][8][9][10][11][12][13] Many ongoing MS trials have incorporated low-contrast acuity as a tertiary outcome.The emergence of optical coherence tomography (OCT) in MS has brought the anterior visual pathway to the forefront as a model for measuring therapeutic efficacy, particularly for trials involving neuroprotection. 14-32 A reliable marker for axonal loss in MS, 24 retina...
PURPOSE To determine the magnitudes of binocular summation for low- and high-contrast letter acuity in a multiple sclerosis (MS) cohort, and to characterize the roles that MS disease, age, interocular difference in acuity, and a history of optic neuritis have on binocular summation. The relation between binocular summation and monocular acuities and vision-specific quality of life (QoL) was also examined. DESIGN Cross-sectional observational study. METHODS Low-contrast acuity (2.5% and 1.25% contrast) and high-contrast visual acuity (VA) were assessed binocularly and monocularly in patients and disease-free controls at 3 academic centers. Binocular summation was calculated as the difference between the binocular and better eye scores. QoL was measured using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and the 10-item neuro-ophthalmic supplement. The relation of the degree of binocular summation to monocular acuity, clinical history of acute optic neuritis, age, interocular acuity difference, and QoL was determined. RESULTS Binocular summation was demonstrated at all contrast levels, and was greatest at the lowest level (1.25%). Increasing age (P < .0001), greater interocular differences in acuity (P < .0001), and prior history of optic neuritis (P = .015) were associated with lower magnitudes of binocular summation; binocular inhibition was seen in some of these patients. Higher magnitudes of summation for 2.5% low-contrast acuity were associated with better scores for the NEI VFQ-25 (P = .02) and neuro-ophthalmic supplement (P = .03). CONCLUSION Binocular summation of acuity occurs in MS but is reduced by optic neuritis, which may lead to binocular inhibition. Binocular summation and inhibition are important factors in the QoL and visual experience of MS patients, and may explain why some prefer to patch or close 1 eye in the absence of diplopia or ocular misalignment.
Objective Ocular motility abnormalities may be a marker of neuro-degeneration beyond motor neurons in amyotrophic lateral sclerosis (ALS). We formally compared clinical neuro-ophthalmic abnormalities in ALS patients and a control population. Methods Patients attending a multidisciplinary ALS clinic (n = 63, age 60.8 +/− 16.4 years) and their caregivers serving as controls (n = 37, ages 55.0 +/− 12.7 years) participated in this cross-sectional study. Visual acuity was assessed. Video recordings of a standardized ocular motility exam including gaze fixation, voluntary saccades, reflex saccades, smooth pursuit, eyelid opening and Bell's phenomenon were rated by two senior neuro-ophthalmologists who were masked to subject group. Results Visual acuity was lower in ALS patients versus control subjects (OR 0.81 (0.71–0.93), p = 0.003, logistic regression). Inter- and intra-rater reliability for ocular motility examination ratings were good (Cohen's Kappa > 0.6). Findings observed only in ALS subjects included gaze impersistence (14%, p = 0.01), moderately or severely restricted voluntary upgaze (13%, p = 0.01), and moderate or severe eyelid opening apraxia (27%, p = 0.0002). Accounting for age, moderately or severely saccadic horizontal smooth pursuits distinguished ALS from control subjects (OR 3.6 (1.2– 10.9), p = 0.02, logistic regression). Conclusions Clinical findings of decreased visual acuity, gaze impersistence, voluntary upgaze restriction, eyelid opening apraxia, and saccadic horizontal smooth pursuits are more frequent in patients with ALS than in similar-aged controls. These findings are potential clinical markers of neurodegeneration beyond upper and lower motor neuron disease in ALS. Further study is warranted regarding their application to disease categorization and outcomes assessment.
Background Neuronal loss in the retina has been demonstrated pathologically in eyes of patients with multiple sclerosis (MS). In vivo, MS eyes have reduced total macular volumes by optical coherence tomography (OCT). Using high-resolution spectral-domain OCT, this pilot study used a manual method to measure ganglion cell layer (GCL) volumes and to determine the relation of these volumes to visual function in MS eyes. Methods Sixteen eyes of eight patients with MS and eight eyes of five disease-free control participants were studied using fast macular OCT scans performed with Spectralis OCT (Heidelberg Engineering). Visual function tests of low-contrast letter acuity and high-contrast visual acuity (VA) were administered. Results MS patient eyes had significantly lower GCL volumes than the control eyes (p<0.001 vs. controls, GEE regression models accounting for age and within-patient, inter-eye correlations). Within the MS group, eyes with a prior history of optic neuritis (ON, n=4) had significantly lower GCL volumes than MS eyes with no ON history (P<0.001). In contrast to measures of high-contrast VA (P=0.14), decreased GCL volumes were associated with worse performance on low-contrast letter acuity testing (P=0.003). Conclusions This pilot study has characterized thinning of the GCL in MS patient eyes, particularly in those with a history of acute ON, which corresponded to a reduced performance on low-contrast letter acuity testing. Studies utilizing computerized segmentation algorithms will continue to facilitate the detection of GCL loss on a larger scale and provide important information in vivo on the role and timing of neuronal vs. axonal loss in MS eyes.
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