yes / N/A

This thesis documents Phase III of a research program undertaken by the Virginia Transportation Research Council and the Virginia Tech Transportation Institute in cooperation with the 3M Company and the Virginia Department of Transportation for the evaluation of visual performance of retroreflective signs of various color combinations. Phase I was an off-road field experiment conducted to determine the best sign color combination, letter stroke width, and letter size for the emergency sign. Based upon the results of Phase I, three color combinations were chosen for testing (black on coral, black on light blue, and yellow on purple) against a baseline color combination of black on orange.Phase II was conducted using an instrumented vehicle through a construction zone-related detour. Questionnaire data were also obtained. The independent variables of interest were sign color combination, age, and visibility condition. The findings of Phase II indicated that use of a color combination other than the traditional black on orange sign would improve driver performance and safety when used for trailblazing during critical incidents, especially when the incident route overlaps a work zone detour. A serious limitation of Phases I and II is that the use of fluorescent colors was not evaluated. Anecdotal evidence suggests that the use of fluorescent colors on signs improves their conspicuity. The purpose of Phase III was to evaluate fluorescent sign color combinations for incident management trailblazing purposes. This study consisted of an on-road investigation using an instrumented vehicle over a 12.2-mile route in urban and rural areas of Montgomery County, Virginia. The following conclusions were made:*A non-fluorescent yellow on non-fluorescent purple sign is least preferred by both older and younger drivers when compared to the other sign color combinations employed in this study.*Both younger and older drivers have a preference for a black on fluorescent yellow-green sign.* Fewer late braking maneuvers and fewer turn errors were recorded during daytime conditions than during nighttime conditions. *Older drivers tended to register more late braking maneuvers than did younger drivers. / Master of Science

No / PURPOSE. Previous studies suggest that optimal reading speed is unaffected by cataract, yet is significantly reduced in age-related macular degeneration (ARMD ). This raises the question of whether a reading speed test could be developed to assess potential vision after cataract surgery. METHODS. Nineteen subjects with cataract, 15 with ARMD, and 13 control subjects with normal, healthy eyes read Bailey-Lovie word charts aloud, and subsequently, critical print size and optimal reading speed were calculated. Measurements were also taken with the charts in reversed-contrast polarity and after pupillary dilation. RESULTS. Although the subjects with cataract had reduced word acuity and increased critical print size, optimal reading speed was similar to that of the control group at a mean of approximately 100 wpm. Optimal reading speed in the subjects with ARMD was substantially worse (mean of 39 wpm). Reversing the contrast polarity of the charts slightly increased the word acuity and optimal reading speed of the subjects with cataract. CONCLUSIONS. The results suggest that optimal reading speed would be useful as a potential-vision test. The proposed test would use text size of at least 1.32 degrees (1.2 log minimum angle of resolution [logMAR]), and pupil dilation would be unnecessary. A reading test with black letters on a white background would be adequate, because charts with reversed-contrast polarity made minimal difference in reading speed.

No / Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on–off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.

Yes / Purpose: To demonstrate methods that enable visual field sensitivities to be compared with normative data without restriction to a fixed test pattern. Methods: Healthy participants (n = 60, age 19–50) undertook microperimetry (MAIA-2) using 237 spatially dense locations up to 13° eccentricity. Surfaces were fit to the mean, variance, and 5th percentile sensitivities. Goodness-of-fit was assessed by refitting the surfaces 1000 times to the dataset and comparing estimated and measured sensitivities at 50 randomly excluded locations. A leave-one-out method was used to compare individual data with the 5th percentile surface. We also considered cases with unknown fovea location by adding error sampled from the distribution of relative fovea–optic disc positions to the test locations and comparing shifted data to the fixed surface. Results: Root mean square (RMS) difference between estimated and measured sensitivities were less than 0.5 dB and less than 1.0 dB for the mean and 5th percentile surfaces, respectively. Root mean square differences were greater for the variance surface, median 1.4 dB, range 0.8 to 2.7 dB. Across all participants 3.9% (interquartile range, 1.8–8.9%) of sensitivities fell beneath the 5th percentile surface, close to the expected 5%. Positional error added to the test grid altered the number of locations falling beneath the 5th percentile surface by less than 1.3% in 95% of participants. Conclusions: Spatial interpolation of normative data enables comparison of sensitivity measurements from varied visual field locations. Conventional indices and probability maps familiar from standard automated perimetry can be produced. These methods may enhance the clinical use of microperimetry, especially in cases of nonfoveal fixation.

Yes / Depictions of vision with AMD in public information material typically show a central region of absolute vision loss. Patients with early and moderate disease frequently do not report this. We aimed to measure how a group of people with AMD perceive everyday scenes in order to produce accurate depictions. We report on six people aged 65-82 years with monocular AMD (visual acuity +0.04 to +1.64 logMAR) and normal vision in the fellow eye. Participants viewed 4 images monocularly, alternating between eyes. The image was digitally altered to approximate participants’ descriptions of their perception with the affected eye. The altered image was viewed with the unaffected eye, and compared with the original image viewed with the affected eye. This was repeated iteratively until a perceptual match was achieved between the modified image/unaffected eye and the original image/affected eye. For five AMD participants with visual acuity +0.04 to +0.50 logMAR the modified images did not resemble those in current public information material. Image modifications required to achieve perceptual similarity with the affected eyes included localised distortion, contrast reduction and blur. Widespread colour desaturation was also required in some cases. One participant with advanced geographic atrophy reported an absolute positive scotoma, similar to existing depictions. Vision in people with AMD may not conform to the common depiction of a central region of absolute vision loss. The accurate representations of AMD patients’ vision produced in this study will enable better understanding of the visual consequences of AMD. / College of Optometrists Postdoctoral Award; National Institute for Health Research Postdoctoral Fellowship

Yes / Fundus-controlled perimetry (FCP, also called 'microperimetry') allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.

Age-related maculopathy (ARM) is a central retinal disease with unclear pathogenesis. It is the major cause of permanent vision loss in adults over 50 years and is increasing in prevalence and incidence, faster than the aging population would suggest. Early in the disease process (early ARM) there is little or no vision loss and there are only slight retinal changes with abnormal deposits within Bruch's membrane. As the disease progresses (late ARM or age-related macular degeneration, AMD) vision loss may be quite severe due to atrophy (dry AMD) or the development of chorioretinal neovascularisation (CNV, wet AMD). It is hard to predict from conventional eye examinations and clinical vision tests which cases will progress to the severe, dry or wet forms of the disease. Moreover, most of the conventional clinical tests are based upon subjective vision measures. Objective tests which detect ARM earlier would be a useful aid to diagnosis and to monitoring progression. The multifocal electroretinogram (mfERG) is a relatively new clinical tool which enables the recording of electrical potentials from multiple, small areas of the central retina and thus assesses function from specific retinal locations. It is therefore useful in detecting focal retinal diseases such as hereditary or acquired maculopathies or in monitoring retinal laser or surgical treatment effects. There is cone and rod impairment in ARM and histopathological and psychophysical evidence for a preferential vulnerability of rods compared to cones. This research project investigated if an objective tool such as the mfERG could detect early ARM,its progression and the treatment effects of multiple photodynamic therapies (PDT) on retinal function in late ARM, prior to a battery of subjective vision measures. For comparison purposes a subjective assessment of central retinal function was performed using high and low contrast distance visual acuities (VA), near VA, low luminance VA (SKILL cards), contrast sensitivity (Pelli-Robson, P-R), saturated and desaturated Panel D-15 (sat Panel D-15, desat Panel D-15) and central visual fields (Humphrey 10-2, mean sensitivity, MS and mean defects, MD). As an objective assessment of central retinal function the cone- and rod-mediated multifocal electroretinograms were recorded. Subjective and objective tests of retinal function were compared in early ARM and an age-matched control group (chapter 3). Seventeen eyes of seventeen subjects with early ARM and twenty control subjects with normal vision were measured. For the cone-mediated mfERG responses conventional averaging methods were used and results were correlated with subjective vision tests. The conventional cone-mediated mfERG failed to distinguish between the early ARM and control subjects whereas subjective vision measures such as HC- and LC-VA, desat Panel D-15, MS, P-R were significantly reduced in the ARM group. However, there were significant correlations between the cone-mediated mfERG and the desat Panel D-15 results in the ARM group. This suggests that the mfERG measures similar retinal processes that detect colour vision deficiency under desaturated conditions. There was no significant correlation between cone-mediated mfERG measures and funduscopic changes. The conclusion from this study was that the subjective vision tests detected early ARM better than the objective cone-mediated mfERG. Thus the aim of detecting early ARM objectively was not met by the cone-mediated mfERG suggesting the need to develop other objective tests such as a rod-mediated mfERG. Whether the preferential rod vulnerability others have reported in early ARM could be detected by the rod-mediated mfERG was determined in the next study (chapter 4). A protocol for recording rod-mediated mfERG responses was developed by determining the optimal testing luminance to reduce the effect of stray light and elicit maximal rod-mediated responses. Sixteen of the seventeen ARM subjects and seventeen control subjects from the previous study were tested. For analysis, a customized computer template fitting method was developed in MATLAB (Mathworks, Natick, MA, USA). This method has been shown to be useful for low signal-to-noise ratio responses that characterize the rod-mediated mfERG. Significantly delayed rod-mediated mfERG responses were found whereas cone-mediated mfERG responses were within the normal range. This suggested that the effect of ARM on the rod system could be detected objectively with the rod-mediated mfERG before changes in the cone-mediated mfERG. Which of the tests best detected progression of vision loss was investigated in chapter 5. Visual function of 26 (13 ARM and 13 control subjects) of the original 37 subjects (17 ARM and 20 control subjects) had cone- and rod-mediated mfERG and the subjective vision measures repeated after one year. The main purpose was to determine which of the tests best detected progression of vision loss. The mfERG results were analysed by using both averaged and local responses and by using the computer template fitting procedure. On average no significant worsening of either objective or subjective function measures was evident after one year. These results reinforce the slow progression of the disease. With a longer follow-up period progression of ARM may translate into measurable changes in the mfERG and the other visual function tests. The effect of multiple photodynamic therapies (PDT) on cone- and rod-mediated function was assessed with the mfERG in the last study (chapter 6). The cumulative treatment effects of PDT in five subjects with late ARM were determined. Having demonstrated that the rod-mediated mfERG was applicable in early ARM, this study also aimed to investigate how useful it was in late ARM where there is substantially greater rod loss. Cone- and rod-mediated mfERGs, visual acuities, contrast sensitivities and central visual fields were investigated a week before treatment began and then one month after each PDT treatment. The subjects received three treatments each over an average period of five and a half months. In some subjects there were significant transient reductions in cone- and rod-mediated amplitudes possibly reflecting alterations in choroidal hypoperfusion dynamics one month after treatment. Further, b-wave component of the mfERG became increasingly misshapen after each PDT treatment suggesting an ischemic insult mainly targeting post-receptoral sites. However, objective and subjective function was stabilized after multiple PDT treatments in most of the subjects. This pilot study of five cases showed that there was no additional damage to cone- and rod-mediated outer retinal function after three PDT treatments. One of the novel findings of this research was that the rod-mediated function measured with the mfERG was impaired in early ARM. This finding supports histopathological and psychophysical evidence of rod vulnerability in early ARM. The results of these studies also suggest that early ARM affects different aspects of visual function which is reflected by different outcomes from objective and subjective vision tests. A model (chapter 7) based upon the results was developed proposing a hypoxic insult with a preferential alteration of post-receptoral sites in early ARM. The cone-mediated mfERG documented the retinal damage and possible treatment effects on outer retinal function of the multiple PDTs which did not further deteriorate. Thus, this technique might assist in the development of optimal treatment modalities for ARM, especially in retreatment regimes. Greater variability was found for the rod-mediated mfERG and its clinical use in PDT treatment regimes still needs to be investigated. In conclusion, this research has provided a better understanding of the disease process and treatment effects in ARM and might contribute to improvements in diagnosis and treatment of ARM.

Longitudinal studies of cognition are preferred to cross-sectional stud- ies, since they offer a direct assessment of age-related cognitive change (within-person change). Statistical methods for analyzing age-related change are widely available. There are, however, a number of challenges accompanying such analyzes, including cohort differences, ceiling- and floor effects, and attrition. These difficulties challenge the analyst and puts stringent requirements on the statistical method being used. The objective of Paper I is to develop a classifying method to study discrepancies in age-related cognitive change. The method needs to take into account the complex issues accompanying studies of cognitive aging, and specifically work out issues related to attrition. In a second step, we aim to identify predictors explaining stability or decline in cognitive performance in relation to demographic, life-style, health-related, and genetic factors. In the second paper, which is a continuation of Paper I, we investigate brain characteristics, structural and functional, that differ between suc- cessful aging elderly and elderly with an average cognitive performance over 15-20 years. In Paper III we develop a Bayesian model to estimate the causal effect of living arrangement (living alone versus living with someone) on cog- nitive decline. The model must balance confounding variables between the two living arrangement groups as well as account for non-ignorable attrition. This is achieved by combining propensity score matching with a pattern mixture model for longitudinal data. In paper IV, the objective is to adapt and implement available impu- tation methods to longitudinal fMRI data, where some subjects are lost to follow-up. We apply these missing data methods to a real dataset, and evaluate these methods in a simulation study.

Åldersrelaterad makuladegeneration (AMD) är en kronisk ögonsjukdom och är den vanligaste orsaken till irreversibel synnedsättning hos äldre personer i den industriella världen. Bakomliggande orsaker kan vara både genetiska och miljömässiga varför prevention och behandling av ögonsjukdomar kan öka livskvaliteten samt minska nedsatt syn och de funktionshinder som synnedsättning medför. Syftet med studien var att belysa ögonsjuksköterskans hälsofrämjande arbete med patienter som har åldersrelaterad makuladegeneration. Denna integrativa litteraturstudie visade att kunskapsnivån om AMD var låg både hos den allmänna befolkningen och patienter. Även patienter med allvarlig synnedsättning på grund av en eller flera ögonsjukdomar var omedvetna om sin diagnos. Patienter med AMD upplevde att de inte fick tillräckligt med information om sjukdomen, riskfaktorer, undersökningar och vilka behandlingar som fanns. Att drabbas av AMD innebar en stor påverkan på patienternas livskvalitet. Det visade sig att det fanns ett starkt samband mellan förlust av synfunktionen och symtom på depression. Ingen av studierna var från Sverige eller belyste svenska förhållanden men belyser vikten av att hälsofrämjande arbete och ökad medvetenhet kring kroniska ögonsjukdomar och dess riskfaktorer är mycket viktigt. Det vore av stort intresse att undersöka de svenska förhållandena som jämförelse. / Age-related macular degeneration (AMD) is a chronic eye disease and is the most common cause of irreversible vision loss amongst elderly people within the industrial world. Underlying causes can be both genetical and environmental, prevention and treatment of AMD can increase quality of life and reduce visual impairment and all dysfunctionalities related to it. The aim of this study was to highlight ophthalmic nurses' health promoting work with patients with age-related macular degeneration. This integrative literature review showed that the level of awareness of AMD was low among both the general population and patients. Even patients with severe vision loss due to one or several eye diseases was unaware of their diagnosis. Patients with AMD felt that they were not given enough information about the disease, the risk factors, available health examinations and what possible treatments were available. To be affected with AMD entails a significant negative effect on patients quality of life. It was shown that there was a strong connection between vision loss and symptoms of depression. None of the studies were from Sweden or highlighted the Swedish conditions but highlights the importance of health promotion, awareness about chronic eye disease and its risk factors as very important. It would be of great interest to investigate the Swedish conditions for comparison.