People living with dementia (PWD) experience unique difficulties in coping with comorbidities, including visual impairment. A recent large-scale study [1] identified visual impairment as more prevalent among PWD compared with older people, generally. Overall, 19% of PWD had a remediable form of visual impairment, and other studies have identified potential links between poor visual acuity (VA) and cognitive decline [2-5]. Recent reviews highlighted that sensory deterioration such as vision and hearing loss can both contribute to or be a consequence of cognitive decline through both direct and indirect mechanisms [6]. For example, dementia-related cortical vision processing abnormalities may give rise to such a link [4,7], but visual problems have also been found to precede cognitive decline and increase the risk of dementia [5,8,9]. However, the mechanisms suggested for this association are being debated, including functional disability affecting engagement with cognitively stimulating activities [5,8,10] and interaction with depressive symptomology [8]. Overall, it is suggested that addressing global sensory deterioration may significantly impact the quality of life for PWD and their caregivers [9-11], with some studies suggesting that routine sight-restoring treatments such as cataract surgery have the potential to modify the trajectory of cognitive decline [12] or increase gray matter volume [13].

Assessment of visual function within larger studies [1,5] was limited to high-contrast VA, excluding another potential source of debilitating visual symptoms—disorders in binocular vision (BV), leading to asthenopia, strabismus, and diplopia. This, with the associated loss of depth perception, can contribute to falls in older people [14], impact fine motor task performance [15], and affect psychosocial well-being [16]. Problems with BV increase in prevalence with advancing age [17] and are often remediable with simple treatments where the etiology is related to oculomotor control, known to be disrupted in some types of dementia [7,18]. However, the literature on the prevalence of BV disorders for PWD is limited; only 3 small-sample studies have evaluated the quality of stereoacuity [2-4], with other grades of BV (eg, motor fusion) unconsidered. The findings in these studies are conflicting, potentially due to differing stereotests used between studies as the upper limit of normality [19], and the impact of refractive blur varies between stereotests [15].

A pilot study explored the measurement of BV among people with cognitive impairment (n=7; Table 1). Although the sample size precludes a formal statistical analysis, the raw data suggest difficulty in attempting static random dot stereotests in comparison with real depth (Frisby) or dynamic (Accurate STEReotest: ASTEROID [20]) stereotests, particularly the Preschool Randot (PSR) stereotest, which lacks a monocular control to facilitate an understanding of the test.

Data were collected from council day center attendees with no history of amblyopia, strabismus, or ocular trauma, scoring ≤21 on the Mini Addenbrookes Cognitive Examination, a score highly likely to have come from someone with dementia. Near tests were conducted at 33 cm, the distance VA test was conducted at 3 m, and all stereotests were performed according to the manufacturer’s instructions. The ASTEROID stereotest was not performed in 1 patient (002) due to a history of seizures. The ethical approval reference number is 18/YH/0152.

Depth perception problems are a commonly cited aspect of living with dementia [21], and there are known impacts of Alzheimer disease on oculomotor nuclei [7], important in binocular eye coordination, and the parietal lobe, integral to binocular processing for depth perception [22]. It is reasonable to hypothesize that the strength of depth perception would deteriorate as dementia progresses, but no studies have attempted to confirm this. Visual perception problems have been proposed as a unique risk factor for falls in PWD [23,24]. Falls are more common in PWD [24], including injurious falls such as hip fractures [25], and hospitalization of older adults carries an increased risk of further cognitive decline [26]. Delirium is a common mechanism for progression of dementia following hip fracture [27]. As such, monitoring of visual functions could identify those living with dementia who are at greater risk of injurious falls and hospitalization that could exacerbate the progression of dementia. Recent reviews have called for more research into the role of visual functions as a less costly and invasive biomarker for the progression or severity of dementia [28,29]. However, the interaction among primary visual function (VA and contrast sensitivity), binocular functions such as stereopsis and horizontal fusional vergence range, and rate of cognitive decline (eg, cognitive test score) in PWD is yet to be evaluated formally. Consideration of strength of depth perception as a potential contributor to visual difficulties in dementia may therefore add predictive value to this suggested marker of disease progression.

Emerging evidence suggests that pupil dynamics could also index the progression of dementia, potentially serving as a biomarker for early diagnosis [30]. Pupillary responses (maximum dilation velocity, average dilation, minimum and maximum size) are mediated by brainstem structures showing early pathological changes in PWD [7]. Measuring task-evoked pupil changes for PWD during a memory task (varying cognitive load level) in addition to monitoring visual, binocular, and cognitive function over time enables a comprehensive evaluation of clinical visual changes in PWD and their relationship to changes in cognitive status via indicators such as the standardized Mini Mental State Examination (MMSE) score.

The addition of structural and functional magnetic resonance imaging (MRI) would enable preliminary evaluation of potential relationships between clinical visual changes, cognitive decline, and cortical structure or activation in PWD. This can be coupled with an evaluation of sleep quality, which is an emerging area of interest in Alzheimer disease due to sleep fragmentation being identified as a risk factor for cognitive decline [31]. Anatomically, the visual system has important input into circadian rhythms [7], with cataract surgery being reported to improve sleep quality because of better light transmittance [32,33]. Furthermore, a recent cross-sectional study identified visual impairment as being associated with the presence of sleep problems in institutionalized individuals with dementia [34]. Despite the known clinical relationship between sleepiness and deterioration of binocular coordination, research in this area has focused on the effects of major or total sleep deprivation [35-37]. No study to our knowledge has attempted to formally explore the relationship between quality of sleep measures, such as sleep latency and fragmentation, and clinical measures of BV. The mapping rate of brain atrophy (on structural MRI) and blood oxygenation level dependent (BOLD) activation levels in visual areas (on functional MRI) against visual function, binocular function, rate of cognitive decline, and baseline sleep quality may help determine whether clinical visual changes possess predictive or diagnostic potential as well as identify possible mechanisms for such an interaction.

This proposed exploratory observational study attempts to address these gaps in the literature based on the study aims presented above. Performing this study on an exploratory basis enables the inclusion of multiple dementia types because of the overall dearth of literature on the occurrence of BV disorders and pupillary changes among dementia types other than Alzheimer disease. Answering these research questions will determine whether changes in BV and pupil dynamics, in addition to changes in visual function, should be given further consideration as potential markers or predictors of both changes in cognitive status (indexed by standardized MMSE, found to agree substantially with the Clinical Dementia Rating for mild-to-severe dementia [38]) and cortical changes in structure or function during the course of recently diagnosed dementia.

This study aims to do the following:

The study is an exploratory observational study.

The inclusion criteria for all participants (maximum, n=210) included the following:

The inclusion criteria or the subset of PWD receiving MRI (n=30; comprising a suitable subsample for the pilot study [39]) included the following:

Frontotemporal dementia was excluded because of the higher likelihood of challenging behavior being exhibited [41], presenting a risk for the lone researcher during testing. Parkinsonian dementia was also excluded as the binocular function and oculomotor deficits in Parkinson disease are well documented [42-44]. A diagnosis window of 24 months was selected over the use of a cognitive test score cap to permit heterogeneity in dementia severity across the sample to explore the prevalence of BV disorders while also minimizing skew toward people with more severe dementia, which may limit the ability to effectively evaluate changes in cognitive status over time. Such heterogeneity can occur within this window because of known diagnostic delays for dementia (18-30 months [45]).

No upper or lower age limits were applied to maximize recruitment, although it was anticipated based on previous audits of the case pool of the recruiting National Health Service (NHS) Trust that the majority of potential participants were likely to be aged 60 years. Research on the prevalence of BV disorders in association with advancing age is limited and excludes PWD, but one large sample study found a 19.1% difference in the prevalence of BV disorders between adults aged between 60 and 69 years and those aged 80 years. To minimize the possible impacts of an unrestricted age range leading to a preponderance of one particular age group affecting the anticipated prevalence of BV disorders within the sample, an average prevalence for binocular vision disorders was calculated for adults aged 60 years using the data from this study and was used to inform the choice of sample size. Previous studies [46,47] have commented on the difficulty in distinguishing visual problems arising from the presence of dementia from those arising as a consequence of advancing age, but fundus or media pathologies such as cataracts and age-related macular degeneration are known to be prevalent in this patient group [1]. Studies evaluating the relationship between the presence of these pathologies and the presence of cognitive impairment or Alzheimer disease have presented conflicting results [7,48,49]. Attempting to restrict recruitment on this basis may limit the generalizability of the study findings and reduce sample size and the ability to explore the data collected.

As the proposed study focuses on tracking clinical changes in visual, pupillary, binocular, and cognitive functions within a restricted time frame, the emphasis is less on the underlying cause of these changes (ie, dementia vs fundus or media pathology) and more on exploring the relationships between them. Thus, for this study, the inclusion of individuals with certain fundus or media pathologies per a previous large-scale study (diabetic retinopathy, cataract, and age-related macular degeneration) [1] can be permitted. This enables the possibility for a subgroup analysis while still achieving the research aims.

Eligible participants, identified by their direct care team within participating NHS Trust community mental health clinics or from a database of research volunteers held by the research & development (R&D) department, will be provided with study information during their clinic appointment or by post following telephone contact if they express an interest to participate.

Sample size is justified on a pragmatic basis, balancing recruitment feasibilities with the research aims of exploring potential relationships between cognitive status and visual, binocular, and task-evoked pupil function. It is anticipated that up to 210 participants could be reasonably tested within a 10-week period, determined by funding constraints to allow completion of the study within 12 months. This assumes a 60-min consent and testing slot per participant, 7 participants per day, 3 days per week. A maximum target sample of 210 participants was permitted.

The participating NHS Trust receives approximately 1890 referrals annually for people with dementia, and diagnoses up to 160 individuals with dementia monthly, providing a large pool of potential participants commonly aged 60 years (unpublished data). Among older people aged 60 years without dementia, the average prevalence of BV disorders was 31.6% [17]. If >200 PWD are recruited, approximately 63 PWD could have reduced binocular function, suitable for exploratory analysis of BV disorders and altered pupil responses with a standard error <3.5% based on the hypothesis that PWD may have greater proportions of abnormal test results than people without dementia.

PWD eligible for MRI subgroup inclusion will be serially recruited during the initial study visit until the subgroup sample size was achieved (n=30). If withdrawing after the first scan, they will not be replaced in recruitment.

Informed consent will be sought from participants or a consultee process will be employed where appropriate, with the capacity to consent determined by a validated brief questionnaire [50] where indicated. Ongoing consent [51,52] will be determined on a per-visit basis. The consent form also includes provisions for the participant to express their wishes concerning participation in the study, should they experience a loss of mental capacity before the study is completed, as an adjunct to these considerations.

A case history (caregiver supported if required), including dementia type and diagnosis date, ensures eligibility criteria are met. Dementia type and diagnosis date, previous ocular history, and previous imaging findings will be corroborated using the patient’s medical records after consent is obtained.

Eligibility screening is supported by optometric information (VA, current prescription, and fundus/media check findings), obtained from the patient's optometrist, or a monocular distance VA test if the last NHS sight test was >1 year ago. If the latter satisfies the eligibility criteria, an updated sight test can be arranged by the researcher (by written agreement) or the participant or their caregiver with a provider of their choice. If eligible to participate, the researcher will contact the participant to organize the initial study visit as well as an MRI scan if eligible.

All participants will be invited to complete the Pittsburgh Sleep Quality Index at each study visit—or this can be proxy-completed by a caregiver with knowledge of the participant’s sleep patterns.

The following clinical tests will be performed at a community clinic or in the participant’s home by the researcher (registered orthoptist) at all study visits:

The testing time is approximately 60 min in total (including computer setup), with breaks offered if required. All tests are low-risk, quick, noninvasive, and (except for pupillometry) routinely performed in orthoptic practice.

All participants will return for 2 follow-up assessments, 4 months apart (plus or minus 2 weeks), repeating the above tests. Adaptations required to enable performance of a test will be documented, for example, change in test target, use of matching card, demonstration of testing procedure, and instances where performing tests was not possible.

The MRI subgroup (n=30; diagnosis of Alzheimer disease) will also receive an MRI scan (within 2 weeks of the first and final study visits) using a 3T TIM Trio MR scanner (Siemens) with a 32-channel array head coil.

Whole-brain scans performed included the following:

Viewing comprised the following:

The minimum duration between scans is 8 months. Visits last no more than 90 min, of which no more than 45 min will be spent in the scanner. A mounted frame and padding will be used to minimize head movement for participants. As all participants must pass a capacity assessment before entering the scanner, it is not anticipated that artifacts such as head motion are any more likely to occur than they would be for any other individual of similar age. A break will be offered between the retinotopic mapping and stereoscopic functional MRI sections to minimize fatigue. The scan order is as follows: T1, retinotopic mapping functional MRI; T2, fluid-attenuated inversion recovery; and stereoscopic target functional MRI. The researcher will speak to the participant via intercom between each of the scans to ensure that the participant is comfortable, understands what is about to happen, and is still awake.

This subgroup will also be invited to wear a sleep-tracking watch (Actiwatch, Camntech) and complete a consensus sleep diary during a 10-day period following the first and final study visits, returning the watch and diary by post in a prepaid envelope.

Abnormal test results will be determined using the criteria adapted from Leat et al (Table 2) [17].

To establish the prevalence of BV disorders, the proportion of abnormal test results will be reported and compared by age group, dementia severity, and dementia type as well as against the data in Leat et al [17]. Pupillometry measures (maximum dilation velocity, average dilation, and minimum/maximum size) for high and low cognitive loads will be similarly compared with age-related norms collected in a separate study of adults aged 50 years with a normal standardized MMSE score (>26 out of 30) using the same paradigm.

MRI data will be visually inspected for quality, and participants with excessive head motion (>3 mm in any axis or >3) will be excluded. Functional MRI data will be preprocessed and analyzed in SPM8 (Wellcome Department of Imaging Neuroscience) using the standard generalized linear model approach. Preprocessing will correct for slice timing and head motion. Smoothing will not be performed to preserve spatial resolution and, because of the within-subject design, spatial normalization will not be required. In each participant’s design matrix, the timing of the stimulus blocks will be entered as regressors of interest and convolved with the canonical hemodynamic response model; head motion parameters will be included as covariates of no interest. To analyze the multifocal retinotopic mapping results, the procedure outlined by Henriksson et al [53] will be followed: coregistration between anatomical and functional data will be performed in SPM before transfer to Freesurfer using each participant’s T1-weighted structural scans and the preprocessed functional MRI data. Eccentricity and polar angle retinotopic maps will be visualized using Freesurfer and used to denote regions of interest (ROIs) for primary visual areas V1, V2, V3, V4, and V3A. For stereoscopic image viewing, within-subject change between the first and final visits in the regional BOLD signal will be calculated for occipital and parietal lobe ROIs. Structural analyses will be conducted using Freesurfer; changes in cortical thickness in the occipital and parietal lobe ROIs and changes in the medial temporal lobe volumes will be calculated at the within-subject level.

A linear mixed model approach will assess, at the within-subject level, changes in the following variables at the level of time (visit number): pupillometry measures (time to maximum dilation, percentage maximum dilation from baseline, percentage maximum constriction from baseline, and baseline pupil size), visual function (VA and contrast sensitivity), binocular function (PSR and Frisby stereoacuity, NPC, and PFR), and standardized MMSE. Linear mixed modeling enables the consideration of repeated measures with the selection of a suitable covariance matrix. It is also effective in the presence of missing data for individual tests, making it an ideal approach to accommodate instances where PWD may, for example, be able to complete the high-load task-evoked pupillometry assessment at one visit but not the next.

Models that control for dementia type will determine relative contributions made by changes in pupillometry measures, visual function, and binocular function to changes in standardized MMSE, regional BOLD activation percentages, brain volume, and cortical thickness (first vs final visit). Results will be contrasted between PWD with and without a diagnosed BV disorder. Further subgroup analyses by presence/absence of fundus/media pathology or BV disorder will be performed depending on prevalence.

For participants who complete sleep actigraphy, linear mixed models will examine the level and rate of change in binocular function measures, standardized MMSE, regional BOLD activation percentages, brain volume, and cortical thickness (first vs final visit) as a function of sleep quality at baseline, adjusted for age, sex, and education, and their interactions with time.

This research was funded in February 2018 and received approval from the NHS Research Ethics Committee in September 2018. The data collection period was from October 1, 2018, to November 30, 2019. A total of 24 participants were recruited for the study. Data analysis is complete, and the results are expected to be published before the end of 2020.

Binocular, visual, and pupil function tests are routine, low-risk, quick, and noninvasive; if found to be interlinked markers of cognitive decline, monitoring their change over time could be an important aspect of future dementia care. Orthoptists, as allied health professionals, are well-placed to take on this role because of their ability to conduct objective assessments of visual function in people with cognitive difficulties, thereby obtaining robust clinical data.

If BV disorders are found to be more prevalent in this group than in older people, further research could explore the impact of treating BV disorders on quality of life for PWD and their caregivers, potentially evidencing to commissioners the need for dedicated orthoptic services for PWD. This would also provide evidence for the inclusion of assessment and treatment of BV disorders within the College of Optometrists [56] and Royal College of Ophthalmologists [57] dementia guidelines and the proposed Dementia Eye Care Pathway [58], where it does not currently feature.

Study information materials have been developed with 3 patient involvement representatives who have dementia or care for someone with dementia. Designing study materials with this patient group ensures that they are suitable for use in the informed consent process. This involvement work supported timely ethics review and has also assisted in developing the best method of approaching people with dementia to participate in the study.

We consulted with our involvement representatives about several issues pertaining to the study, such as the best approach toward eligibility screening and redistribution of funds allocated for honorariums where a participant does not have the capacity and is unable to receive it. We also sought advice from the patient involvement staff at the Alzheimer’s Society to ensure that our approach reflected best practices.

For honorariums, it was recommended that a discussion take place at the point of entry to the study, in instances where the participant has capacity to consent, to establish their preferences for distribution of the honorarium in the event that their capacity deteriorates. Another alternative suggested where capacity was not present at the point of enrolment in the study was reallocating the honorarium amount toward reimbursement of other costs associated with study participation as appropriate, for example, meal vouchers and increased travel budget.

For eligibility screening, our representatives shared their experiences of having their eyes tested and felt that offering to organize the test would be acceptable to avoid inducing the burden of participation, provided potential participants and their caregivers are also given the option to organize their own test if they wish and they have given consent for contact details or test results to be exchanged for this purpose.

Our patient involvement volunteers remain involved throughout the study, with additional patient involvement meetings scheduled for after data collection, to discuss any issues with the recruitment approach or study methods that may require an amendment, and at the end of the study to present the findings, establish the key take-home messages relevant to people with dementia and their caregivers, and to develop a lay summary of the findings. The Health Research Authority and INVOLVE patient involvement standards [62] were used to develop the initial recruitment materials and information pack for being involved in the study and are being used for communications with our involvement representatives throughout the study. HRA guidance on discussing public involvement embedded within the Integrated Research Application System application form was also followed.