Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> The effects of diffuse cerebral dysfunction on oculomotor reaction time were assessed in patients with dementia of presumed Alzheimer's etiology and in normal age-matched control subjects. Patients were classified into mild, moderate, and severe groups on the basis of independent neurological, neuropsychological, and neuroradiological ratings for disease severity. Saccadic latencies to targets appearing in parafoveal and near peripheral vision showed significant increases from the normal controls to dementia groups, with each severity subdivision clearly differentiated from the others in terms of mean oculomotor reaction time. These data offer strong evidence for a direct relationship between degree of cortical structural integrity and simple oculomotor reaction time and suggest a higher cortical regulatory role in sensory-motor integration. <s> BIB001 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> We measured saccadic latencies in patients with Alzheimer's dementia (AD) and other types of dementia. The saccadic latencies for both groups were considerably longer than those for age-matched controls. The prolongation was as extensive in patients with other types of dementia as it was in those with AD. There was no correlation between latency and the severity of the dementia. <s> BIB002 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Saccades were measured by magnetic search coil technique in 13 patients with Alzheimer's disease and compared with those of 11 age-matched control subjects. We analyzed responses to target motion of predictable and unpredictable timing or amplitude, and responses to briefly flashed targets. Latencies were significantly prolonged and peak velocities reduced only when the timing of target motion was unpredictable. Saccades to predictable amplitude targets were abnormally hypometric. In 8 patients, impersistence of gaze was manifested by large-amplitude saccadic intrusions away from the intended position of gaze. When instructed to make saccades away from a flashed target, patients made reflexive saccades toward the target. We attribute this visual grasp reflex to frontal lobe degeneration. These eye movement deficits can be used to quantify motor dysfunction in Alzheimer's disease. <s> BIB003 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Abstract Visual fixation and saccadic eye movements were assessed in 31 mild to moderately demented patients with probable Alzheimer's disease (AD) and 31 age- and education-matched nondemented elderly control subjects. Seventeen AD and 17 matched control subjects were reassessed after a 9-month interval. On a fixation task, duration of fixation and number of intrusive saccades were not different between groups at baseline or follow-up. Both AD patients and control subjects showed more intrusive saccades at follow-up than at baseline. AD patients showed increased latency to initiation of saccades at baseline and on follow-up. Amplitude and velocity of saccades were not different between groups at any visit. Changes in measures of fixation, but no saccade measure, correlated with changes in MMSE scores over testing sessions. These data suggest that fixation is more sensitive than are saccades to the progression of AD. <s> BIB004 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimer's disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimer's disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimer's disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimer's disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders. <s> BIB005 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> The number of people living with Alzheimer's disease (AD), the major cause of dementia, is projected to increase dramatically over the next few decades, making the search for treatments and tools to measure the progression of AD increasingly urgent. The antisaccade task, a hands- and language-free measure of inhibitory control, has been utilized in AD as a potential diagnostic test. While antisaccades do not appear to differentiate AD from healthy aging better than measures of episodic memory, they may still be beneficial. Specifically, antisaccades may provide not only a functional index of the Dorsolateral Prefrontal Cortex (DLPFC), which is damaged in the later stages of AD, but also a tool for monitoring the progression of AD. Further work is required to: 1) strengthen the link between antisaccade errors, in AD, with the DLPFC; 2) insure that antisaccade errors do not result from memory, visuospatial, or other deficits associated with AD; and 3) further validate the clinical analogue of the antisaccade task. <s> BIB006 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Holmqvist, K., Nystrom, N., Andersson, R., Dewhurst, R., Jarodzka, H., & Van de Weijer, J. (Eds.) (2011). Eye tracking: a comprehensive guide to methods and measures, Oxford, UK: Oxford University Press. <s> BIB007 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Background: Studying saccades is a useful tool to investigate brain function. There is still controversy regarding deficits in prosaccades in Alzheimer’s disease (AD), and a study of saccades in subjects with mild cognitive impairment (MCI) has not been published to date. Methods: We examined horizontal saccades in 10 healthy elderly, and 9 MCI and 9 AD patients. Two tasks were used: gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). Eye movements were recorded with the Skalar IRIS system. Results: (1) Latencies were shorter in the gap than in the overlap task (a gap effect) in all three groups of subjects: healthy elderly, MCI and AD; (2) for both tasks, latency of saccades was longer for AD patients than for healthy and MCI subjects, and (3) accuracy and mean velocity were normal in MCI and AD subjects, however, variability in accuracy-speed was higher for AD patients than for healthy and MCI subjects in the overlap task. Conclusions: Abnormalities in reaction time and accuracy-speed variability reflect deficits in cerebral areas involved in the triggering and execution of saccades; a saccade test can be useful to follow up the evolution of MCI subjects as some of them may develop AD disease. <s> BIB008 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Saccadic impairment in Alzheimer’s disease (AD) was found in horizontal saccades. The present study extends investigation to vertical saccades in a large number of subjects, including AD and amnestic mild cognitive impairment (aMCI). We examined both horizontal and vertical saccades in 30 healthy elderly, 18 aMCI, and 25 AD. Two tasks were used: gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). Eye movements were recorded with the Eyeseecam system. (1) Robust gap effect (shorter latencies in gap than in overlap) exists for AD and aMCI patients as for healthy elderly; (2) abnormal long latency of saccades in gap and overlap tasks for AD relative to healthy elderly and aMCI patients; (3) longer latency for aMCI patients than for healthy elderly for the overlap task; (4) significant correlation between scores of Mini-Mental State Examination (MMSE) and latencies of saccades considering the AD group only; (5) higher coefficient of variation in latency for AD patients than for healthy elderly and for aMCI patients; (6) variability of accuracy and speed is abnormally higher in AD patients than in aMCI and healthy elderly. Abnormalities of latency and latency–accuracy–speed variability reflect deficits of cerebral areas involved in the triggering and execution of saccades; latency of saccades can be used as follow-up test for aMCI and AD patients with its significant correlation with the changes of MMSE scores. <s> BIB009 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> The antisaccade task, a hands- and language-free metric, may provide a functional index of the dorsolateral prefrontal cortex (DLPFC), a region damaged in the later stages of Alzheimer's disease (AD). Our objective was to determine if patients with mild AD made more errors relative to age-matched controls. Thirty patients with mild AD (Mini Mental Status Exam [MMSE] ≥ 17) and 31 age-matched controls completed a laptop version of the prosaccades and antisaccades tasks. Patients with AD made more antisaccade errors, and corrected fewer errors, than age-matched controls. Error rates, corrected or uncorrected, were not correlated with AD MMSE or Dementia Rating Scale scores. Our findings indicate that antisaccade impairments exist in mild AD, suggesting clinically detectable DLPFC pathology may be present earlier than suggested by previous studies. <s> BIB010 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Alzheimer’s disease (AD) is a disorder of progressive memory loss and executive dysfunction. Little is known about the progression from amnestic mild cognitive impairment (aMCI; isolated memory loss) to AD. Studies have found impairments in mild-stage AD and aMCI in specific tests of executive function. Here, we used objective saccade tasks to determine if they can effectively assess executive function deficits otherwise assessed by neuropsychological testing. To determine which executive function deficits the saccade tasks are most sensitive to, we also investigated the relationship between performance on saccade tasks and neuropsychological test scores. Twenty-two aMCI patients (63–90 years), 24 mild AD patients (61–87 years) and 76 healthy controls (60–85 years) performed a battery of neuropsychological tests, and two saccade tasks designed to probe sensory, motor and cognitive function. The prosaccade task requires a fast, automatic saccade toward an eccentric visual stimulus. The antisaccade task requires additional executive processing to inhibit the automatic prosaccade toward the stimulus, so that a voluntary saccade can be initiated to a location opposite the stimulus. Antisaccade performance was impaired similarly in aMCI and AD patients relative to controls; both groups were slower to initiate correct antisaccades and they made more direction errors (erroneous prosaccades), suggesting similar brain deficits. Scores on the Stroop task were inversely correlated with the percentage of short-latency direction errors in the antisaccade task for controls and aMCI patients, whereas other more global measures of executive function were not related to saccade measures in any subject group. Our results show that the antisaccade task is useful for detecting executive dysfunction in aMCI and AD, especially dysfunction in selective attention. Saccade tasks may therefore have potential to assess executive dysfunction when use of neuropsychological tests is not possible. <s> BIB011 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> A great amount of research has been developed around the early cognitive impairments that best predict the onset of Alzheimer’s disease (AD). Given that mild cognitive impairment (MCI) is no longer considered to be an intermediate state between normal aging and AD, new paths have been traced to acquire further knowledge about this condition and its subtypes, and to determine which of them have a higher risk of conversion to AD. It is now known that other deficits besides episodic and semantic memory impairments may be present in the early stages of AD, such as visuospatial and executive function deficits. Furthermore, recent investigations have proven that the hippocampus and the medial temporal lobe structures are not only involved in memory functioning, but also in visual processes. These early changes in memory, visual, and executive processes may also be detected with the study of eye movement patterns in pathological conditions like MCI and AD. In the present review, we attempt to explore the existing literature concerning these patterns of oculomotor changes and how these changes are related to the early signs of AD. In particular, we argue that deficits in visual short-term memory, specifically in iconic memory, attention processes, and inhibitory control, may be found through the analysis of eye movement patterns, and we discuss how they might help to predict the progression from MCI to AD. We add that the study of eye movement patterns in these conditions, in combination with neuroimaging techniques and appropriate neuropsychological tasks based on rigorous concepts derived from cognitive psychology, may highlight the early presence of cognitive impairments in the course of the disease. <s> BIB012 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer’s dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer’s disease. The aim of our work was to compare the pattern and duration of clinical trajectories before Alzheimer’s dementia in individuals with low and high education within the PAQUID cohort involving 20 years of follow-up. The sample comprises 442 participants with incident Alzheimer’s disease (27.2% were male)—171 with low education (mean age = 86.2 years; standard deviation = 5.3 years) and 271 with higher education (mean age = 86.5; standard deviation = 5.4)—and 442 control subjects matched according to age, sex and education. At each visit and up to the 20-year follow-up visit, several cognitive and clinical measures were collected and incident cases of Alzheimer’s disease clinically diagnosed. The evolution of clinical measures in pre-demented subjects and matched controls was analysed with a semi-parametric extension of the mixed effects linear model. The results show that the first signs of cognitive decline occurred 15 to 16 years before achieving dementia threshold in higher-educated subjects whereas signs occurred at 7 years before dementia in low-educated subjects. There seemed to be two successive periods of decline in higher-educated subjects. Decline started ∼15 to 16 years before dementia with subtle impairment restricted to some cognitive tests and with no impact during the first 7 to 8 years on global cognition, cognitive complaints, or activities of daily living scales. Then, ∼7 years before dementia, global cognitive abilities begin to deteriorate, along with difficulties dealing with complex activities of daily living, the increase in self-perceived difficulties and depressive symptoms. By contrast, lower-educated subjects presented a single period of decline lasting ∼7 years, characterized by decline concomitantly affecting specific and more global cognitive function along with alteration in functional abilities. This study demonstrates how early cognitive symptoms may emerge preceding Alzheimer’s dementia particularly in higher-educated individuals, for whom decline occurred up to 16 years before dementia. It also demonstrates the protective role of education in the clinical trajectory preceding Alzheimer’s dementia. We suggest that the initial decline in cognition occurs at the onset of comparable Alzheimer’s disease pathology in both groups, and is associated with immediate decline to dementia in the lower education group. In contrast, higher education protects against further cognitive decline for ∼7 years until pathology becomes more severe. ::: ::: * Abbreviations ::: : CES-D ::: : Centre for Epidemiologic Studies-Depression Scale ::: DSST ::: : Digit Symbol Substitution Test ::: IADL ::: : Instrumental Activities of Daily Living ::: IST ::: : Isaacs Set Test ::: MMSE ::: : Mini-Mental State Examination <s> BIB013 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Older adults appear to have greater difficulty ignoring distractions during day-to-day activities than younger adults. To assess these effects of age, the ability of adults aged between 50 and 80 years to ignore distracting stimuli was measured using the antisaccade and oculomotor capture tasks. In the antisaccade task, observers are instructed to look away from a visual cue, whereas in the oculomotor capture task, observers are instructed to look toward a colored singleton in the presence of a concurrent onset distractor. Index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were compared with capture errors, and with prosaccade errors on the antisaccade task. A higher percentage of capture errors were made on the oculomotor capture tasks by the older members of the cohort compared to the younger members. There was a weak relationship between the attention index and capture errors, but the visuospatial/constructional index was the strongest predictor of prosaccade... <s> BIB014 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Dementia (most notably, Alzheimer's Disease) is often associated with impairments of both working memory and inhibitory control. However, it is unclear whether these are functionally distinct impairments. We addressed the issue of whether working memory and inhibitory control can be dissociated, using data from a sample of patients who were recruited in a longitudinal study (Crawford et al., 2013, 2015). The first case revealed a preserved working memory capacity together with poor inhibitory control in the anti-saccade task. A longitudinal follow-up revealed that the defective inhibitory control emerged 12-months before the dementia was evident on the mini-mental state examination assessment. A second case revealed a poor working memory together with a well-preserved level of inhibitory control. The dissociation of working memory and inhibitory control was confirmed statistically in 7 additional cases. These findings yield converging evidence that working memory and inhibitory control are distinct cognitive operations and challenges the Kimberg and Farah (2000) cognitive model of working memory. <s> BIB015 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Purpose of reviewAbnormalities of oculomotor control accompany the pathological changes underlying many neurodegenerative diseases. Clinical examination of eye movements can contribute to differential diagnosis, whereas quantitative laboratory measures can provide detailed insight into the disease p <s> BIB016 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Saccadic Eye Movements and <s> Objective ::: Several studies have demonstrated saccadic eye movement (SEM) abnormalities in Alzheimer's disease (AD) when patients performed prosaccade (PS) and antisaccade (AS) tasks. Some studies have also showed that SEM abnormalities were correlated with dementia rating tests such as the Mini Mental State Evaluation (MMSE). Therefore, it has been suggested that SEMs could provide useful information for diagnosis. However, little is known about predictive saccades (PreS)-saccades triggered before or very quickly after stimuli appearance-and their relationships with cognition in AD. Here, we aimed to examine the relationships between our usual dementia screening tests and SEM parameters in PS, AS, and also PreS task. ::: ::: ::: Method ::: We compared SEMs in 20 patients suffering from AD and in 35 healthy older adults (OA) in PS, AS, and PreS task. All participants also completed a neuropsychological evaluation. ::: ::: ::: Results ::: We showed that AD patients had higher latency and latency variability regardless the tasks, and also higher AS cost, in comparison with OA. Moreover, AD patients made more uncorrected AS and took more time-to-correct incorrect AS. In PreS task, AD patients showed higher gain and gain variability than OA when they made anticipated saccades. Close relationships were found between the majority of SEM variables in PS, AS, and PreS tasks and dementia screening tests, especially the MMSE and episodic memory measures. ::: ::: ::: Conclusion ::: Our findings, in agreement with previous studies, demonstrated that AD affects several SEM parameters. SEM abnormalities may reflect selective and executive-attention impairments in AD. <s> BIB017
Alzheimer's Disease. Traditional studies using saccadic eye movements (SEM) tasks have reported differences between PwAD and control groups. A saccade is a rapid motion of the eye (typically lasting between 30 to 80 ms to complete) BIB007 . Example of these studies includes prosaccades and antisaccades analysis  BIB015 . To study prosaccades, a participant has to saccade from a initial point to an appearing peripheral target. Then, the reaction time or latency is measured from the subject to fixate on the presented peripheral target. The research described in BIB009 BIB008 BIB005 reports increased latency of saccades from PwAD when compared to control groups that can be associated with cognitive process. On the other hand, to study antisaccades, the participant must fixate an opposite direction from a presented peripheral target BIB006 . As the participants have to inhibit the automatic saccade towards the stimulus, the antisaccade task requires additional executive processing from participants BIB011 . The nature of antisaccades can be associated with executive attention and research results indicate that patients with AD have shown more antisaccade errors with fewer corrections than control groups BIB010 . The papers  BIB016 BIB012  review work conducted on eye movements and their relationship with AD. There are different challenges regarding eye movements studies and AD. The first challenge arises because oculomotor abnormalities are not exclusive from AD and it is important to develop techniques that properly distinguish AD from other diseases. For example, SEM abnormalities have been encountered in Multiple System Atrophy, such as slower prosaccade and increased antisaccade errors  . Furthermore, SEM abnormalities might be related to aging. For example, in BIB017 it is reported that latencies uncorrected or increased time to correct error in antisaccades increase with aging. Older adults appear to have stronger difficulty ignoring distractions during day-to-day activities than younger adults. It seems that any variable that reduces the strength of the top-down neural signal to produce a voluntary saccade, or that increases saccade speed, will enhance the likelihood that a reflexive saccade to a stimulus with an abrupt onset will occur BIB014 . So, what is the effect of "normal" aging on eye saccade speed? It has been shown BIB013 that the Digit Symbol Substitution Test can be altered as far as 20 years before AD in older individuals with a high level of study is manifest. The performance in this test is related to the speed of eye saccades. This decline in performance speed and executive functions might be nonspecific prodromal Alzheimer's but could as well characterize a state of cerebral vulnerability on which the illness would progress more easily. Despite the relationship between age related cognitive decline and saccadic eye movements (SEM) deficits has been outlined, specific cognitive alterations underlying age-related changes in saccadic performance remain unclear. The nature of aging effects on SEMs has been only rarely approached. The progressive age-related decline of processing speed and executive attention is associated with and can be highlighted through saccadic age movement deficits as well in prosaccade and antisaccade tasks. As can be see from Table 1 , research from five years ago mainly focused in studying prosaccades and antisaccades. Indeed, the study of SEM was dominant since the earliest approaches dedicated to analyze eye movements and its relation to AD BIB008 BIB004 BIB002 BIB003 BIB001 . As described, in SEM experiments the participants must fixate to a target. Although SEM studies have reported significant difference between persons with AD and control groups, there is still a research gap to fill in order to use SEM analysis as a marker for AD. Differentiate SEM abnormalities from AD, "normal" aging, and other conditions are among the main challenges from SEM analysis. Prosaccade and antisaccade tasks have been popular in research studies due to their simplicity BIB017 . These tasks require a controlled scenario to conduct the evaluations. As research has evolved, more complex tasks have been studied towards associating eye movements deficits to support AD diagnosis. In Section 3.2 studies involving the execution of more complex tasks than attending to single target points are described. However, this research still lies in a category of controlled scenarios.