Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Abstract The rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) contains premotor neurons essential for the generation of rapid vertical eye movements. The Alzheimer's disease (AD)-related cytoskeletal changes and β-amyloid deposits in this nucleus were examined in 30 autopsy cases and compared to the involvement of three associated nuclei — Edinger–Westphal nucleus, nucleus of Darkschewitsch and interstitial nucleus of Cajal. The riMLF displays slight cytoskeletal alterations already in the early stages in the development of the cortical cytoskeletal pathology (cortical NFT/NT-stages I–II, representing the preclinical phase of AD). In the cortical NFT/NT-stages III–IV (i.e. incipient phase of AD), the cytoskeletal pathology in the riMLF is pronounced and in stages V–VI (i.e. clinical phase of AD) it is severe. The progression of the cytoskeletal pathology in the riMLF correlates significantly with the cortical NFT/NT-stages I–VI that reflect the clinical course of AD. Isolated β-amyloid deposits appear in the riMLF for the first time in the final β-amyloid stage. In the Edinger–Westphal nucleus, in the nucleus of Darkschewitsch and most markedly in the interstitial nucleus of Cajal, the pathological changes were significantly less severe than those in the riMLF. In the event that the cytoskeletal pathology impairs the function of the premotor neurons of the riMLF, one would predict a progressive slowing of vertical saccades corresponding to the advancing cortical NFT/NT-stages. <s> BIB001 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD. We found that 52% of the cognitively intact subjects, and all subjects with mild cognitive impairment or dementia, had dense neurofibrillary tangles (NFTs), neuropil threads, and tau-immunoreactive neurites surrounding neuritic plaques (NPs) in visual association cortex Brodmann area 19. All cognitively intact subjects with area 19 NFTs also had dense core NP and β amyloid (Aβ) angiopathy in area 19. Area 19 pathology was occasionally present in the absence of substantial pathology in the hippocampus or entorhinal cortex and was not correlated with medial temporal lobe pathology. Dense AD pathology in area 19 is present in some cognitively intact subjects with preclinical AD. The unique metabolic, connectional, and vascular features of this region may confer enhanced vulnerability to neurodegeneration. <s> BIB002 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> BACKGROUND ::: Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD). ::: ::: ::: OBJECTIVE ::: To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses. ::: ::: ::: DESIGN ::: An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry. ::: ::: ::: SETTING ::: Memory and Aging Center, Department of Neurology, University of California, San Francisco. ::: ::: ::: PARTICIPANTS ::: A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls. ::: ::: ::: RESULTS ::: All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume. ::: ::: ::: CONCLUSION ::: Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy. <s> BIB003 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Although several studies have suggested that cortical alterations underlie such age-related visual deficits as decreased acuity, little is known about what changes actually occur in visual cortex during healthy aging. Two recent studies showed changes in primary visual cortex (V1) during normal aging; however, no studies have characterized the effects of aging on visual cortex beyond V1, important measurements both for understanding the aging process and for comparison to changes in age-related diseases. Similarly, there is almost no information about changes in visual cortex in Alzheimer’s disease (AD), the most common form of dementia. Because visual deficits are often reported as one of the first symptoms of AD, measurements of such changes in the visual cortex of AD patients might improve our understanding of how the visual system is affected by neurodegeneration as well as aid early detection, accurate diagnosis and timely treatment of AD. Here we use fMRI to first compare the visual field map (VFM) organization and population receptive fields (pRFs) between young adults and healthy aging subjects for occipital VFMs V1, V2, V3, and hV4. Healthy aging subjects do not show major VFM organizational deficits, but do have reduced surface area and increased pRF sizes in the foveal representations of V1, V2, and hV4 relative to healthy young control subjects. These measurements are consistent with behavioral deficits seen in healthy aging. We then demonstrate the feasibility and first characterization of these measurements in two patients with mild AD, which reveal potential changes in visual cortex as part of the pathophysiology of AD. Our data aid in our understanding of the changes in the visual processing pathways in normal aging and provide the foundation for future research into earlier and more definitive detection of AD. <s> BIB004 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Alzheimer disease (AD) is a progressive, age-related debilitating condition that is a growing public health problem in the developed world. Visual system abnormalities in AD were recognized in the early 1970s, but were initially considered to be of strictly cortical origin. Studies in the past 20 years reveal that all parts of the visual system may be affected, including the optic nerve and the retina. Some aspects of this involvement are still not well understood and are the subjects of intensive research. We summarize and focus on findings that may be of more practical interest to the ophthalmologist. <s> BIB005 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <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> BIB006 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area. <s> BIB007 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Alzheimers disease (AD) is the most common form of dementia affecting the growing ageing population today, with prevalence expected to rise over the next 35 years. Clinically, patients exhibit a progressive decline in cognition, memory and social functioning due to deposition of amyloid β (Aβ) protein and intracellular hyperphosphorylated tau protein. These pathological hallmarks of AD are visualised either through neuroimaging, CSF analysis or diagnosed post-mortem. Importantly, neuropathological progression occurs in the eye as well as the brain, and multiple visual changes have been noted in both human and animal models of AD. The eye offers itself as a transparent medium to cerebral pathology and has thus potentiated the development of ocular biomarkers for AD. The use of non-invasive screening such as retinal imaging and visual testing may enable earlier diagnosis in the clinical setting, minimizing invasive and expensive investigations. It also potentially improves disease management and quality of life for AD patients, as an earlier diagnosis allows initiation of medication and treatment. In this review, we explore the evidence surrounding ocular changes in AD and consider the biomarkers currently in development for early diagnosis. <s> BIB008 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <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> BIB009 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> As any cognitive task, visual search involves a number of underlying processes that cannot be directly observed and measured. In this way, the movement of the eyes certainly represents the most explicit and closest connection we can get to the inner mechanisms governing this cognitive activity. Here we show that the process of eye movement during visual search, consisting of sequences of fixations intercalated by saccades, exhibits distinctive persistent behaviors. Initially, by focusing on saccadic directions and intersaccadic angles, we disclose that the probability distributions of these measures show a clear preference of participants towards a reading-like mechanism (geometrical persistence), whose features and potential advantages for searching/foraging are discussed. We then perform a Multifractal Detrended Fluctuation Analysis (MF-DFA) over the time series of jump magnitudes in the eye trajectory and find that it exhibits a typical multifractal behavior arising from the sequential combination of saccades and fixations. By inspecting the time series composed of only fixational movements, our results reveal instead a monofractal behavior with a Hurst exponent , which indicates the presence of long-range power-law positive correlations (statistical persistence). We expect that our methodological approach can be adopted as a way to understand persistence and strategy-planning during visual search. <s> BIB010 </s> Computational Techniques for Eye Movements Analysis towards Supporting Early Diagnosis of Alzheimer's Disease: A Review <s> Eye Movements and Alzheimer's Disease <s> Alzheimer's disease (AD) is an increasingly common disease with massive personal and economic costs. While it has long been known that AD impacts the visual system, there has recently been an increased focus on understanding both pathophysiological mechanisms that may be shared between the eye and brain and how related biomarkers could be useful for AD diagnosis. Here, were review pertinent cellular and molecular mechanisms of AD pathophysiology, the presence of AD pathology in the visual system, associated functional changes, and potential development of diagnostic tools based on the visual system. Additionally, we discuss links between AD and visual disorders, including possible pathophysiological mechanisms and their relevance for improving our understanding of AD. <s> BIB011
Several researches on predementia have reported manifestations of visual symptoms produced by senile plaques and tangles located in the visual regions of the brain BIB002 BIB004 . The pathological changes in the visual system caused by neurodegenerative diseases are reviewed in BIB011 BIB007  BIB008 . Examples of these pathological changes are visual acuity changes, atypical pupillary responses, and alteration in the oculomotor performance BIB009 . Eye movements involve a complex oculomotor control system formed by extensive cerebral regions BIB005 . Through post mortem studies, there is evidence that pathologies associated with AD affect the oculomotor brain regions BIB001 BIB003 . Altered eye movements patterns reflect the resulting underlying visuospatial and executive function impairments. Thus, movement patterns are related to higher cognitive control processes BIB006 . That is why, for example, eye movements allow exploring the cognitive process underlying visual search, providing information about how people forage and plan when performing visual search tasks BIB010 . Typically, the studies dedicated to explore relationships between eye movements and AD compare certain outcome measures between persons with AD (PwAD) and control groups when they accomplish a specific oculomotor tasks.