Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk

Kremen, William S.; Panizzon, Matthew S.; Elman, Jeremy A.; Granholm, Eric; Andreassen, Ole A.; Dale, Anders M.; Gillespie, Nathan A.; Gustavson, Daniel E.; Logue, Mark W.; Lyons, Michael J.; Neale, Michael C.; Reynolds, Chandra A.; Whitsel, Nathan; Franz, Carol E.

doi:10.1016/j.neurobiolaging.2019.09.001

Cited by 31 publications

(29 citation statements)

References 64 publications

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“…Likewise, pupillometry has been used for over five decades as a measure of cognitive workload in the domains of psychophysiology, cognitive neuroscience, and human factor engineering, such as aviation or driving. Only recently has pupillometry received attention in the medical field as a potential marker of disease progression in adults with AD, Parkinson’s disease, and breast cancer [ 15 , 21 , 29 , 32 ]. This rekindled interest in pupillary response to cognitive workload as a marker of cognitive decline warrants an investigation of its psychometric properties.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in camera angle and eye movements may also interfere with raw pupillary recording [ 20 , 23 ]. Nonetheless, previous studies found increased TEPR in individuals with elevated risk of AD [ 15 , 21 ]. An alternative to pupillometric baseline-related difference measures is the moment-to-moment pupillary diameter measurement.…”

Section: Introductionmentioning

confidence: 91%

“…A previous study found increased pupillary dilation in participants with single-domain mild cognitive impairment compared to cognitively normal participants, despite performance in the normal ranges [ 15 ]. Furthermore, participants with a genetic predisposition for AD showed greater relative pupillary size in tasks with high cognitive demand [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Psychometric Properties of NASA-TLX and Index of Cognitive Activity as Measures of Cognitive Workload in Older Adults

et al. 2020

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Cognitive workload is increasingly recognized as an important determinant of performance in cognitive tests and daily life activities. Cognitive workload is a measure of physical and mental effort allocation to a task, which can be determined through self-report or physiological measures. However, the reliability and validity of these measures have not been established in older adults with a wide range of cognitive ability. The aim of this study was to establish the test–retest reliability of the National Aeronautics and Space Administration Task Load Index (NASA-TLX) and Index of Cognitive Activity (ICA), extracted from pupillary size. The convergent validity of these measures against event-related potentials (ERPs) was also investigated. A total of 38 individuals with scores on the Montreal Cognitive Assessment ranging between 17 and 30 completed a working memory test (n-back) with three levels of difficulty at baseline and at a two-week follow-up. The intraclass correlation coefficients (ICC) values of the NASA-TLX ranged between 0.71 and 0.81, demonstrating good to excellent reliability. The mean ICA scores showed fair to good reliability, with ICCs ranging between 0.56 and 0.73. The mean ICA and NASA-TLX scores showed significant and moderate correlations (Pearson’s r ranging between 0.30 and 0.33) with the third positive peak of the ERP at the midline channels. We conclude that ICA and NASA-TLX are reliable measures of cognitive workload in older adults. Further research is needed in dissecting the subjective and objective constructs of cognitive workload.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Psychometric Properties of NASA-TLX and Index of Cognitive Activity as Measures of Cognitive Workload in Older Adults

et al. 2020

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“…In addition to the above reported changes, irregularities in efferent ocular pathways in conjunction with retinal abnormalities were also associated with altered pupillary light response (PLR) in patients. These alterations include increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum constriction velocity and acceleration (Chougule et al, 2019), and altered pupil dilation response during cognitive tasks (Granholm et al, 2017;Kremen et al, 2019). Therefore, there is growing interest in exploring various aspects of pupillary responses, using specialized pupillometry tools, in pre-clinical and clinically diagnosed AD patients.…”

Section: Functional and Visual Changes In Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

et al. 2020

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The neurosensory retina emerges as a prominent site of Alzheimer's disease (AD) pathology. As a CNS extension of the brain, the neuro retina is easily accessible for noninvasive, high-resolution imaging. Studies have shown that along with cognitive decline, patients with mild cognitive impairment (MCI) and AD often suffer from visual impairments, abnormal electroretinogram patterns, and circadian rhythm disturbances that can, at least in part, be attributed to retinal damage. Over a decade ago, our group identified the main pathological hallmark of AD, amyloid β-protein (Aβ) plaques, in the retina of patients including early-stage clinical cases. Subsequent histological, biochemical and in vivo retinal imaging studies in animal models and in humans corroborated these findings and further revealed other signs of AD neuropathology in the retina. Among these signs, hyperphosphorylated tau, neuronal degeneration, retinal thinning, vascular abnormalities and gliosis were documented. Further, linear correlations between the severity of retinal and brain Aβ concentrations and plaque pathology were described. More recently, extensive retinal pericyte loss along with vascular platelet-derived growth factor receptor-β deficiency were discovered in postmortem retinas of MCI and AD patients. This progressive loss was closely associated with increased retinal vascular amyloidosis and predicted cerebral amyloid angiopathy scores. These studies brought excitement to the field of retinal exploration in AD. Indeed, many questions still remain open, such as queries related to the temporal progression of AD-related pathology in the retina compared to the brain, the relations between retinal and cerebral changes and whether retinal signs can predict cognitive decline. The extent to which AD affects the retina, including the susceptibility of certain topographical regions and cell types, is currently under intense investigation. Advances in retinal amyloid imaging, hyperspectral imaging, optical coherence tomography, and OCT-angiography encourage the use of such modalities to achieve more accurate, patient-and user-friendly, noninvasive detection and monitoring of AD. In this review, we summarize the current status in the field while addressing the many unknowns regarding Alzheimer's retinopathy.

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“…These results suggest that pupillary changes may capture subtle cognitive abnormalities not yet manifest in cognitive performance measures and that pupil dilation can differentiate between MCI subtypes. Interestingly, impaired task-evoked pupil dilation in cognitively normal adults correlated with a higher risk of progression to MCI (Kremen et al, 2019 ). This supports the use of task-evoked pupillary measures in identifying at-risk individuals for AD.…”

Section: Efferent Biomarkersmentioning

confidence: 99%

Afferent and Efferent Visual Markers of Alzheimer’s Disease: A Review and Update in Early Stage Disease

Masurkar

Balcer

2020

Front. Aging Neurosci.

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Vision, which requires extensive neural involvement, is often impaired in Alzheimer's disease (AD). Over the last few decades, accumulating evidence has shown that various visual functions and structures are compromised in Alzheimer's dementia and when measured can detect those with dementia from those with normal aging. These visual changes involve both the afferent and efferent parts of the visual system, which correspond to the sensory and eye movement aspects of vision, respectively. There are fewer, but a growing number of studies, that focus on the detection of predementia stages. Visual biomarkers that detect these stages are paramount in the development of successful disease-modifying therapies by identifying appropriate research participants and in identifying those who would receive future therapies. This review provides a summary and update on common afferent and efferent visual markers of AD with a focus on mild cognitive impairment (MCI) and preclinical disease detection. We further propose future directions in this area. Given the ease of performing visual tests, the accessibility of the eye, and advances in ocular technology, visual measures have the potential to be effective, practical, and non-invasive biomarkers of AD.

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Pupillary dilation responses as a midlife indicator of risk for Alzheimer's disease: association with Alzheimer's disease polygenic risk

Cited by 31 publications

References 64 publications

Psychometric Properties of NASA-TLX and Index of Cognitive Activity as Measures of Cognitive Workload in Older Adults

Psychometric Properties of NASA-TLX and Index of Cognitive Activity as Measures of Cognitive Workload in Older Adults

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

Afferent and Efferent Visual Markers of Alzheimer’s Disease: A Review and Update in Early Stage Disease

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