Afferent Visual Dysfunctoin in Neurodegenerative Disease
Sung-Hee Kim
Department of Neurology, Kyungpook National University Chilgok Hospital
AFFERENT VISUAL DYSFUNCTOIN IN NEURODEGENERATIVE DISEASE
10 Oct 2018 Sung-Hee Kim
Department of Neurology, Kyungpook National University Chilgok Hospital The Korean Society of Neuro-ophthalmology
■Alzheimer’s disease (AD) is the most common form of dementia affecting the growing aging population today
■Patients exhibit a progressive decline in cognition, memory, and social functioning due to deposition of amyloid β (Aβ) protein and intracellular hyperphosphorylated tau protein.
PUPIL
• A hypersensitive pupil responsive to cholinergic antagonist, tropicamide (0.01%) : AD patients’ pupils dilated to 13% more than controls.
• Significant differences in pupil sizes were found at a lower dose of tropicamide (0.005%), : A clear biological link between ApoE allele status and pupillary response to dilute tropicamide.
: The use of the tropicamide test as a diagnostic tool for AD is controversial
• Changes in the Edinger–Westphal nucleus and degeneration in the nucleus basalis of Meynert causing cholinergic deficit
• Repetitive stimulation of the PLR over time is less pronounced in AD patients, with lower amplitude and latency of maximum reaction
• A significant correlation between increased pupillary size and CSF measures of both Aβ and tau HYPERSENSTIVITITY TO ANTICHOLINERGIC
PUPILLARY LIGHT REFLEX
RETINA
• Smaller, more sparse, tortuous retinal vessels, and significantly decreased retinal venous blood flow in AD patients.
• MCI patients’ blood flow was intermediate between AD patients and controls.
: Retinal blood flow (ml/min) may be used to monitor disease progression.
• Retinal oxygen saturation in arterioles and venules was elevated in AD patients as compared to controls.
• Retinal nerve fiber layer thickness thinning : but not significantly between AD patients and both MCI and control groups.
• RGC degeneration particularly in superior and inferior peripheral retina
• Overall reduction in RGC axon numbers
• Aβ deposition in retina Retinal Vasculature
RNFL
RETINA
• Tau accumulation has been observed in the hippocampus and amygdala of triple-transgenic mice.
• Hyperphosphorylated tau was observed in adjacent sections of Aβ deposition in the ganglion cell layer
• Double-transgenic mice APP/PS1 also displayed hyperexpression of tau in the retina with upregulation of p35, p25, and calpain, which has been widely hypothesized to cause synaptic dysfunction and calcium dysregulation in the context AD-related apoptosis.
Tau in the Retina
Location of APP & Aβ in the Animal Retina
CHOROID
• Significantly reduced choroidal thickness as compared to age-matched controls.
• Upregulation of complement factor C3, which has previously been noted to play a role in RGC related apoptosis
• Age-dependent Aβ deposits in the retinal and choroidal vasculature of two strains of transgenic mice
OPTIC NERVE
• Cell death of RGC and changes in the optic nerve: AD optic nerves had approximately half the RGC axon density of controls.
• The larger “M” cell type RGCs are chiefly affected by AD.
• This degeneration is more pronounced in the superior and inferior peripheral regions.
• Multiple studies, using OCT and confocal laser scanning, have found greater cup-to-disk ratio and increased pallor of the AD optic nerve, representing a significant loss of RGC axons
VISUAL ACUITY & CONTRAST SENSITIVITY
• Many studies have found no significant difference in visual acuity between AD patients and control subjects.
• A significantly poorer accuracy and ability in recognition of pictures in low luminance and low spatial frequency, as compared to controls VISUAL ACUITY: The spatial-resolving power of the visual system
• AD patients have markedly reduced visual contrast sensitivity as compared to age-matched controls CONTRAST SENSITIVITY: Recognizing objects over background luminance
COLOR VISION & VISUAL FIELD
• Visual field loss in AD is likely attributed to the neurodegenerative changes and synaptic dysfunction, particularly due to Aβ accumulation.
• The sensitivity losses occur particularly in the inferior hemifield of AD patients, and degree of loss correlated with degree of dementia.
• VF testing with frequency doubling technology also found that AD patients had VF deficits as compared to age-matched controls COLOR VISION
• Changes in color vision: retinal disease with blue–yellow visual changes and optic nerve disease with red–green visual loss.
• Earlier studies in AD patients have indicated deficiencies in the tritan axis. More recent studies show no significant interaction in color axes.
• An inversely proportional correlation with MMSE score and color discrimination error.
VISUAL FIELD LOSS
MOTION PERCEPTION
• Patients with AD had higher thresholds across all spatial and temporal frequencies of visual motion processing, as compared to age-matched controls
• Correlation with dementia severity
• Patients with AD required significantly greater thresholds for perceiving shapes defined by motion cues compared with controls
• There were no significant differences between the two groups in static visual acuity, static contrast sensitivity and dynamic visual acuity, and motion direction discrimination.
• Mild to moderate AD has significant effects on the perception of structure from motion with relative sparing of motion direction discrimination.
• This complex motion imagine processing deficit is likely to have a cerebral bias and has the potential to affect navigation and the recognition of objects in relative motion, as encountered during walking and automobile driving
MOTION PERCEPTION: Process of deducing speed and direction of elements
Random Dot Kinetogram (RDK)
Stäblein, M., et al. (2016).
Impaired working memory for visual motion direction in schizophrenia: Absence of recency effects and association with psychopathology.
Neuropsychology, 30(6), 653–663.
Rizzo M, Nawrot M. (1998)
Perception of movement and shape in Alzheimer's disease.
Brain. 2259-70.
MOTION PERCEPTION & STEREOPSIS
• Bifoveal fixation, normal retinal correspondence, two healthy retinas to perceive images that are similar in size and clarity, sensory fusion, and motor fusion
: Images falling on slightly disparate retinal areas of two eyes are fused by cortical binocular neurons to achieve binocular single vision in 3 dimensions.
STEREOPSIS
MOTION PERCEPTION & STEREOPSIS
• Stereopsis may be impaired in AD patients, but their performance does not correlate to the severity of dementia.
• AD subjects were found to have reduced stereoacuity thresholds compared with controls measured with the random dot stereo test.
• In an study using MRI and stereo motion tests in AD patients, there was no stereopsis deficit, although areas processing these task were neuroanatomically different from controls.
• Damage to binocular neurons in the visual cortex is a biomarker for late AD.
STEREOPSIS
Mitochondrial alterations in Alzheimer’s disease Journal of Alzheimer’s Disease 9 (2006) 119–126
Brandt T, et al. Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans, Brain 128 (2005), 2732-2741.
■ Hippocampal place cells and head direction cells as the interactive components of a brain circuit that guides navigation.
: The place cell exhibits its peak discharge when the animal occupies that cell’s “place field,” a particular subregion of the larger environment : Head direction cells encode directional heading, with each cell firing when the rat’s head is oriented in a particular “preferred firing direction.”
HIPPOCAMPUS AND VESTIBULAR SYSTEM
HIPPOCAMPUS AND VESTIBULAR SYSTEM
■ Lesions of the vestibular system impair:
1) a rat’s ability to return to a goal location following passive transport (Miller et al., 1983) 2) spontaneous alternation (Potegal et al., 1977)
3) navigation in the absence of a visual landmark (Stackman and Herbert, 2002) 4) spatial learning in a radial-arm maze task (Ossenkopp and Hargreaves, 1993).
■ Patients with vestibular abnormalities are known to have cognitive deficits, including loss of short-term memory, poor concentration, and inability to multitask.
TAKE HOME MESSAGE
• 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 biomarkers are crucial for disease monitoring and the recruitment of preclinical AD patients for clinical trials.
• The ocular biomarkers holding the most promise are those specific for AD pathophysiological such as the detection of Ab-related retina changes.
• The vestibular system and hippocampus have linked as well as the vestibular system and topographical memory and other functions subserved by the hippocampus
THANK YOU 감사합니다.
