NANOS 2018 Using the visual system to study neurologic diseases - PowerPoint PPT Presentation

NANOS 2018 Using the visual system to study neurologic diseases GREGORY P. VAN STAVERN, M.D. PROFESSOR, DEPARTMENT OF OPHTHALMOLOGY AND VISUAL SCIENCES AND NEUROLOGY DIRECTOR, VISUAL ELECTROPHYSIOLOGY SERVICES WASHINGTON UNIVERSITY IN ST. LOUIS

Disclosures  I have no relevant financial disclosures

Goals  Rationale for using visual system to study neurodegenerative diseases  Reviewing available tools  Discussing applications in several neurodegenerative diseases

The Cookie Thief Picture is highly sensitive to the presence of simultagnosia  1. True  2. False

Evidence of Alzheimer’s disease can be detected before the onset of cognitive dysfunction  1. True  2. False

Model of an Ideal System  Pervasive  Accessible  Tools to assess structure-function relationships  Assessment methods minimally invasive and inexpensive

Visual system  Large amount of brain devoted to vision  Functional changes may not occur in parallel with structural changes- need a system where both can be quantified  Retinotopic organization  Fewer synapses and less modulation than other systems  Redundancy  neuroplasticity  Tools readily available to ophthalmologists and neurologists

Disability and Vision  Visual dysfunction contributes significantly to reduced QOL in neurologic disease  Often under-recognized and under-measured in neurodegenerative disease  Multiple Sclerosis:  EDSS underestimates visual disability  AD:  Prominent visual-spatial dysfunction  Impaired reading and driving  Most dementia scales (MMSE, CDR) do not directly address impact of visual disability Balcer LJ. J Neuro Ophth 2014 Heesen C et al. Mult Scl 2008

Vision and Neurologic Disease  Quantifiable metrics of visual function might be valuable surrogate markers  Detectable early in disease stage  Monitoring and tracking progression of disease  Assess efficacy of neuroprotective strategies  May capture “hidden” aspects of disability  Some diseases ideally suited for visual structure- function metrics

Tools of the trade  Structural:  Ophthalmoscopy  Optical coherence tomography (OCT)  MRI (conventional, DTI, etc)  Functional:  Psychophysical  Visual acuity (high and low contrast)  Perimetry  Color perception  Visual electrophysiology  OCT angiography

Psychophysical tests (functional markers)  Visual acuity (high and low contrast)  Contrast sensitivity  Color discrimination  Perimetry (automated or kinetic)  VFQ-25 QOL Surveys

Optical Coherence Tomography • Generates high resolution images measuring echo time delay of reflected light • Interference data from multiple rapid scans used to generate color-coded map of retina  Retinal nerve fiber layer= axons  Macular volume= ganglion cells (neurons)  Outer retina= photoreceptors (neurons)  Resolution ~1 u

Visual Electrophysiology  Captures functional changes in visual system  Quantifiable metrics  More objective assessment  May allow more precise structure-function correlations  Relatively accessible and inexpensive

Test Advantages Disadvantages Pattern VEP Widely available Reliant upon cooperation, fixation, refraction Macular dominated response Non-localizing Photopic negative RGC function Measuring baseline Less reliant upon fixation Eye movement artifact response Full field ERG Objective assessment of rod and No topographic information cone function More time consuming than Isolates inner and outer retinal other EP tests function Less dependent upon fixation and cooperation Widely available Multi-focal ERG Assesses localized retinal Dependent upon dysfunction cooperation and fixation Correlation with field loss Not widely available Pattern ERG Information about macular Dependent upon cooperation and fixation and RGC function Not widely available Easy to perform Requires good VA

OCT Angiography  Novel technique using motion subtraction technology to analyze retinal and optic nerve blood flow  Visualizes capillary-level circulation at each level of retina  No dye/contrast required  Powerful tool to assess blood flow to retina and optic nerve

Sequential Imaging to Detect Motion

Retinal� Angiography� – Vessel� Density Retinal angiography scan combines data from repeated B-scans in the horizontal and vertical planes over the macula and then uses a Split Spectrum Amplitude Decorrelation Angiography (SSADA) algorithm to determine tissue locations with active flow indicating underlying large and small blood vessels.

Optic nerve angiography scan combines data from repeated B-scans in the horizontal and vertical planes over the optic nerve and then uses a Split Spectrum Amplitude Decorrelation Angiography (SSADA) algorithm to determine tissue locations with active flow indicating underlying large and small blood vessels.

King-Devick Test • Rapid number naming test • Captures saccades, attention and language • Requires integration of brainstem, cerebellum, and cortex • Can be administered in 1-2 minutes with minimal training • Applications in TBI, MS, and Galetta KM et al. The King-Devick test and sports related other neurologic diseases concussion. J Neurol Sci 2011;309:34-39 Ventura RE et al. Ocular motor assessment in Concussion. J Neurol Sci 2016;361:79-86

Neurodegenerative disease and Vision  Alzheimer’s disease  Parkinson’s disease  Multiple Sclerosis  Isolated optic neuritis  Axonal loss in anterior visual pathway  Traumatic brain injury  Ocular motor dysfunction  Mitochondrial diseases  LHON

Preclinical and Symptomatic AD Transition Zone Synaptic/Neuronal Integrity ↑ CSF tau Spread of tau (PET) accumulation + Amyloid Brain atrophy Imaging Altered task and resting fMRI Subtle decline in ↓ CSF Aβ 42 episodic memory and attention CDR ↑ CSF SNAP -25 0.5  1  2  3 Cognitively Normal and Neurogranin No AD Preclinical AD Symptomatic AD ~20 y ~7-10 y Death Roe CC et al Amyloid imaging results from the AIBL Study of Aging. Neurobiol Aging 2010 31:1275-83 Alzheimer’s Disease Neuroimaging Initiative (ADNI)

The Eye in Alzheimer’s Disease AB plaques and neurofibrillary  tangles present in retina Loss of axons and RGC neurons in  retinal in AD vs controls Correlation to retinal dysfunction  by visual electrophysiology Retinal vascular abnormalities  cortical AB burden Detection of A β in retina using  curcumin labeling Frost S et al. Ocular biomarkers for early detection of AD. J Alz Dis 2010;22:1-16

PET Biomarkers n = 20 n = 7 0.398 0.288 PET Negative PET Positive Subjects Subjects

MS and OCT • Association between rNFL thinning and macular volume loss confirmed with multiple studies 1 • rNFL loss begins ~2-3 months after ON, max @ ~6 mo 2 • Correlates with Low Contrast VA 1 • Short term progression of rNFL and LCVA in longitudinal studies 1,3 Disease free controls All MS MS, no ON MS, +ON 1. Sakai RE, Balcer LJ et al. Vision in MS. J Neuro-Ophthalmol 2011;31:362-373 2. Henderson AP, Altmann DR et al. A serial study of retinal changes following optic neuritis. Brain 2010;133;2592-2602 3. Talman LS, Bisker ER et al. Longitudinal study of vision and rNFL in MS. Ann Neurol 2010;67:749-760

164 MS and 64 HC Serial of SD-OCT with segmentation 6% MS patients had microcystic ME during follow up Increased INL associated with increased risk of disease activity

TBI and Concussion  1.4-3.8 million sports-related TBI/year in US  Visual system frequently affected in TBI:  Acute changes in saccadic latencies, memory-guided saccades, spatial accuracy ( Heitger MH et al, Prog Brain Res 2002 )  Longer term changes in saccadic accurary and gap saccade test ( Drew AS et al, Neurosci Lett 2007 )  Ocular motor metrics can assessed quantitatively and qualitatively

Cortical and Sub-cortical Control of Saccades Structure Location/Brodman Function n’s area Frontal Eye Anterior to pre- Initiates voluntary, non-visually guided, Fields motor cortex; contraversive saccades Brodmann Area 8 Parietal Eye Lateral bank of Initiates voluntary, visually guided, Fields interparietal contraversive saccades sulcus; adjacent to Brodmann area 7a Supplementary Anterior to Involved in planning and learning of Eye Fields supplementary saccadic movements motor cortex (area 6), dorsal medial frontal lobe Dorsolateral Dorso-lateral Involved in memory guided saccades Prefrontal frontal lobe; (saccades toward remembered objects) Cortex Brodmann area 9,46 Superior Caudal midbrain, Regulates excitatory and inhibitory Colliculus posterior to signals involved in generation of Periaqueductal saccades, and control of eye-head gray movement Paramedian Paracentral pons, Direct projections to effector Pontine anterior and extraocular muscles to move eye Reticular lateral to medial Formation longitudinal fasciculus