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

• phthalmologists 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 response

RGC function Less reliant upon fixation Measuring baseline Eye movement artifact

Full field ERG

Objective assessment of rod and cone function Isolates inner and outer retinal function Less dependent upon fixation and cooperation Widely available

No topographic information More time consuming than

• ther EP tests

Multi-focal ERG

Assesses localized retinal dysfunction Correlation with field loss Dependent upon cooperation and fixation Not widely available

Pattern ERG

Information about macular and RGC function Easy to perform

Dependent upon cooperation and fixation Not widely available 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

• f retina

 No dye/contrast required  Powerful tool to assess blood flow to retina and

• ptic 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
• ther neurologic diseases

Ventura RE et al. Ocular motor assessment in

• Concussion. J Neurol Sci 2016;361:79-86

Galetta KM et al. The King-Devick test and sports related

• concussion. J Neurol Sci 2011;309:34-39

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

Preclinical AD ~20 y No AD Symptomatic AD ~7-10 y Synaptic/Neuronal Integrity

↑ CSF tau + Amyloid Imaging ↓ CSF Aβ42

Transition Zone

0.5  1  2  3

Cognitively Normal

Spread of tau (PET) accumulation Brain atrophy Altered task and resting fMRI Subtle decline in episodic memory and attention ↑ CSF SNAP-25 and Neurogranin

Death

CDR

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 Aβ 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

PET Negative Subjects PET Positive Subjects

n = 20 0.398 n = 7 0.288

• Association between rNFL thinning and macular

volume loss confirmed with multiple studies1

• rNFL loss begins ~2-3 months after ON, max @ ~6

mo2

• Correlates with Low Contrast VA1
• Short term progression of rNFL and LCVA in

longitudinal studies1,3

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 Disease free controls All MS MS, no ON MS, +ON

MS and OCT

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

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

Cortical and Sub-cortical Control of Saccades

King-Devick test and TBI

 Reliably distinguishes concussed from non-concussed athletes  Valid across multiple ages group and sports  Easily administered and scored with minimal training  Increases sensitivity of other sideline assessment tests (SAC

and BESS)

 Meta analysis of 15 studies showed that K-D test has sensitivity

• f 86% and specificity of 90% for detecting concussion

 Vision and eye movements critical components of concussion

and TBI assessment

• Ventura M et al. Diagnostic tests for concussion. J Neuro Ophthalmol

2015;35:73-81

• Galetta KM et al. The King Devick test: meta analysis and systematic
• review. Concussion 2015

Summary

 Visual system may be an attractive model for

studying neurologic disease

 Emerging evidence that structural and

functional retinal, optic nerve, and ocular motor changes occur in wide variety of neurologic conditions

 Opportunity for collaborations between neuro-

• phthalmologists and other sub-specialty

neurologists