Investigating eye measurements for early detection of neurodegenerative diseases

General Inclusion Criteria (All Subgroups)

Participants must meet each of the following criteria for enrolment into the study:

1. Written informed consent obtained and documented
2. Male or post-menopausal female (minimum of one year since the last menstrual period)
3. 50-90 years of age
4. Self-reported proficiency in speaking and understanding spoken English questions
5. ≥8 years education
6. Capable of cooperating for the duration of the study procedures and assessments
7. Willing to undergo study procedures and remain unaware of the results (unless there are findings that are of clinical significance and would require further action, in the opinion of the study physician)
8. Sufficient vision to participate in cognitive testing (corrected near visual acuity of Snellen 20/70 in at least one eye) and eye-tracking (able to identify symbols and stimuli presented on a computer screen in front of them)
9. Sufficient corrected hearing to participate in cognitive testing
10. Good venous access for phlebotomy to be performed
11. Able to walk, with or without an assistive aid (e.g., cane, walker)

Subgroup-Specific Inclusion Criteria

Cognitively Normal Controls

1. Cognitively normal and functionally independent in pre-screening history
2. Within normal limits on the TorCA (formally known as Behavioural Neurology Assessment - Revised (BNA-R)
3. Within normal limits on the study neuropsychological battery

Mild Cognitive Impairment (MCI)

1. Meets the National Institute on Aging-Alzheimer's Association criteria for single or multi-domain amnestic MCI
2. Impairment of episodic memory plus or minus other cognitive domains on the TorCA
3. Montreal Cognitive Assessment (MoCA) score ≥18
4. Mini-Mental State Examination (MMSE) \> 20
5. In the opinion of the investigator if required: reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

Alzheimer's Disease (AD)

1. Meets the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria for probable or possible AD dementia
2. Mild early AD stage, as defined by MMSE score ≥18, Atypical cases with a MoCA ≥ 14 will also be allowed.
3. Impairment in two or more cognitive domains on the TorCA
4. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

Lewy Body Disease (LBD) Spectrum PD-MCI

1. Meets the proposed Level I criteria for Mild Cognitive Impairment in Parkinson's Disease
2. MMSE score ≥20
3. MoCA score ≥18
4. Hoehn \& Yahr stage 1-3
5. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

LBD-MCI

1. Meets the criteria for Dementia with Lewy Bodies (McKeith et al, 2017 in press)but has preserved daily functioning
2. MMSE score ≥20
3. MoCA score ≥18
4. Hoehn \& Yahr stage ≤3
5. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

Dementia with Lewy Bodies (DLB)

1. Meets the criteria for probable or possible Dementia with Lewy Bodies (McKeith et al, 2017 in press)
2. MMSE score ≥14
3. MoCA score ≤25
4. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

PDD

1. Meets the criteria for probable Parkinson's Disease - Dementia
2. MMSE score ≥18
3. MoCA score ≤25
4. Hoehn \& Yahr stage ≤4
5. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

Subcortical Vascular Cognitive Impairment (VCI)

1. Presence of subcortical vascular disease, indicated by the following:

   i. Periventricular Fazekas score = 3, with or without subcortical lacunes or small cortical infarcts (\<1.5 cm in longest diameter); or ii. Fazekas score ≥ 2, with 2 or more subcortical lacunes or small cortical infarcts (\<1.5 cm in longest diameter); or iii. Fazekas score = 0 or 1, with 3 subcortical lacunar infarcts (\<1.5 cm in diameter), at least 1 in each hemisphere; or

   iv. Probable or possible Cerebral Amyloid Angiopathy using the Modified Boston Criteria
2. Reliable and capable partner who has regular interaction with them, can provide a collateral history, can assist in compliance with study procedures, and who is willing to act as the Study Partner (provide written informed consent) and remain unaware of the results

Exclusion criteria General Exclusion Criteria (All Subgroups)

Participants who exhibit any of the following conditions will be excluded from the study:

1. Underlying conditions (other than the disease being studied) which in the opinion of the investigator may interfere with the participant's ability to participate in the study or may compromise study results, including but not limited to:

   1. Unstable cardiac, pulmonary, renal, hepatic, endocrine (i.e. diabetes) or hematologic disease
   2. Active malignancy or infectious disease
   3. Significant psychiatric illness, including life-long depressive illness
   4. History of significant learning disability
   5. Significant other neurologic disease (e.g., multiple sclerosis, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma) or cognitive complications of cancer
   6. Symptomatic stroke within the past 6 months
   7. Substance abuse within the past year or history of alcohol or drug abuse which in the opinion of the investigator may interfere with the participant's ability to comply with the study procedures
   8. History of significant head trauma or recurrent concussions requiring hospitalization followed by persistent neurologic defaults or known structural brain abnormalities
   9. Pain or sleep disorder that could interfere with cognitive testing
   10. Any disability that would limit the ability to perform study assessments
2. Ocular conditions, including:

   a. Clinical diagnosis of glaucoma, taking eye drops for glaucoma, or previous surgery (including laser) for glaucoma b. Any other serious eye disease or treatment or eye surgery, including any history of intra-vitreal injections c. History of optic neuritis d. Previous retinal laser therapy (either pan-retinal, or grid/focal) for diabetic retinopathy e. Cupping of the optic nerve head (ONH) consistent with a diagnosis of glaucoma, as clinically determined by expert ophthalmological assessment of digital colour fundus images centered on the ONH. Specifically, one or more of the following (assessed as part of SD-OCT visit at Kensington Eye Institute): i. a cup/disc ratio of 0.7 or greater in either eye ii. a cup/disc asymmetry of more than 0.2 iii. disc hemorrhage iv. notch f. Wet/exudative age-related macular degeneration (ARMD) in one or both eyes, as clinically determined by expert ophthalmological assessment of digital color fundus images centered on the fovea (assessed as part of SD-OCT visit at Kensington Eye Institute)
3. Intra-ocular pressure greater than 22mmHg or a difference in intra-ocular pressure (Goldmann tonometry) greater than 5mmHg between the two eyes (assessed as part of SD-OCT visit at Kensington Eye Institute)
4. Brain imaging abnormalities detected either on clinical MRI or CT prior to enrollment or on study MRI, including but not limited to:

   1. Evidence of infection
   2. Focal compressive mass lesions (tumours, subdural hematomas, malformations, etc.)
5. Known hypersensitivity to Pittsburgh Compound B \[11C\]-PIB or any components of the\[11C\]-PIB Injection formulation
6. Contraindications to 3T MRI, as listed in the site-specific Magnetic Resonance Environment Screening Questionnaire (e.g. metal implant)
7. Unable to tolerate the MRI environment (e.g., due to physical size and/or claustrophobia)
8. Currently enrolled in a disease-modifying therapeutic trial that in the opinion of the Principal Investigator can potentially compromise study results

Subgroup-Specific Exclusion Criteria Cognitively Normal Controls

1. Subjective memory complaints
2. Brain imaging abnormalities detected either on clinical MRI or CT prior to enrollment or on study MRI, including but not limited to:

   1. Periventricular Fazekas score = 2.5 or 3
   2. Subcortical non-lacunar infarct or more than 1 subcortical lacunar infarct (\<1.5 cm in longest diameter)
   3. Cortical ischemic stroke Cortical or subcortical hemorrhagic stroke \>1.5cm in diameter

MCI, AD, and LBD Spectrum

(1) Brain imaging abnormalities detected either on clinical MRI or CT prior to enrollment or on study MRI, including but not limited to:

1. Periventricular Fazekas score = 2.5 or 3
2. Subcortical non-lacunar infarct or more than 1 subcortical lacunar infarct (\<1.5 cm diameter)
3. Cortical ischemic stroke \>1.5cm in longest diameter
4. Cortical or subcortical hemorrhagic stroke \>1.5cm in diameter