BEAM: Brain-Eye Amyloid Memory Study (BEAM)

Description

1. Retinal correlations with neurodegeneration:
   1. Retinal nerve fiber layer (RNFL) pattern will differ in participants in the MCI and early stages of LBD spectrum, AD, and VCI, relative to normal elders. i) RNFL thinning around the optic disc and macular thinning will correlate with hippocampal atrophy and with the cortical thickness signature of MCI and AD2-4. ii) If detected in the other disorders, RNFL thinning will also correlate with this topographical AD pattern of atrophy in those who are amyloid positive on PET. iii) Retinal and cortical thinning will predict brain amyloid PET. iv) Selective peripapillary RNFL thinning in the superior and inferior quadrants described in MCI/milder AD cases will correlate with precuneus and lingual gyrus cortical thinning respectively.
   2. Retinal artery narrowing will correlate with presence of covert lacunar infarcts and retinal venular widening with moderate to severe periventricular white matter hyperintensities.
   3. Amyloid deposition above accepted cut-offs will vary across the 4 cohorts and when present will correlate meaningfully with cognitive and behavioural patterns, including ocular (retinal and eye tracking), gait and balance measures and brain imaging results.

Specific hypotheses are:

1. Apoelipoprotein E e4 carrier status will increase likelihood of amyloid positivity across the cohorts.
2. Amyloid positivity will be associated with poorer short term memory performance, smaller hippocampal volumes, greater cortical thinning in signature areas traditionally associated with Alzheimer's disease, and also with lobar microbleed counts.
3. Small Vessel Disease burden as quantified on PD/T2 and FLAIR MRI will be associated with speed of processing, attention and executive functions and with a different pattern of cortical thinning involving more inferior and medial frontal regions.
4. Amyloid deposition as measured by regional standardized uptake value ratio (SUVR), and Small Vessel Disease burden will correlate differentially with structural imaging measures, as well as both functional and structural brain connectivity measures.

Study Procedures Overview The study procedures are listed below in the recommended order of assessment but may be performed in any sequence (with specific exceptions as described). Multiple assessments may be performed on the same day for participant convenience. Brain imaging and neuropsychology procedures should be completed within 4 months of screening.

Screening Visit Consent. The study will be explained and written informed consent for participation will be obtained from the patient or his/her substitute decision maker and the participant's study partner (if applicable).

Screening. The general and disease-specific inclusion and exclusion criteria will be assessed. If the MMSE, MoCA, DOC (Depression, Obstructive Sleep Apnea, Cognition) questionnaire and/or TorCA (formally known as Behavioural Neurology Assessment - Revised (BNA-R) have not been administered within the past four months, they will be administered at the screening visit. Information on the patient's concomitant medications, medical, surgical, ophthalmological history, family health history and other relevant history will be collected, as well as information on both the patient's and the study partner's demographics. The patient's corrected near visual acuity will be checked. Auditory acuity at various frequencies will be assessed using an audiometer. Fasting blood will be drawn, for analysis of HbA1c, CBC, electrolytes, creatinine, urea, lipid profile, glucose, liver function (AST, ALT, ALP, bilirubin), homocysteine, B12 and TSH. Blood will also be drawn for genomics and fluid biomarkers (see next section.)

Genomics and Fluid Biomarkers. Fasting blood samples for genetic testing including apoliprotein E4 status, as well as for proteomic, lipidomic and other fluid biomarkers of neurodegeneration and vascular disease, will be collected from each participant.

Neuropsychological Battery and Questionnaires. The cognitive battery comprises most of the tests used in the Ontario Neurodegenerative Disease Research Initiative (ONDRI) study, a new province-wide neurodegeneration research collaboration, with some modifications. It includes measures of executive function, memory, language, and visuospatial ability. Function, mood and behaviour, and caregiver burden will also be assessed using the questionnaires used in ONDRI. The full list of the assessment procedures is included in the BEAM neuropsychology manuals.

SD-OCT. Assessments to meet ocular criteria will include visual acuity, intra-ocular pressure (IOP) measurement and a non-mydriatic fundus camera recording, performed by a certified ophthalmic technician. The participant will then undergo SD-OCT to determine retinal nerve fiber layer thickness.

Vital Signs and Neurological Exam. Vital signs will be measured and a neurological examination will be performed.

Gait and Balance Assessment. Information on aid use and balance will be collected using questionnaires. Participants' leg length, calf circumference, height, and weight will be measured and recorded when possible.

Eye Tracking. Participants will be asked to look at a computer monitor and perform three sets of tasks (pro-saccade, anti-saccade, and dynamic free viewing) while a specialized camera tracks and records their eye movements. Participants who are unable to complete these assessments will be allowed to continue participation in the study.

SV-OCT at Sunnybrook. SV-OCT will be done in subsamples with high SVD vs. minimal SVD loads. A rapid (>100 fps) 3D scanning protocol will be applied to SD-OCT, allowing acquisition of speckle variance due to microscopic blood flow in the retinal vasculature. Image processing using GPU based technique will provide real-time assessment of microvasculature morphology.

MRI. 3DT1 SPGR, interleaved spin echo PD/T2 and FLAIR to assess SVD, and gradient echo images to assess microbleeds, will be obtained on the 3 Tesla scanners at each of the TDRA sites. The PD/T2 and FLAIR images are co-registered to the T1-weighted image to remove non-brain tissues to determine total supratentorial intracranial volume to correct for head size, classify brain tissue compartments and automatically identify subcortical and white matter hyperintensities using a published in-house pipeline, "Lesion Explorer", which with manual editing yields number, size, location, and volume of the hyperintensities. For hippocampal volume, we use our fully automated segmentation pipeline based on a template library registration117, 118. We will also acquire DTI to generate total and regional fractional anisotropy (FA) and Mean Diffusivity Maps, using FSL and DTI tool box, and a resting state fMRI to explore Default Mode Network (DMN) connectivity, using a processing pipeline steps previously applied to AD patients and controls119.

Arterial Spin Labeling (ASL) will be included at certain sites which are capable of acquiring this sequence, to obtain measures of regional cerebral perfusion.

Amyloid PET. PIB, labelled with the positron emitting atom carbon-11, is a radiotracer that targets A-aggregates (-amyloid) in vivo. -amyloid deposits are present in the brain of patients with Alzheimer's Disease (AD). Therefore, A-plaques in the brain may be a useful biomarker of the disease and its progression and [11 C]-PIB may be a useful tool to detect these plaques in the human living brain with PET.

[11 C ]-PIB is an investigational positron emitting radiopharmaceutical (PER) not yet marketed in Canada. The ligand will be manufactured at CAMH PET centre. PET imaging will be performed using [11 C] PIB at CAMH PET Centre with PET/CT-Discovery MI scanner using the standardized acquisition protocol.

The PET imaging protocol begins with a low dose CT scan (less than 0.05 mSv) for attenuation correction. Immediately following this acquisition, a bolus containing approximately 10 1 mCi of [11 C]-PIB is administered by IV injection, followed by 90 minutes acquisition. Acquisition and reconstruction of PET images are done according to the standard PET Centre Imaging Protocols.

Phone Check Ups: For safety measures the participants will be contacted by phone to discuss any possible adverse event and general well-being two times during the course of the study:

• 24-72 hours after the PET scan
• 30 days (+/- 7 days) after PET Scan and/or the last study procedure

Details