BEAM: Brain-Eye Amyloid Memory Study

  • STATUS
    Recruiting
  • End date
    Dec 1, 2023
  • participants needed
    345
  • sponsor
    Sunnybrook Health Sciences Centre
Updated on 1 October 2021
early diagnosis
cytokines
cognitive impairment
brain imaging
dementia
mini-mental state examination
optical coherence tomography
alzheimer's disease
parkinson's disease
mild cognitive impairment
amyloid
amyloidosis
mental state examination
apolipoprotein e
pittsburgh compound b
vascular disease
functional imaging
cognitive assessment

Summary

The main objectives for this study are:

  1. To investigate novel, non-invasive ocular measurements including optical coherence tomography and eye tracking in a cross-sectional study of participants with various neurodegenerative dementias against standard cognitive assessments and brain imaging measures; and
  2. To assess the potential utility of ocular assessments for early detection in the pre-dementia, i.e. the so-called Mild Cognitive Impairment (MCI) stage, across the common neurodegenerative dementia syndromes and, Vascular Cognitive Impairment (VCI) due to small vessel disease (SVD).
  3. To determine the prevalence and relevance of amyloid uptake on PET scanning across the dementias most commonly associated with amyloidosis. Specifically we aim to examine correlations with amyloid uptake status in patients symptomatic from the most common proteinopathies (ie amyloid, tau, synuclein) combined in varying degrees with the most common vasculopathies (ie small vessel disease) using multimodal structural and functional imaging, cognitive behavioral, and gait and balance measures, taking into account genetic risk markers (particularly apolipoprotein E genotypes) and fluid biomarkers ( eg cytokines, oxidative stress, lipidomics).

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
Condition Lewy Body Disease, Dementia, Alzheimer's Disease, Parkinson's disease, Mild Cognitive Impairment, Vascular Cognitive Impairment, Mild Neurocognitive Disorder, Lewy Body Dementia, diffuse lewy body disease, parkinson's, parkinson disease, alzheimer, dementia alzheimer's type
Treatment Flutemetamol PET scan, Fluroescent Ligand Eye Scanning (FLES), Pittsburgh Compound B [11C]-PIB
Clinical Study IdentifierNCT02524405
SponsorSunnybrook Health Sciences Centre
Last Modified on1 October 2021

Eligibility

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note