Amyloid and Glucose PET Imaging in Alzheimer and Vascular Cognitive Impairment Patients With Significant White Matter Disease (MITNEC C6)

May 3, 2022 updated by: Dr. Sandra E Black

The prevalence of both Alzheimer's Disease (AD) and stroke doubles each decade over 65 years old. Both are major causes of dementia, currently estimated to affect 46 million people worldwide. The current costs globally are $818 billion. Additionally, in population studies elders over 65 years, "covert" cerebral small vessel disease appears on MRI scans as silent lacunar infarcts in 25% as Microbleeds in 10%, and as focal or diffuse 'incidental' white matter disease (WMD) in 95%. WMD is extensive in 20%, with a clinical threshold effect around 10cc2. Small vessel disease is even more common in dementia, often coexisting with AD and independently contributing to cognitive decline and progression to dementia. Longitudinal imaging using cerebral amyloid labeling opens a new opportunity to understand the additive/interactive effects of small vessel disease and AD.

The design of this study includes recruitment of two cohorts, including Mild Cognitive Impairment (MCI) and/or early Alzheimer Disease subjects from memory clinics and subjects with strokes/TIA from stroke prevention clinics. Inclusion criteria include the presence of moderate/extensive white matter disease, eg. Fazekas score of 2 (with confluent peri-ventricular hyperintensities) or Fazekas score of 3, as determined by previous MR or CT, > 60 years of age, Mini-Mental Status Exam (MMSE) scores ≥ 20. Subjects will undergo 3T structural MRI (including T1, PD/T2, FLAIR, GRE, DTI, ASL, and resting state fMRI), glucose PET, amyloid PET (using AV-45 florbetapir) and neuropsychological testing, as well as blood sampling. Repeat MR and PET/CT imaging and neuropsychological testing will be conducted at 24 months. The follow up assessments can also be completed at either year 1 or year 3 or Year 4 depending on the availability of study participants. The imaging portion is designed to closely parallel the Alzheimer's Disease Neuroimaging Initiative (ADNI) in order to benefit from the availability of both cognitively normal controls (NC), MCI and Alzheimer's disease subjects with minimal WMD.

Study Overview

Detailed Description

This study will be a multi-center trial to be conducted in centers across Canada and approximately 80 patients will be enrolled. Participants will be recruited from both stroke prevention (N=40) and memory clinics (N=40). For comparison, we will access the publically-available data using a very similar protocol being collected from normal controls (N=250), MCI (N=250 early MCI, N=150 late MCI) and AD patients (N=150) without significant white matter disease, who are participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI-GO and ADNI 2, N=800), to choose representative samples for comparison to those with scores ≤ 1 who represent the non-white matter disease group.

Three imaging modalities will be used with each participant. 3 Telsa MRI scans will be acquired, using an ADNI based protocol, except for the addition of a PD/T2 interleved sequence. Participants will also undergo 18-fluoro PET with the AVID-45 ligand and 18-fluorodeoxyglucose PET using the ADNI protocols.

The primary objectives are to characterize at baseline and 2-year follow-up in patients with significant Periventricular White Matter Hyperintensities (pvWMH), presenting as transient cerebrovascular events or memory problems, patterns of: 1. Uptake of amyloid on Florbetapir F-18 PET/CT 2. Glucose uptake on 18F-FDG PET/CT 3. Volumetric measures of brain structure on MRI imaging 4. Performance on standard neuropsychological assessments, activities of daily living and gait speed.

Secondary objectives are to: 1. Compare the relationship between amyloid brain uptake, pvWMH volumes, and cognitive scores in patients with significant pvWMH and a control group of individuals that are cognitively normal, MCI or AD, with mild pvWMH, identified from the ADNI database. 2. Examine the relationship between amyloid uptake, ApoE e4 genotype, and structural MRI volumes in patients with a high burden of pvWMH. 3. Evaluate the utility of baseline brain amyloid to predict cognitive decline and increases in pvWMH volume at 2 years follow up. 4. Evaluate the safety of a single intravenous dose of Florbetapir F 18 Injection (370 MBq +/- 10%) in subjects with significant pvWMH.

Study Type

Observational

Enrollment (Anticipated)

80

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Quebec, Canada, J1H 5H3
        • Completed
        • CHU de Sherbrooke
    • Alberta
      • Calgary, Alberta, Canada
        • Recruiting
        • University of Alberta Health Services
        • Principal Investigator:
          • Eric Smith, MD
    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 2B5
        • Recruiting
        • University of British Columbia Hospital
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Recruiting
        • Hamilton General Hospital
        • Principal Investigator:
          • Jim Sahlas, MD
      • London, Ontario, Canada, N6C 5J1
        • Recruiting
        • Parkwood Hospital St. Joseph's Health Care
        • Principal Investigator:
          • Michael Borrie, MD
      • Toronto, Ontario, Canada, M4N 3M5
        • Recruiting
        • Sunnybrook Health Sciences Centre
    • Quebec
      • Montreal, Quebec, Canada, H3T 1E2
        • Recruiting
        • Jewish General Hospital
        • Principal Investigator:
          • Alex Thiel, MD
      • Quebec city, Quebec, Canada
        • Recruiting
        • CHU de Québec
        • Principal Investigator:
          • Robert LaForce, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Two groups of patients will participate in this study:

  1. Patients with early Alzheimer's Disease (AD) or amnestic or multi-domain Mild Cognitive Impairment who have extensive pvWMH; recruited from memory clinics (n= 40)
  2. Patients who have had a stroke or a Transient Ischemic Attack (TIA) with extensive pvWMH; recruited from stroke prevention clinics (n= 40)

Description

Eligible subjects must meet the following criteria before they are enrolled into the study:

  1. Patients with early AD or amnestic, non-amnestic single or multi-domain MCI who have confluent pvWMH; recruited from memory clinics. Or Patients who have had a minor stroke (e.g. subcortical lacunar infarct ≤1.5cm) or a TIA with confluent pvWMH; recruited from stroke prevention clinics.
  2. Age ≥ 60
  3. Patients who have provided written informed consent
  4. Patients with greater than 8 years of education
  5. Patients with an expected survival of greater than 2 years
  6. Patients that are sufficient fluency in French or English for cognitive testing
  7. Patients with a Mini-Mental State Exam score of (MMSE) ≥ 20
  8. Patients with pvWMH score on CT or MRI of ≥2 on the periventricular Fazekas scale 31 NOTE: Fazekas 2 patients can be included if they have bilateral posterior or anterior periventricular caps extending only 10mm from the ventricle (i.e. halfway into the surrounding white matter vs extending out to most of the surrounding white matter required for Fazekas 3)

Exclusion Criteria:

  1. Subject meeting any one of the following criteria are not eligible for the the study:
  2. Patients with cortical or non-lacunar infarct on imaging
  3. Patients with persisting hemiparesis after a motor stroke, leg strength <4/5 on the Medical Research Council (MRC) scale; significant cerebellar ataxia
  4. Patients with contraindications to 3T MRI
  5. Patients with major psychiatric disorder during the preceding 5 years
  6. History of substance abuse within the past 2 years
  7. Serious/chronic systemic or neurological illness (other than AD) such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities
  8. Pain or sleep disorder that could interfere with testing
  9. Claustrophobia
  10. Patients that have received radiation therapy to the head or neck or have been in another research study involving radiation
  11. Patients who are unable or unwilling to comply with protocol requirements or deemed by the investigator to be unfit for the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Alzheimer's Disease
Individuals with early Alzheimer's Disease (AD) or amnestic or multi-domain Mild Cognitive Impairment who have extensive Periventricular White Matter Hyperintensities
Transient Ischemic Attack/Mild Subcortical Stroke
Individuals who have had a mild subcortical stroke or a Transient Ischemic Attack (TIA) with extensive Periventricular White Matter Hyperintensities in the absence of cortical infarcts

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in F18 florbetapir SUVR over 2 years in patients with moderate-severe White Matter Hyperintensities, at baseline and 1 year follow-up brain uptake of Florbetapir F 18
Time Frame: 24 months
Standardized measures of F18 florbetapir brain uptake will be compared to baseline uptake patterns and prevalence of signal uptake in various areas
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Florbetapir F18 SUVR brain uptake, regional FDG metabolic measures and regional volutmetrics on MRI based volume including grey and white matter, small vessel disease, as well as regional cortical thickness measures.
Time Frame: 24 months
Standardized measures of F18 florbetapir brain uptake will be correlated with posterior-cingulate and parietal-temporal metabolism. We will also correlate with hippocampal, ventricular and regional volumes and with cortical thickness, derived with Lesion Explorer enhancement
24 months
F18 florbetapir SUVR brain uptake, with Periventricular White Matter Hyperintensity volumes and cognitive scores.
Time Frame: 24 months
The relationship between F18 florbetapir brain uptake, Periventricular White Matter Hyperintensity volumes, executive function and memory scores, in patients with significant pvWMH, accounting for relevant co-variates (age, education), using multivariate analysis including Partial Least Squares (PLS).
24 months
F18 florbetapir brain SUVR uptake, Periventricular White Matter Hyperintensity volumes and cognitive scores in an age-matched group of normal controls, MCI and AD subjects with minimal or mild degrees of pvWMH.
Time Frame: 24 months
Mutlivariate analysis will be used to carry out this analysis, including PLS
24 months
F18 florbetapir SUVR brain uptake, ApoE e4 genotype status, and White Matter Hyperintensity volumes in patients with a high burden of pvWMH.
Time Frame: 24 months
24 months
Baseline F18 florbetapir SUVR brain uptake, cognitive score decline and increase in White Matter Hyperintensity volume at 2 year follow up.
Time Frame: 24 months
24 months
Assess any adverse events or serious adverse events occurring with a a single intravenous dose of F18 florbetapir Injection (370 MBq +/- 10%) in subjects with significant pvWM
Time Frame: 24 months
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Sandra E. Black, MD, Sunnybrook Health Sciences Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2014

Primary Completion (Anticipated)

February 1, 2025

Study Completion (Anticipated)

February 1, 2025

Study Registration Dates

First Submitted

June 27, 2014

First Submitted That Met QC Criteria

December 31, 2014

First Posted (Estimate)

January 5, 2015

Study Record Updates

Last Update Posted (Actual)

May 4, 2022

Last Update Submitted That Met QC Criteria

May 3, 2022

Last Verified

May 1, 2022

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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