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

Alzheimer's Disease Clinical Trial

— MITNEC C6  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02330510
• Other study ID #: Ml1-112246
• Status: Recruiting
• Start date: August 2014
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: Sunnybrook Health Sciences Centre
• Contact: Aparna Bhan, MSc.
• Email: aparna.bhan[@]sri.utoronto.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease
• Cognitive Dysfunction
• Leukoencephalopathies
• Small Vessel Disease White Matter Hyperintensities Subtype
• Vascular Cognitive Impairment

Locations

Country	Name	City	State
Canada	University of Alberta Health Services	Calgary	Alberta
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	Parkwood Hospital St. Joseph's Health Care	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	CHU de Sherbrooke	Quebec
Canada	CHU de Quebec	Quebec city	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University of British Columbia Hospital	Vancouver	British Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Dr. Sandra E Black

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	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.	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
Secondary	F18 florbetapir SUVR brain uptake, with Periventricular White Matter Hyperintensity volumes and cognitive scores.	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
Secondary	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.	Mutlivariate analysis will be used to carry out this analysis, including PLS	24 months
Secondary	F18 florbetapir SUVR brain uptake, ApoE e4 genotype status, and White Matter Hyperintensity volumes in patients with a high burden of pvWMH.		24 months
Secondary	Baseline F18 florbetapir SUVR brain uptake, cognitive score decline and increase in White Matter Hyperintensity volume at 2 year follow up.		24 months
Secondary	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		24 months