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

NCT02330510 | Completed DMC

• 1 other identifier: Ml1-112246
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 8

Brief 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.

Conditions

Alzheimer's Disease; Small Vessel Disease White Matter Hyperintensities Subtype; Vascular Cognitive Impairment

Keywords

Alzheimer's Disease; White Matter Hyperintensities; Vascular Cognitive Impairment; Amyloid Imaging; Transient Ischemic Attack

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 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.

  24 months

• F18 florbetapir SUVR brain uptake, with Periventricular White Matter Hyperintensity volumes and cognitive scores.

  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.

  24 months

• F18 florbetapir SUVR brain uptake, ApoE e4 genotype status, and White Matter Hyperintensity volumes in patients with a high burden of pvWMH.

  24 months

• Baseline F18 florbetapir SUVR brain uptake, cognitive score decline and increase in White Matter Hyperintensity volume at 2 year follow up.

  24 months

Study Arms (2)

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

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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)

You may not qualify if:

• Subject meeting any one of the following criteria are not eligible for the the study:
• Patients with cortical or non-lacunar infarct on imaging
• Patients with persisting hemiparesis after a motor stroke, leg strength \<4/5 on the Medical Research Council (MRC) scale; significant cerebellar ataxia
• Patients with contraindications to 3T MRI
• Patients with major psychiatric disorder during the preceding 5 years
• History of substance abuse within the past 2 years
• 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
• Pain or sleep disorder that could interfere with testing
• Claustrophobia
• Patients that have received radiation therapy to the head or neck or have been in another research study involving radiation
• Patients who are unable or unwilling to comply with protocol requirements or deemed by the investigator to be unfit for the study.

Sponsors & Collaborators

• Dr. Sandra E Black: lead

Study Sites (8)

University of Alberta Health Services

Calgary, Alberta, Canada

Location

University of British Columbia Hospital

Vancouver, British Columbia, V6T 2B5, Canada

Location

Hamilton General Hospital

Hamilton, Ontario, L8L 2X2, Canada

Location

Parkwood Hospital St. Joseph's Health Care

London, Ontario, N6C 5J1, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

CHU de Sherbrooke

Québec, Quebec, J1H 5H3, Canada

Location

CHU de Quebec

Québec, Quebec, Canada

Location

Related Publications (6)

• Xhima K, Ottoy J, Gibson E, Zukotynski K, Scott C, Feliciano GJ, Adamo S, Kuo PH, Borrie MJ, Chertkow H, Frayne R, Laforce R Jr, Noseworthy MD, Prato FS, Sahlas DJ, Smith EE, Sossi V, Thiel A, Soucy JP, Tardif JC, Goubran M, Black SE, Ramirez J; Medical Imaging Trials Network of Canada (MITNEC). Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology. Alzheimers Dement. 2024 May;20(5):3687-3695. doi: 10.1002/alz.13791. Epub 2024 Apr 4.

  PMID: 38574400 DERIVED

• Boone L, Biparva M, Mojiri Forooshani P, Ramirez J, Masellis M, Bartha R, Symons S, Strother S, Black SE, Heyn C, Martel AL, Swartz RH, Goubran M. ROOD-MRI: Benchmarking the robustness of deep learning segmentation models to out-of-distribution and corrupted data in MRI. Neuroimage. 2023 Sep;278:120289. doi: 10.1016/j.neuroimage.2023.120289. Epub 2023 Jul 24.

  PMID: 37495197 DERIVED

• Ottoy J, Ozzoude M, Zukotynski K, Kang MS, Adamo S, Scott C, Ramirez J, Swardfager W, Lam B, Bhan A, Mojiri P, Kiss A, Strother S, Bocti C, Borrie M, Chertkow H, Frayne R, Hsiung R, Laforce RJ, Noseworthy MD, Prato FS, Sahlas DJ, Smith EE, Kuo PH, Chad JA, Pasternak O, Sossi V, Thiel A, Soucy JP, Tardif JC, Black SE, Goubran M; Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease. J Cereb Blood Flow Metab. 2023 Jun;43(6):921-936. doi: 10.1177/0271678X231152001. Epub 2023 Jan 25.

  PMID: 36695071 DERIVED

• Ottoy J, Ozzoude M, Zukotynski K, Adamo S, Scott C, Gaudet V, Ramirez J, Swardfager W, Cogo-Moreira H, Lam B, Bhan A, Mojiri P, Kang MS, Rabin JS, Kiss A, Strother S, Bocti C, Borrie M, Chertkow H, Frayne R, Hsiung R, Laforce RJ, Noseworthy MD, Prato FS, Sahlas DJ, Smith EE, Kuo PH, Sossi V, Thiel A, Soucy JP, Tardif JC, Black SE, Goubran M; Medical Imaging Trial Network of Canada (MITNEC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET. Alzheimers Dement. 2023 Apr;19(4):1503-1517. doi: 10.1002/alz.12750. Epub 2022 Sep 1.

  PMID: 36047604 DERIVED

• Mojiri Forooshani P, Biparva M, Ntiri EE, Ramirez J, Boone L, Holmes MF, Adamo S, Gao F, Ozzoude M, Scott CJM, Dowlatshahi D, Lawrence-Dewar JM, Kwan D, Lang AE, Marcotte K, Leonard C, Rochon E, Heyn C, Bartha R, Strother S, Tardif JC, Symons S, Masellis M, Swartz RH, Moody A, Black SE, Goubran M. Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation. Hum Brain Mapp. 2022 May;43(7):2089-2108. doi: 10.1002/hbm.25784. Epub 2022 Jan 28.

  PMID: 35088930 DERIVED

• Ntiri EE, Holmes MF, Forooshani PM, Ramirez J, Gao F, Ozzoude M, Adamo S, Scott CJM, Dowlatshahi D, Lawrence-Dewar JM, Kwan D, Lang AE, Symons S, Bartha R, Strother S, Tardif JC, Masellis M, Swartz RH, Moody A, Black SE, Goubran M. Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs. Neuroinformatics. 2021 Oct;19(4):597-618. doi: 10.1007/s12021-021-09510-1. Epub 2021 Feb 1.

  PMID: 33527307 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood will be collected to better understand the possible contribution of genetics to white matter disease. DNA will be extracted from blood samples to assess the Apolipoprotein (ApoE) gene type, as ApoE e4 genotype may influence the rate of disease progression.

MeSH Terms

Conditions

Alzheimer Disease; Ischemic Attack, Transient

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Brain Ischemia; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Sandra E. Black, MD

  Sunnybrook Health Sciences Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 27, 2014
• First Posted: January 5, 2015
• Study Start: August 1, 2014
• Primary Completion: December 10, 2024
• Study Completion: December 10, 2024
• Last Updated: December 16, 2024

Record last verified: 2024-12

Locations

CA (8)