The Aging Brain and Cognition: Contribution of Vascular Injury, Amyloid Plaque and Tau Protein to Cognitive Dysfunction After Stroke

Stroke can lead to signficiant neurological deficits, and about one-third of stroke patients will be diagnosed of vascular mild cognitive impairment or post-stroke dementia. Post-stroke dementia includes all types of dementia that happen after stroke, irrespective of their cause, and vascular dementia (VaD), degenerative dementia (especially Alzheimer's disease), or mixed dementia (dementia as a result of the coexistence of vascular lesions of the brain and neurodegenerative lesions) are the most common causes of post-stroke dementia. However, it is difficult to determine to what extent cognitive impairment may be attributable to stroke versus concomitant Alzheimer disease. With the advent of PET imaging technique, we are able to conduct a multi-modal neuroimaging study to explore the composite influence of vascular injury, amyloid plaque and Tau protein the the cognitive performance after stroke.

Study Overview

• Status: Completed
• Conditions: Post-stroke Dementia; Vascular Mild Cognitive Impairment
• Intervention / Treatment: Drug: THK-5351; Drug: AV-45

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Guishan
    • Taoyuan, Guishan, Taiwan, 333
      • Department of Neurology, Chang-Gung memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Inclusion criteria for stroke/TIA patients

• Males or females with age >= 50 years old
• Having cerebral stroke or transient ischemic attack
• Modified Rankin Scale < 4
• Ability to participate in cognitive and neuroimaging assessments
• Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception after the final study
• Provision of signed informed consent

Inclusion criteria for healthy elderly controls

• Males or females with age >= 50 years old
• Without history of cerebral stroke or transient ischemic attack
• Ability to participate in cognitive and neuroimaging assessments
• Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception after the final study
• Provision of signed informed consent

Exclusion Criteria:

Exclusion criteria for all subjects

• Presence of dementia diagnosis before the index stroke or at the initial screening History of vascular MCI (VaMCI)
• The Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score >=104 [24] at the initial screening.
• Presence of large infarction or lobar encephalomalacia on brain CT or MRI.
• Severe language impairment precluding cognitive assessments, defined as a score of 3 points in the language score of the National Institute of Health Stroke Scale.
• Life expectancy less than 1 year.
• Clinically significant abnormal laboratory values.
• Clinically significant or unstable medical or psychiatric illness.
• Epilepsy history.
• Cognitive impairment resulting from trauma or brain damage.
• Substance abuse or alcoholism in the past 1 year
• General MRI, and / or PET exclusion criteria.
• Pregnant or becoming pregnant during the study (as documented by pregnancy testing at screening or at any date during the study according to the PI discretion) or current breast feeding.
• History of allergy to 18F-labelled radionucleic agents, [18F]AV-45 or [18F]THK-5351.
• Subjects having high risks for the study according to the PI discretion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: THK-5351; Name: [18F]THK5351，(S)-6-[(3-Fluoro-2-hydroxy)propoxy]-2-(2-Methylaminopyrid-5-yl)-quinoline Dosage form: intravenous injection Dose(s): 10mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the tau protein Pharmacological category：Radio pharmaceutical	Drug: THK-5351; [18F]THK-5351 PET Imaging; Drug: AV-45; [18F]AV-45 PET Imaging
Other: AV-45; Name: [18F]AV-45, (E)-4-(2-(6-(2-(2-(2-[18F]fluoroethoxy) ethoxy) ethoxy)pyridin-3-yl)vinyl)-N-methylbenzenamine Dosage form: intravenous injection Dose(s): 10mCi Dosing schedule: Visit 2 Mechanism of action (if known): high affinity radiotracer for the β- amyloid protein Pharmacological category：Radio pharmaceutical	Drug: THK-5351; [18F]THK-5351 PET Imaging; Drug: AV-45; [18F]AV-45 PET Imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CDR score of cognition deteriorating group and stable group	The CDR is a 5-point scale (0、0.5、1、2、3) used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. The necessary information to make each rating is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g., family member). Global score 0 = Normal、0.5 = Very Mild Dementia、1 = Mild Dementia、2 = Moderate Dementia、3 = Severe Dementia. The cognition deteriorating group is defined as CDR score declines from 0 or 0.5 at Month 3 to >=1 at Month 18. The cognition stable group is defined as CDR score remains at 0 or 0.5 at Month 18.	through study completion, an average of 1.5 year
Imaging positive and negative conditions	PET images are visually assessed by independent raters, who are nuclear medicine doctors and blinded to all clinical and diagnostic information. The raters classify each scan as 0-1 (no significant uptake)、2 (suspicious uptake)、3-4 (significant uptake). The score >= 2 is deemed as positive condition.	through study completion, an average of 1.5 year

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2016
• Primary Completion (Actual): March 29, 2016
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Neurocognitive Disorders; Pathological Conditions, Anatomical; Cognition Disorders; Stroke; Cognitive Dysfunction; Plaque, Amyloid; Vascular System Injuries
• Other Study ID Numbers: 103-7584A

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No