Evaluating Cerebrospinal Fluid Biomarkers in Alzheimer's, Progressive Supranuclear Palsy Subjects, and Controls

Experimental Medicine Study to Evaluate the Kinetics of Cerebrospinal Fluid Biomarkers in Subjects With Alzheimer's Disease and Progressive Supranuclear Palsy Compared to Healthy Subjects Using a Heavy Water Labeling Method

This is an experimental medicine study to evaluate the kinetics of cerebrospinal fluid (CSF) biomarkers in subjects with Alzheimer's disease (AD) or progressive supranuclear palsy (PSP) compared to healthy controls using a heavy water (2H2O) labeling method. This study is exploring the time profile of appearance and disappearance of pulse deuterium-labeled cargo proteins in CSF of subjects with AD and/or PSP, which is different from healthy controls, due to deficits in fast axonal transport.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Progressive Supranuclear Palsy

Detailed Description

Primary Objective:

To compare the time profile of appearance and disappearance in CSF of pulse deuterium-labeled chromogranin B, sAPPα and β-Trace in AD and PSP subjects compared to healthy controls.

Secondary Objectives:

• To measure body water enrichment of deuterium in saliva and plasma (2H-enrichment (%))
• To explore the effect of age on the kinetics of deuterium labeling of CSF biomarkers
• To assess intra and inter subject variability of deuterium-labeling of chromogranin B, sAPPα and β-Trace

Subjects will undergo screening evaluations to determine eligibility prior to heavy water (2H20) administration. Eligible subjects will be admitted to the clinical facility on Day -1. On Day 1, subjects will ingest small doses of 2H20 during their inpatient stay. They will also drink 2H20 for 7 more days. Subjects will undergo two lumbar punctures (LPs) for CSF samples. Subjects will return to the study site approximately 7 days after the last LP (or early termination) for a follow-up assessment and discharge.

• Study Type: Observational
• Enrollment (Actual): 16

Contacts and Locations

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Parexel
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Centers of America Inc.
  • Texas
    • San Antonio, Texas, United States, 78217
      • Worldwide Clinical Trials

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

AD, PSP and EHV subjects will be recruited via Contract Research Organizations (CROs). Recruitment efforts will target the general population residing in communities in proximity to the CROs.

Description

Inclusion Criteria:

All subjects

• Body Mass Index of 18-32.
• Subjects can have common non-neurological age-related disorders (hypertension, diabetes) and on stable medication for the last 3 months.
• Screening score of < 4 on the Modified Hachinski Ischemia Scale.
• Women not of childbearing potential and men.
• Women with negative pregnancy test prior to starting heavy water and not breastfeeding.

AD

• Diagnosis of probable AD.
• Mild to moderate disease severity according to mini-mental state examination score (MMSE) of 16-26.
• Documented cognitive decline began 6 months prior to screening.
• On stable doses of approved AD medications for 2 months prior to screening.
• Non-medicated AD subjects are free of AD medications for 2 months prior to screening.
• Mild to moderate white matter disease and up to 2 lacunar infarcts acceptable as determined by brain MRI at screening.
• Investigator determines subjects to be medically stable and physically able to complete the study.
• Minimum of 6 years of education and able to read, write and communicate effectively.
• Adequate hearing, vision, and language skills.
• Subjects and their caregivers must agree to the dosage regimens and procedures, report for scheduled visits, and communicate with study personnel.

PSP

• Diagnosis of probable PSP.
• Brain MRI at screening excluding potential causes of parkinsonism, especially cerebrovascular and space occupying lesions.
• Mild-to-moderate stage of disease severity by a Golbe Staging System score of 1-3.
• Subjects and their caregivers must agree to the dosage regimens and procedures, report for scheduled visits, and communicate with study personnel.
• Currently on stable doses of PSP medications for 2 months prior to screening.
• Investigator determines subjects to be medically stable and able to complete the study.
• Minimum of 6 years of education and able to read, write and communicate effectively.
• Adequate hearing, vision, and language skills.

EHV

• No clinically significant deviation from healthy for their age group.
• No subjective or objective memory loss.
• MMSE score of 28 to 30.

Exclusion Criteria:

• Diseased subjects with a medical condition (not AD or PSP) that could contribute to the subjects dementia or Parkinsonism.
• History of pallidotomy, thalamotomy, active DBS or fetal tissue transplant.
• Any significant acute or chronic illness.
• Major surgery within 4 weeks of Day 1.
• Blood/plasma donation to a blood bank or a clinical study (except a screening visit) within 4 weeks of Day 1.
• Blood transfusion within 4 weeks of Day 1.
• Inability to be venipunctured.
• Inability to be lumbar punctured or contraindications to lumbar puncture or epidurals.
• > 10 cigarettes/day.
• Recent drug or alcohol abuse or positive urine screen for drugs of abuse.
• Subjects deemed inappropriate to undergo a MRI.
• Any medical, psychiatric or social reason as determined by the investigator.
• AD subjects with a history of CSF or amyloid imaging studies not consistent with Alzheimer's pathology.
• Healthy subjects with a history of CSF or amyloid imaging studies consistent with Alzheimer's pathology.
• Allergies to local anesthetics.
• Any significant drug allergy.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Elderly Healthy Control (EHV); No clinically significant deviation from healthy in medical history, physical examination, ECGs, MRI and clinical laboratory determinations for their respective age group.
Progressive Supranuclear Palsy (PSP); A diagnosis of possible or probable PSP according to clinical criteria of National Institute of Neurologic Diseases and Stroke - the Society for PSP plus a MRI at screening to exclude other potential causes of parkinsonism as well as a mild-to-moderate stage of disease severity according to a score of 1 to 3 in Golbe Staging System.
Alzheimer's Disease (AD); A diagnosis of probable AD Based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and The Diagnostic and Statistical Manual of Mental Disorders as determined by a mini-mental state examination (MMSE) score of 16 to 26, inclusive.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Measures	o Levels of deuterium-labeled chromogranin B, sAPPα and β-Trace in CSF	Up to 32 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Measures	o Body water enrichment of deuterium in saliva and plasma (2H-enrichment(%))	Up to 32 days

Collaborators and Investigators

• Sponsor: KineMed
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Marc K Hellerstein, M.D., Ph.D., KineMed

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: May 3, 2011
• First Submitted That Met QC Criteria: May 4, 2011
• First Posted (Estimate): May 5, 2011

Study Record Updates

• Last Update Posted (Estimate): October 24, 2014
• Last Update Submitted That Met QC Criteria: October 22, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Biomarker; Progressive Supranuclear Palsy; CSF; Cerebrospinal Fluid; Alzheimers Disease; Heavy Water; Cargo proteins
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Neurocognitive Disorders; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cranial Nerve Diseases; Ocular Motility Disorders; Ophthalmoplegia; Alzheimer Disease; Paralysis; Supranuclear Palsy, Progressive
• Other Study ID Numbers: CN167001