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

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.

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.