PET Measures of CSF Clearance in Preclinical Alzheimer's Disease

The impaired clearance of amyloid-β (Aβ) leading to the accumulation of Aβ plaques and consequent neurodegeneration, is a partially understood mechanistic hypothesis for late onset Alzheimer's disease (AD). Using Positron Emission Tomography (PET) and a tracer for tau lesions, with a low molecular weight that rapidly enters and clears the brain, the investigators developed, replicated, and validated a non-invasive method to estimate the clearance of CSF at ventricular and brain levels. The investigators propose to complete over five years, a 2y longitudinal study designed to test in preclinical AD the hypothesis that reduced CSF clearance measured with the tau tracer [18F]-MK6240 is predictive of: a) future amyloid lesions (PiB-PET or Florbetaben-PET); b) brain atrophy (MRI); and c) cognitive decline.

Inclusion criteria

• Male and female subjects between 20-100 years old will be enrolled. Younger subjects are not included as the risk for brain amyloid lesions is too low
• All subjects will speak English as their first language or demonstrate proficiency in English.
• All subjects may have normal cognition or cognitive impairment.
• All subjects will be in good general health and able to participate in the LP and imaging exams. This determination is made by the study neurologist and reviewed at a consensus meeting for each subject.

Exclusion criteria

• Uncontrolled hypertension or metabolic disease
• Neurodegenerative disorders (i.e. Parkinson disease. LBD, or FTD).
• Long life major depression. Baseline scores ≥20 on Beck Depression Inventory at baseline
• Long-life DSM-IV axis 1 disorders.
• Mental retardation.
• Substance abuse.
• Concurrent medication limiting validity of neuropsychological tests or imaging.
• Anti-depressants with anti-cholinergic properties
• Monoamine oxidase inhibitors (MAOi)
• Regular use of narcotic analgesics (>2 doses per week).
• Use of neuroleptics
• Individuals taking over the counter memory enhancing or protecting medications (e.g. ginkgo biloba, vitamins) are not excluded.
• Implanted medical devices that are incompatible with MRI imaging.
• Radiation exposures exceeding annual Rad Worker limits.
• Heart failure stage D as defined by American Heart Association (7).
• Chronic kidney disease in stages ≥ 4, as defined per National Kidney Foundation (8).
• Brain tumor and other neoplastic disorders outside the brain where disease itself or its treatment (radiation, chemotherapy) is likely to affect brain structure or function.
• Stroke when meeting criteria for total anterior, partial anterior or posterior circulation infarct according to the Oxford Community Stroke Project classification. Patients with clinically silent of lacunar strokes and transient ischemic attacks will not be excluded.
• Significant head trauma.
• Hydrocephalus.
• Hostility or refusal to cooperate
• Person's receiving chronic anti-coagulation therapy
• Person's participating in other research projects will be excluded when the other project(s) 1) involve radiation exposure which in combination with the current project would increase radiation exposure above federal guidelines, 2) involve administration of study drug or other experimental therapy, or 3) prohibit participation in other research projects.
• Participants in this study will be allowed to participate in other observational research studies. The investigators will review at enrollment the full array of projects a subject may be involved in and inform the other PI's to ensure that subject safety and research data integrity is not compromised.