Orexin and Tau Pathology in Cognitively Normal Elderly

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Current consensus is that the AD pathological process begins decades before clinical symptoms occur. This long "preclinical" phase of AD might first become detectable in middle-age as deposits of hyperphosphorylated tau (P-tau) in the transentorhinal cortex and subcortical nuclei such as the locus coeruleus (LC) and the nucleus basalis of Meynert. There is strong preliminary evidence showing that cerebrospinal fluid (CSF) levels of orexin-A (OxA) are associated with increased P-tau (r=.52, p\<.01) and total-tau (T-tau) (r=.42, p\<.01) in cognitively normal older adults (mean age: 69.6±8.6 years).

This study poses that onset of tauopathy in the LC results in down regulation of orexin receptors, leading to a homeostatic increase of OxA production by the hypothalamus, which results in changes in core body temperature (CBT) and sleep disruption that cause further neurodegeneration. This hypothesis will be tested by demonstrating that increases in CSF P-tau are associated in vivo with tau PET uptake, and that tau binding in the LC is associated with increases in CSF OxA (Aim 1); and second, by analyzing the downstream consequences of increased central nervous system (CNS) OxA on sleep architecture and CBT (Aim 2). To test these hypotheses, 19 older adults (age 55-75) balanced by sex, will first perform a full clinical evaluation and PET-MRI where Tau burden will be analyzed by PET-MR using 18F-MK6240 (visits 1-2). Subjects will later undergo 7 days of actigraphy followed by nocturnal polysomnography (NPSG) for 2 consecutive nights (N1-2) during which we will measure CBT (visits 3-4). A morning lumbar puncture (LP) will be performed after N2 to obtain CSF.

There is the potential to identify: 1) an association between CSF P-tau and in vivo 18F-MK6240 uptake; 2) a mechanism by which tau pathology may contribute to orexin dysfunction; 3) evidence that orexin dysfunction disrupts sleep and CBT rhythm; and, 4) CNS orexin dysfunction as a new therapeutic target for AD prevention.

Eligibility Criteria:
Inclusion Criteria:

* Male and female subjects with normal cognition and 55-75 years of age will be enrolled.
* Subjects will be within normal limits on neurological and psychiatric examinations. All subjects enrolled will have both a Clinical Dementia Rating (CDR)=0 and a MMSE≥27
* All subjects will have had a minimum of 12 years of education. Among minority subjects \>80% of the elderly individuals coming to the NYU-ADC meet this criterion. (The education restriction reduces performance variance on cognitive test measures and improves the sensitivity for detecting pathology and disease progression using the robust norms available at NYU. Given the majority of subjects will meet this criterion we do not consider this a major selection bias or generalization limitation for this study).
* An informed family member or life-partner (preferably bed-partner) will be interviewed over the phone or on the first or second visit to confirm the reliability of the subject interview.

Exclusion Criteria:

* History of brain tumor, MRI evidence of brain damage or brain disease including significant trauma, hydrocephalus, seizures, mental retardation or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders). Subjects with a Fazekas scale \>2 will be excluded109.
* Significant history of alcoholism or drug abuse.
* History of psychiatric illness (e.g., schizophrenia, bipolar, PTSD, or life-long history of major depression).
* Geriatric Depression Scale (short form)\>5.
* Insulin dependent diabetes.
* Evidence of clinically relevant cardiac, pulmonary, endocrine or hematological conditions (e.g. low platelet levels).
* Physical impairment of such severity as to adversely affect the validity of psychological testing.
* Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard for MRI imaging or CBT measurements.
* History of a first-degree family member with early onset (age \<60 years) dementia.
* Irregular sleep-wake rhythms (based on the actigraphy recordings) or significant OSA (AHI4%≥15).
* Medications affecting cognition or sleep.
* Presence of any known or suspected obstructive disease of the gastrointestinal tract, including but not limited to diverticulitis and inflammatory bowel disease.
* History of disorders or impairment of the gag reflex.
* Previous gastrointestinal surgery.
* Previous felinization of the esophagus.
* Subjects who might undergo Nuclear Magnetic Resonance (NMR) or MRI scanning during the period that the CorTemp® Disposable Temperature Sensor is within the body.
* Subjects hypomotility disorders of the gastrointestinal tract including but not limited to Ileus.