Orexin and Tau Pathology in Cognitively Normal Elderly

Summary

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.

Conditions

• Elderly
• Alzheimer Disease

Interventions

PROCEDURE

Actigraphy

Recording of sleep/wake cycle and TST by actigraphy to be completed at home by subject over 7 days

PROCEDURE

Nocturnal Polysomnograpahy (NPSG)

N1 habituation and N2 data collection

Sponsors & Collaborators

• National Institute on Aging (NIA)

  collaborator NIH

• NYU Langone Health

  lead OTHER

Principal Investigators

• Ricardo Osorio, M.D · NYU Langone Health

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

55 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-03-27

Primary Completion

2019-05-13

Completion

2019-05-13

Countries

• United States

Study Locations