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Orexin and Tau Pathology in Cognitively Normal Elderly

Primary Purpose

Elderly, Alzheimer Disease

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Actigraphy

Nocturnal Polysomnograpahy (NPSG)

About this trial

This is an interventional treatment trial for Elderly focused on measuring Orexin, Core Body Temperature

Eligibility Criteria

55 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

New York University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Elderly Patients

Arm Description

Outcomes

Primary Outcome Measures

Cerebral Spinal Fluid (CSF) P-Tau measured with PET-MR

CSF P-tau is associated with cortical tau uptake

18MK6240 binding amount measured with PET-MR

Tau binding in the brainstem is associated with increases in CSF OxA. PET-MR using 18MK6240 (PET Radiotracer for Imaging Neurofibrillary), which will be performed 1-4 weeks before the LP (visit 2).

Secondary Outcome Measures

Full Information

NCT ID

NCT03053908

First Posted

February 8, 2017

Last Updated

February 23, 2021

Sponsor

NYU Langone Health

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT03053908

Brief Title

Orexin and Tau Pathology in Cognitively Normal Elderly

Official Title

Orexin and Tau Pathology in Cognitively Normal Elderly (A New Prevention Strategy for Alzheimer's Disease)

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

March 27, 2018 (Actual)

Primary Completion Date

May 13, 2019 (Actual)

Study Completion Date

May 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

NYU Langone Health

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Elderly, Alzheimer Disease

Keywords

Orexin, Core Body Temperature

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

25 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Elderly Patients

Arm Type

Experimental

Intervention Type

Procedure

Intervention Name(s)

Actigraphy

Intervention Description

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

Intervention Type

Procedure

Intervention Name(s)

Nocturnal Polysomnograpahy (NPSG)

Intervention Description

N1 habituation and N2 data collection

Primary Outcome Measure Information:

Title

Cerebral Spinal Fluid (CSF) P-Tau measured with PET-MR

Description

CSF P-tau is associated with cortical tau uptake

Time Frame

4 Weeks

Title

18MK6240 binding amount measured with PET-MR

Description

Tau binding in the brainstem is associated with increases in CSF OxA. PET-MR using 18MK6240 (PET Radiotracer for Imaging Neurofibrillary), which will be performed 1-4 weeks before the LP (visit 2).

Time Frame

2 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

55 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ricardo Osorio, M.D

Organizational Affiliation

NYU Langone Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

New York University School of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

35550158

Citation

Blessing EM, Parekh A, Betensky RA, Babb J, Saba N, Debure L, Varga AW, Ayappa I, Rapoport DM, Butler TA, de Leon MJ, Wisniewski T, Lopresti BJ, Osorio RS. Association between lower body temperature and increased tau pathology in cognitively normal older adults. Neurobiol Dis. 2022 Sep;171:105748. doi: 10.1016/j.nbd.2022.105748. Epub 2022 May 10.

Results Reference

derived

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Orexin and Tau Pathology in Cognitively Normal Elderly

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