Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study

NCT04080544 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: STU 092015-003
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators will conduct tau positron emission tomography (PET) scans on 125 adults using the radiopharmaceutical Flortaucipir F18 (\[18F\]AV-1451). This will allow the investigators to determine tau deposition across adults of different ages and assess the relationship of current tau burden to cognitive function and amyloid deposition collected over the previous 10-year interval.

Conditions

Alzheimer Disease; Cognitive Decline

Keywords

Positron Emission Tomography

Outcome Measures

Primary Outcomes (1)

• Standardized Uptake Value Ratios (SUVrs) Calculated From [18F]AV-1451 PET Scans

  Tau accumulation in the temporal lobe will be measured as the standardized uptake value ratio (SUVR) computed from each participant's \[18F\]AV-1451 PET scans averaged across six bilateral regions of interest (ROls) by normalizing regional counts to the whole cerebellum. The 6 ROls are: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Each participant's PET scan and the six bilateral ROIs will be coregistered to their T1-weighted MRI (MP-RAGE). Finally, the mean observed tracer count from each region will be extracted and normalized using whole cerebellum as the reference. Observed tau SUVR scores in humans range from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation. Unless otherwise specified, all subsequent analyses will use this temporal tau SUVR and will involve examination of cross-sectional relationships between tau SUVR and key outcome measures at Wave 3 of the DLBS.

  An average of 3-months post-PET study visit

Secondary Outcomes (11)

• Relationship of Tau Burden to Episodic Memory Function

  1-year post study completion

• Relationship of Amyloid Accumulation to Tau Burden

  1-year post study completion

• Relationship of Tau Burden to Speed of Processing

  1-year post study completion

• Relationship of Tau Burden to Reasoning

  1-year post study completion

• Relationship of Tau Burden to Working Memory

  1-year post study completion

Study Arms (1)

Follow up DLBS participants

EXPERIMENTAL

Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014.

Drug: [18F]AV-1451; Procedure: Positron Emission Tomography

Interventions

[18F]AV-1451 DRUG

The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451.

Also known as: Flortaucipir F18

Follow up DLBS participants

Positron Emission Tomography PROCEDURE

Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Also known as: PET

Follow up DLBS participants

Eligibility Criteria

• Age: 38 Years - 96 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participated in Wave 1 or 2 of the DLBS study.
• Subjects must indicate that they are not currently pregnant if they are women of child-bearing potential. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1) Has not undergone a hysterectomy or bilateral oophorectomy; or 2) Has not been naturally post-menopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Volumetric Brain MRI Image (T-1 Weighted MPRage) collected as part of DLBS Wave 1, 2, or 3 protocol.
• Completed at least 9 years of formal education, or the equivalent of freshman year of high school.
• Fluent English speakers.
• Tolerate laying 20 minutes on a flat table for the PET scan.
• Ability to understand and the willingness to sign a written informed consent.

You may not qualify if:

• Mini-Mental State Examination (MMSE) score lower than 22; all DLBS participants at the time of initial Wave 1 enrollment between 2008 - 2014 had an MMSE score of 26 or above, indicating normal cognitive function. However, in the time interval between Wave 1 and Wave 3, it is possible that mental capacity may have deteriorated. The investigators will exclude all participants in Wave 3 testing who have an MMSE lower than 22.
• Taking some types of sedatives, benzodiazepines, or anti-psychotics.
• Currently undergoing chemotherapy or radiation for cancer.
• New history of substance abuse.
• Has a history of drug or alcohol dependence within the last year, or prior prolonged history of dependence.
• Recreational drug use in past six months.
• Central nervous systems disease or brain injury that would preclude participation in the study.
• Psychiatric or neurological disorder that would preclude participation in this study.
• Has clinically significant hepatic, renal, pulmonary, metabolic or endocrine disturbances which pose safety risk.
• Has a current clinically significant cardiovascular disease that poses a safety risk.
• Has a current clinically significant infectious disease or a medical comorbidity which poses a safety risk.
• Has either: 1) Screening electrocardiogram (ECG) with corrected QT Interval (QTc) \> 450 millisecond (msec) if male, or QTc \> 470 msec if female; or 2) A history of additional risk factors for Torsades de Pointes (TdP) (e.g., hypokalemia, family history of Long QT syndrome) or are taking drugs that are known to cause QT prolongation (a list of prohibited and discouraged medications is provided by the Sponsor); Patients with a prolonged QTc interval in the setting of intraventricular conduction block (examples right bundle branch block or left bundle branch block), may be enrolled with sponsor approval.
• Has received or will receive investigational medication within the 30 days of PET/CT scan.
• Has received or will receive a radiopharmaceutical for imaging or therapy within 24 hours of PET/CT scan.
• Is a participant who, in the opinion of the investigator(s), is otherwise unsuitable for a study of this type.

Sponsors & Collaborators

• Neil M Rofsky, MD, MHA: lead

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Publications (18)

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  BACKGROUND

• Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol. 2006 May;5(5):406-12. doi: 10.1016/S1474-4422(06)70417-3.

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• Convit A, de Leon MJ, Golomb J, George AE, Tarshish CY, Bobinski M, Tsui W, De Santi S, Wegiel J, Wisniewski H. Hippocampal atrophy in early Alzheimer's disease: anatomic specificity and validation. Psychiatr Q. 1993 Winter;64(4):371-87. doi: 10.1007/BF01064929.

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• Killiany RJ, Moss MB, Albert MS, Sandor T, Tieman J, Jolesz F. Temporal lobe regions on magnetic resonance imaging identify patients with early Alzheimer's disease. Arch Neurol. 1993 Sep;50(9):949-54. doi: 10.1001/archneur.1993.00540090052010.

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• Jack, C., Knopman, D., Jagust, W., Petersen, R., Weiner, M., Aisen, P., … Trojanowski, J. (2013). Update on hypothetical model of Alzheimer's disease biomarkers. Alzheimer's & Dementia, 9(4), 521-522.

  BACKGROUND

• Jack CR Jr, Petersen RC, Xu YC, Waring SC, O'Brien PC, Tangalos EG, Smith GE, Ivnik RJ, Kokmen E. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology. 1997 Sep;49(3):786-94. doi: 10.1212/wnl.49.3.786.

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• Mohs RC, Ashman TA, Jantzen K, Albert M, Brandt J, Gordon B, Rasmusson X, Grossman M, Jacobs D, Stern Y. A study of the efficacy of a comprehensive memory enhancement program in healthy elderly persons. Psychiatry Res. 1998 Feb 27;77(3):183-95. doi: 10.1016/s0165-1781(98)00003-1.

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• Park DC, Reuter-Lorenz P. The adaptive brain: aging and neurocognitive scaffolding. Annu Rev Psychol. 2009;60:173-96. doi: 10.1146/annurev.psych.59.103006.093656.

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• Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol. 2001 Sep;58(9):1395-402. doi: 10.1001/archneur.58.9.1395.

  PMID: 11559310 BACKGROUND

• Reuter-Lorenz PA, Park DC. How does it STAC up? Revisiting the scaffolding theory of aging and cognition. Neuropsychol Rev. 2014 Sep;24(3):355-70. doi: 10.1007/s11065-014-9270-9. Epub 2014 Aug 21.

  PMID: 25143069 BACKGROUND

• Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. doi: 10.1016/j.jalz.2011.03.003. Epub 2011 Apr 21.

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• Storandt M, Grant EA, Miller JP, Morris JC. Rates of progression in mild cognitive impairment and early Alzheimer's disease. Neurology. 2002 Oct 8;59(7):1034-41. doi: 10.1212/wnl.59.7.1034.

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MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Limitations and Caveats

Although several of these participants had an earlier PET-tau scan and we originally proposed to analyze longitudinal effects of tauopathy, a new PET scanner was implemented for this final wave of PET-tau data collection; preliminary analyses and discussions indicated the two scanners were not comparable and so we opted to focus on only this final wave of PET-tau data.

Results Point of Contact

• Title: Dr. Joseph Hennessee
• Organization: The University of Texas at Dallas

joseph.hennessee@utdallas.edu

408-813-4488

Study Officials

• Denise Park, PhD

  The University of Texas at Dallas

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor and Chair, Department of Radiology

Study Record Dates

• First Submitted: September 3, 2019
• First Posted: September 6, 2019
• Study Start: January 15, 2019
• Primary Completion: June 30, 2022
• Study Completion: June 30, 2022
• Last Updated: September 28, 2023
• Results First Posted: September 28, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)