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

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.

Alzheimer's disease (AD) is a highly prevalent disorder of dementia in older adults. AD neuropathology is marked by the presence of amyloid plaques and tau neurofibrillary tangles. Autopsy studies, as well as magnetic resonance imaging (MRI) studies in living persons, have established that the neurodegenerative changes in AD begin in medial temporal lobe structures and later progress to adjacent temporal, parietal and frontal neocortical regions. Magnetic resonance image studies of AD consistently reveal volumetric loss in the hippocampus using both cross-sectional and longitudinal approaches. The primary symptom of early-stage AD is memory impairment possibly accompanied by deficits in attentional control. Normal aging, however, is also marked by cognitive decline, as well as structural brain changes. Autopsy data had shown in the past that about 30% of older adults with no obvious cognitive impairment show some degree of the neuropathology typically associated with dementia at autopsy.

Importantly, the recent ability to image beta-amyloid and tau deposits in vivo using positron emission tomography (PET) scanning has revolutionized our understanding of early stages of AD. Evidence suggests that amyloid deposits may be detected 10 - 15 years before memory symptoms appear. These findings are leading to the ability to diagnose AD years before symptoms begin. Much less is known about the impact and developmental course of tau deposition as compared to beta-amyloid because the ligand to image tau was only recently invented. There is increasing evidence that tau is particularly toxic to the brain and is a later precursor of AD than amyloid deposits. Additional research on beta-amyloid and tau deposition in aging is crucial, as much work suggests that treatment of AD may be most effective when implemented early in the time course of the disease. Understanding the impact of tau deposits and its interactions with amyloid deposition allows the investigators to see the development of early markers of AD, which are important in understanding the trajectory of the disease. An important approach to understand the amyloid/tau puzzle and its relationship to AD is a large-scale longitudinal study of normal aging that integrates extensive neuroimaging and cognitive assessments along with tau imaging. A key aspect in understanding pathological aging is the need to be able to clearly differentiate normal aging from early pathology. The present Tau imaging study described here is an important component of the Dallas Lifetime Brain Study (DLBS).

The Dallas Lifespan Brain Study (DLBS) began in 2008 and was designed to utilize the new in vivo imaging techniques to address uncertainty regarding how AD pathology relates to the developmental process of aging and cognition, fueled in part by the partial overlap of pathological markers and decline in mnemonic function observed in a substantial proportion of 'normal' aged individuals. A total of 296 participants were recruited for Wave 1 from 2008 to 2014 to the DLBS and they received cognitive testing, structural and functional MRI, as well as a scan for beta amyloid using the radioligand AV-45 Florbetapir F 18 (also known as "\[18F\]AV-45"). A total of 183 returning participants were tested four years later in Wave 2, and they received the same battery as in Wave 1. In addition, 60 of these were also scanned with Flortaucipir F 18 (also known as "\[18F\]AV-1451"). \[18F\]AV-1451 is a newly-developed Phase II ligand that measures tau deposit in the human brain and this drug was provided to the DLBS by Avid Radiopharmaceuticals.

The objective of the current study is to test 125 DLBS participants with \[18F\]AV-1451 (Flortaucipir F 18) at the University of Texas Southwestern Medical Center (UTSW). The inclusion of tau imaging in Wave 3 will allow the investigators to relate tau deposition in the brain to the 10-year history of amyloid deposition and cognitive decline in the DLBS participants and understand the independent and joint contributions of tau to cognitive decline and early AD at different ages.

Eligibility Criteria:
Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.