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

Cause or Effect: Untangling the Relationship With Amyloid and Tau Deposits to 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.

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

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

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

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.

Episodic memory is a construct that measures how well individuals can store, maintain, and retrieve detailed information in long-term memory. Episodic memory will be a composite score using the Hopkins Verbal Learning test with 3 subcomponents (immediate recall: range 0-12, delayed recall: range 0-12, and recognition: range 0-24) and the immediate recall of the CANTAB Verbal Recognition Memory task (range 0-12). Scores from the tasks will be converted to Z-scores and averaged to form an episodic memory composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates better episodic memory, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Episodic Memory Z-score.

Amyloid accumulation throughout the Dallas Lifespan Brain Study (6-9.8 years) will be measured with Florbetapir F18 and calculated as an Amyloid Standard Uptake Value ratio (SUVR) by normalizing regional counts to the whole cerebellum. Amyloid SUVR scores will be averaged across eight cortical regions spanning most of the cortex: dorsal lateral prefrontal cortex, orbitofrontal cortex, lateral parietal cortex, posterior cingulate cortex, anterior cingulate cortex, precuneus, lateral temporal cortex, and lateral occipital lobe. Amyloid SUVR scores observed in this study have ranged from 0.88 to 1.74, with higher scores being indicative of greater amyloid accumulation. Finally, annualized change scores for these amyloid SUVRs across the full study duration (6-9.8 years) will be calculated to determine the extent that the rate of amyloid accumulation relates to tau burden at the end of the study.

Speed of processing is a construct that measures how rapidly individuals can process information. To assess speed of processing, a composite score will be created using the Digit Comparison task and the Wechsler Adult Intelligence Scale (WAIS) Digit Symbol task. Observed DLBS raw scores range from 27 to 116 for Digit Comparison task and 20 to 90 for Digit Symbol task. Participants' raw scores are converted to Z-scores and averaged to form a speed of processing composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates better speed of processing, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Speed of Processing Z-score.

The construct of reasoning measures an individual's ability to recognize novel patterns and the conceptual relationship among objects and effectively apply these patterns to solve similar problems. To assess reasoning, a composite score will be created using the Raven's Progressive Matrices task and Educational Testing Service (ETS) Letters Sets task. Observed DLBS raw scores range from 9 to 30 for Raven's Progressive Matrices task and from 0.5 to 30 for ETS Letters Sets task. Raven's Progress Matrices and ETS Letter Sets will be converted to Z-scores and averaged to form a reasoning composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates higher reasoning ability, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Reasoning Z-score.

Working memory is a construct that measures the ability of individuals to simultaneously manipulate and store information. To assess working memory, a composite score will be created using the CANTAB Spatial Working Memory task (reverse scored) and the Wechsler Adult Intelligence Scale (WAIS-III) Letter Number Sequencing task. Observed DLBS raw scores range from 0 to 86 total errors for the CANTAB Spatial Working Memory task and 2 to 20 for the WAIS-III Letter Number Sequencing task. Participants' raw scores are converted to Z-scores and averaged to form a working memory composite, and then this final value with be converted to a Z-score. A higher working memory composite Z-score indicates better working memory, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Working Memory Z-score.

Linear regressions between the AV-1451 SUVR in each of the temporal regions of interest with participant age will be calculated, and in additional analyses, non-linear effects of age will be examined via quadratic and growth modeling. Observed AV-1451 SUVR scores in humans have ranged from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation. The investigators predict that tau accumulation will accelerate in old age, thus supporting a non-linear rate of deposition.

Regional cortical thickness will be estimated from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3), with surface parcellation manually edited when necessary by our team of experts. The regions selected for analyses of cortical thickness were the ROIs used to estimate temporal tau SUVR: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Observed cortical thickness in these regions range from 1.38 to 3.83 mm with higher scores indicating greater thickness.

Hippocampal volume will be estimated from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3), with surface parcellation manually edited when necessary by our team of experts. This region was selected for analysis as it was one of the ROIs used to estimate temporal tau SUVR. Observed DLBS hippocampal volume ranged from 1843 to 5342 mm^3 with higher scores indicating greater volume.

White matter integrity will be assessed using the estimated volume of white matter hypointensities from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3). Observed DLBS white matter hypointensities range from 796 to 35,037 mm^3 with higher scores indicating greater volume of hypointensities and reflecting worse white matter integrity.

For functional measures, blood oxygenation level dependent signal from contrasts of interest using selected ROls will be created. For the semantic judgment task (easy judgments - fixation), the investigators will focus on ROIs associated with processing meaning, including inferior frontal gyrus, precuneus, and middle temporal gyrus. Observed BOLD activation values (betas) ranged from -1.00 to 1.30 with higher values indicating greater activation.

Resting-state brain system segregation was computed on data collected from a separate resting-state scan using graph theory. System segregation is calculated as (Zw - Zb) / Zw, where Zw is the mean Fisher z-transformed r between nodes with the same system and Zb is the mean Fisher z-transformed r between nodes of one system to all nodes in other systems. Higher values indicate reduced node-node connectivity between systems relative to within-system connectivity. A score of 0 would reflect equal resting-state connectivity between nodes within the same functional system and between nodes of separate systems. Like all Z-scores, these scores typically range from -3 to 3. Higher scores are observed in younger adults than in older adults and may suggest a more youth-like brain, though higher scores are not objectively better. Systems were defined based on Power et al., (2011, Neuron) and more details on this measure are described in Chan et al. (2014, PNAS).

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.

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