Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Follow up DLBS participants 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
The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of [18F]AV-1451.
Other Names:
Procedure: Positron Emission Tomography
Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Standardized Uptake Value Ratios (SUVrs) Calculated From [18F]AV-1451 PET Scans [An average of 3-months post-PET study visit]
Tau accumulation will be measured as the standardized uptake value ratio computed from each participant's [18F]AV-1451 PET scans averaged across six regions of interest (ROls) by normalizing regional counts to cerebellar grey matter. The 6 ROls are: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Both left and right hemisphere SUVrs will be computed for each region of interest (ROI). Each participant's PET scan will be coregistered to their T1-weighted MRI (MPRAGE) and warped to the Statistical Parametric Mapping (SPM)8 template. The PET data will be smoothed with an 8 mm Gaussian kernel to account for individual anatomic differences. SUVrs will be computed in each voxel by normalizing counts to cerebellar gray. Observed tau SUVr scores in humans range from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation.
Secondary Outcome Measures
- Relationship of Tau Accumulation with Episodic Memory Function [1-year post study completion]
Episodic memory will be a composite score using the following tasks: (1) Hopkins Verbal Learning test with 3 subcomponents (immediate recall: range 0-12, delayed recall: range 0-12, and recognition: range 0-24); (2) the immediate recall of the CANTAB Verbal Recognition Memory task (range 0-12), and (3) NIH Toolbox Picture Sequence Memory test (observed, uncorrected DLBS scores range from 76 to 136). Scores from the tasks will be converted to z-scores and then averaged to form an episodic memory composite; a higher composite z-score indicates better episodic memory.
- Relationship of Tau Accumulation with Amyloid Accumulation [1-year post study completion]
Amyloid accumulation will be measured with Florbetapir F18 and calculated as an Amyloid Standard Uptake Value ratio (SUVr). Amyloid SUVr scores will be averaged across eight cortical regions: dorsal lateral prefrontal cortex, orbitofrontal cortex, lateral parietal cortex, posterior cingulate cortex, anterior cingulate cortex, precuneus, lateral temporal cortex, and occipital lobe after normalizing regional counts to cerebellar grey matter. Amyloid SUVr scores observed in this study have ranged from 0.62 to 1.27, with higher scores being indicative of greater amyloid accumulation. Participants with Amyloid SUVr values above 1.09 (liberal threshold) or 1.12 (conservative threshold) will be considered Amyloid positive.
- Relationship of Tau Accumulation with Speed of Processing [1-year post study completion]
Speed of processing is a construct that measures how rapidly individuals can process information. Four tasks make up the speed of processing task: (1) digit comparison task; observed DLBS raw scores range from 27 to 116), (2) Wechsler Adult Intelligence Scale (WAIS) Digit Symbol Task; observed DLBS raw scores range from 20 to 90, and (3) NIH Toolbox Pattern Comparison Processing Speed Test; observed, uncorrected DLBS scores range from 63 to 155. Participants' raw scores are converted to z-scores and then averaged to form a speed of processing composite. A higher composite z-score indicates higher speed of processing.
- Relationship of Tau Accumulation with Reasoning Function [1-year post study completion]
To assess reasoning function, a composite score will be created using the Raven's Progressive Matrices task, Educational Testing Service (ETS) Letters Sets task, and CANTAB Stockings of Cambridge task. Observed DLBS raw scores range from 0.5 to 24 for Raven's Progressive Matrices task, from 5 to 24 for ETS Letters Sets task and from 4 to 11 for CANTAB Stockings of Cambridge task. Raven's Progress Matrices, ETS Letter Set, and CANTAB Stockings of Cambridge Scores will be converted to z-scores and then averaged to form a reasoning composite. A higher composite z-score indicates higher reasoning ability.
- Relationship of Tau Accumulation with Crystallized Intelligence [1-year post study completion]
Crystallized intelligence provides estimation about the participant's world or vocabulary- based knowledge. Three tasks will be used to create a composite Crystallized Intelligence measure: ETS Advanced Vocabulary task, NIH Toolbox Picture Vocabulary test, and NIH Toolbox Oral Reading Recognition test. Observed DLBS raw scores range between 4.25 and 36 for the ETS Advance Vocabulary task. Observed uncorrected scores for DLBS NIH Toolbox Picture Vocabulary test ranged from 100 to 153 and for DLBS NIH Toolbox Oral Reading Recognition test the range was 90 to 151. The scores from these 3 tests will be converted to z-scores and then averaged to form a Crystallized Intelligence composite. A higher composite z-score indicates higher crystallized intelligence.
- Relationship of Tau Accumulation with Participants' Age [1-year post study completion]
A linear regression between the AV-1451 SUVr in each of our temporal regions of interest with participant age will be calculated. 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.
- Comparison of Tau SUVr scores with Hippocampal Volume and Cortical Thickness [1-year post study completion]
Hippocampal volume and regional cortical thickness will be estimated from previously acquired T1-weighted structural magnetic resonance imaging (MRl) using FreeSurfer (ver. 5.3), with surface parcellation manually edited when necessary by our team of experts. Relationships between estimated tau deposition (SUVr) with hippocampal volume and cortical thickness will be estimated by entering these variables as continuous measures in linear mixed-model analyses with interaction terms including time of scanning/testing. All of these variables will then be used in further modeling to understand their independent and interactive relationship to the measures of cognition, with a particular focus on memory.
- Comparison of Tau Accumulation with White Matter Integrity [1-year post study completion]
Estimates of white matter integrity will be collected using diffusion tensor images from previously acquired data at 3 different timepoints over 10-years. To determine differences in white matter integrity between those with and without tau and amyloid pathology, the investigators will perform multiple linear mixed-model analyses. All variables of interest will be included as continuous measures. Tau SUVr x time and amyloid SUVr x time interaction terms will be entered in these models to predict how amyloid and tau pathology predicts longitudinal changes in white matter integrity. All of these variables will then be used in further modeling to understand their independent and interactive relationship to the measures of cognition, with a particular focus on memory.
- Comparison of Tau Accumulation with Functional magnetic resonance imaging (MRI) [1-year post study completion]
For functional measures, blood oxygenation level dependent signal from contrasts of interest using selected ROl's will be created. For the subsequent memory task, the investigators will focus on ROI's functionally associated with encoding (EG, hippocampus, parahippocampus, entorhinal cortex, prefrontal cortex) in past research. For the semantic judgment task the investigators will focus on ROI's associated with processing meaning, including inferior frontal gyrus, precuneus, and middle temporal gyrus. Finally, for resting state data, the investigators will use measures of connectivity and network integrity derived from graph theory.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Participated in Wave 2 of the DLBS and Amyloid PET studies.
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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
- 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).
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Volumetric Brain MRI Image (T-1 Weighted MPRage) collected as part of DLBS Wave 3 protocol.
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Completed at least 9 years of formal education, or the equivalent of freshman year of high school.
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Fluent English speakers.
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Tolerate laying 20 minutes on a flat table for the PET scan.
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Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
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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.
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Taking some types of sedatives, benzodiazepines, or anti-psychotics.
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Currently undergoing chemotherapy or radiation for cancer.
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New history of substance abuse.
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Has a history of drug or alcohol dependence within the last year, or prior prolonged history of dependence.
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Recreational drug use in past six months.
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Central nervous systems disease or brain injury that would preclude participation in the study.
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Psychiatric or neurological disorder that would preclude participation in this study.
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Has clinically significant hepatic, renal, pulmonary, metabolic or endocrine disturbances which pose safety risk.
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Has a current clinically significant cardiovascular disease that poses a safety risk.
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Has a current clinically significant infectious disease or a medical comorbidity which poses a safety risk.
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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.
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Has received or will receive investigational medication within the 30 days of PET/CT scan.
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Has received or will receive a radiopharmaceutical for imaging or therapy within 24 hours of PET/CT scan.
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Is a participant who, in the opinion of the investigator(s), is otherwise unsuitable for a study of this type.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UT Southwestern Medical Center | Dallas | Texas | United States | 75390 |
Sponsors and Collaborators
- Neil M Rofsky, MD, MHA
Investigators
- Principal Investigator: Denise Park, PhD, University of Texas at Dallas
Study Documents (Full-Text)
None provided.More Information
Publications
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- 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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- STU 092015-003