Clinical trial NCT03373604
Conditions: Alzheimer Disease
Keywords: 18F-MK-6240 Cognitive Impairment Alzheimer's
Sponsor: Patrick Lao
Start date: 2017-12-11; Completion date: 2022-05-11
Enrollment: 71 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to learn about tau tangles in Alzheimer's disease. A type of positron emission tomography (PET) scan is used to measure the abnormal accumulation of protein called tau in the brain. These are thought to be involved in Alzheimer's disease. The investigators will also perform brain MRI and to tests to measure the participant's memory and thinking.

Detailed description:
This study is being done to determine the relationship between tau tangles and cognitive impairment in elderly subjects with and without Alzheimer's disease (AD). Subjects will undergo screen that includes neuropsychological testing and brain MRI. This study uses a special type of scan called a PET scan to take pictures of the brain. During the PET scan, a special radioactive dye called 18F-MK-6240 is injected into the body. 18F-MK-6240 sticks to abnormal tangles made of the protein tau. Subjects will have the option to have lumbar puncture performed to measure CSF concentrations of biomarkers.

Arms: arm 1: Alzheimer's disease (mild cognitive impairment or mild stage Alzheimer's disease dementia) arm 2: Healthy controls
Interventions: intervention 1: 18F-MK-6240 intervention 2: Lumbar Puncture (optional)
Intervention descriptions: intervention 1: 18F-MK-6240 is a PET radioligand that binds abnormal tangles made of the protein tau. These tau tangles develop in the brain in people with Alzheimer's disease. intervention 2: Subjects have the option to have lumbar puncture performed for the measurement of Alzheimer's disease biomarkers in cerebrospinal fluid.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
IMAGING TAU IN ALZHEIMER’S DISEASE AND 
NORMAL AGING 
 
 
 
 
NCT03373604 
 
Date: December 21, 2022 
 


 
 
 
Background 
 
While amyloid plaques are a pathological hallmark of Alzheimer’s disease (AD), whether 
β-amyloid is the causal agent of neurodegeneration in AD remains unclear. Evidence supporting 
the hypothesis that amyloid is a primary contributor to AD pathogenesis (the amyloid-first 
hypothesis) include the finding that genetic mutations responsible for inherited forms of AD 
cause increased amyloid production. Studies using positron emission tomography (PET) to 
measure amyloid plaque burden in vivo have demonstrated amyloid positivity before obvious 
atrophy or cognitive decline in healthy older controls. While tau positive neurofibrillary tangles 
represent the second hallmark of AD, tau mutations are seen in patients with variants of 
frontotemporal dementia, not AD. The propagation of tau pathology is thought to follow 
amyloidosis, suggesting amyloid in some way induces tau mediated degeneration. However, the 
link between amyloid and tau not clear as there are spatial and temporal distinctions. For 
example, bulk of amyloid burden in medial parietal cortex and frontal cortex early on, while tau 
burden begins in medial temporal cortex. 
While β-amyloid has been shown to have direct neurotoxic effects in vitro, these effects 
are seen at concentrations of β-amyloid much higher than found in human brain[1].Therefore, 
amyloid may not confer significant direct toxicity. In addition, autopsy findings of pre-tangle 
pathology occurring in midlife prior to amyloidosis[2] suggest that tauopathy may begin prior 
and independent to significant amyloid plaque deposition. Since amyloid burden correlates 
poorly with cognition[3], tau may be a more important mediator of neurodegeneration in AD. 
Investigational Agent 
18F-MK-6240 is a PET radioligand that binds to paired helical filament tau aggregates. 
This radioligand has only been used for research purposes. 18F-MK-6240 will be administered in 
tracer doses (≤20 µg) at activity of 4 to 5 mCi (148 - 185 MBq) ±10% per injection. 
Study Objectives 
 
The primary objective is to determine the extent and spatial distribution of tau at different 
stages along the cognitive spectrum of aging (cognitively normal older adults, adults with mild 
cognitive impairment, and adults with Alzheimer’s disease dementia). 
 
Secondary objectives are to determine how 18F-MK-6240 binding in brain relates to 
cognitive performance, amyloid binding, atrophy on MRI, and CSF concentrations of markers of 
inflammation and neurodegeneration. 
 
Study Design 
 
150 subjects will undergo screening including history, physical examination, routine 
laboratory studies, neuropsychological testing, and brain MRI. 
Target sample size is 100 elders with impairment (50 amnestic MCI and 50 Alzheimer’s 
disease) and 50 elders without impairment (150 subjects total). 
One brain MRI will be performed on each subject using a 3 T Philips scanner. Sequences 
performed will include 3D T1 (MPRAGE, 180 slice 1 mm resolution, 256 x 256 voxel count) for 
volumetric analysis and clinical sequences to exclude subjects with significant intracranial 
pathology unrelated to AD, such as malignant brain tumor of subdural hematoma. PET scans will 
take place on a Biograph mCT PET scanner (Siemens Healthcare) at the CUMC Kreitchman 
PET Center. Subjects will have one PET scan with 18F-MK-6240 (injected activity 4 to 5 mCi = 
148 - 185 MBq ±10%). PET imaging will be performed without arterial sampling. Vital signs 


 
 
 
(blood pressure, heart rate, respiratory rate, and temperature) will be checked prior to injection of 
18F-MK-6240, then at the completion of the PET scan. 18F-MK-6240 will be purchased from 
Cerveau Technologies, Inc. via a licensed production facility. Subjects will not be informed of 
18F-MK-6240 PET scan results, as this scan is used only in research and have not yet been 
validated for clinical use. Subjects will be informed if a clinically important abnormality is 
detected on MRI or PET imaging (e.g., brain tumor). 
FreeSurfer (http://surfer.nmr.mgh.harvard.edu/), the MRI software package comprising a 
suite of automated tools for segmentation, reconstruction, and derivation of regional volumes and 
surface-based rendering, will be used for derivation of regions-of-interest (ROIs). Eleven ROIs 
will be extracted from the structural T1 image: entorhinal cortex, hippocampus, inferior temporal 
cortex, combined superior and middle temporal cortex, superior parietal lobule, inferior parietal 
lobule, precuneus, occipital cortex, prefrontal cortex, striatum, and thalamus. 
18F-MK-6240 PET images will be analyzed as follows: Freesurfer based ROIs will be 
applied to coregistered PET images. Correction for partial volume effects using a region-based 
voxel-wise method[23] will be applied. Regional time-activity curves using 60-120 min of scan 
data will be extracted from the PET scans, including cerebellum which will be used as a 
reference region. Standard uptake value ratio (SUVR) values will be calculated by dividing 
SUV values for each target region by that of the cerebellum. 
Subjects will have the option of having one lumbar puncture (LP) for CSF collection. 
Subjects may refuse the LP and still participate in the other study procedures. CSF analysis will 
be performed to determine CSF concentrations of total tau, phospho-tau, β-amyloid, and markers 
of inflammation such as IL-1β, TNF-α, glial fibrillary acidic protein, S100B, and YLK-40. 
 
Primary Study Endpoints 
 
Because the drugs used in this study are radioligands given at tracer doses, there are no clinical 
endpoints of the study. 
 
The primary outcome measures are: 
1. Amount of 18F-MK-6240 binding. 
 
Secondary outcome measures are: 
1. Correlation Between Tau, Neurodegeneration and Inflammation 
 
Statistical Plan 
Sample Size Determination 
Because 18F-THK-5351 is a recently developed radioligand, we do not have adequate 
preliminary data for a formal power calculation. This protocol is designed to generate 
information about 18F-MK-6240 binding in a large number of subjects over the spectrum from 
normal aging to mild cognitive impairment to Alzheimer’s disease. 
 
Statistical Methods 
The primary outcome measure will be regional standardized uptake value ratio (SUVR) 
values for 18F-MK-6240 using cerebellum as reference region. Multiple brain regions will be 


 
 
 
measured, with particular attention to medial temporal cortex structures such as hippocampus 
and entorhinal cortex. Analysis will be performed using a one-way ANOVA with cognitive 
status (AD vs. MCI vs. normal) as independent variable. Effect of age and education will be 
determined in post-hoc analysis. 
Regression models will be fit for 18F-MK-6240 binding as dependent variable and 
cognitive scores, voxel count on MRI, and CSF concentrations of markers of inflammation and 
neurodegeneration as independent variables. 
 
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