Tau Imaging of Chronic Traumatic Encephalopathy

NCT ID: NCT02191267

Last Updated: 2018-05-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2016-09-30

Brief Summary

Chronic traumatic encephalopathy (CTE) is a progressive degenerative brain disease with symptoms that include memory loss, problems with impulse control, and depression that can lead to suicide. As the disease progresses, it can lead to dementia. Currently CTE can only be diagnosed postmortem where an over-accumulation of a protein called tau is observed. There is now a new experimental measure that makes it possible, for the first time, to measure tau protein in the living human brain using a novel positron emission tomography (PET) ligand, [F-18] AV-1451 (aka, [18F]-T807).

The main objective of this study is to use a novel PET approach to measure tau accumulation in the brain. The presence of CTE at autopsy in deceased National Football League (NFL) players has been well documented. Accordingly, we will conduct this study in a group of retired NFL players who have clinical symptoms of CTE and are suspected of having CTE based on high levels of tau in their spinal fluid and abnormalities seen on research brain scans. We will compare them with a control group of former elite level athletes who have not experienced any brain trauma, deny any clinical symptoms, and who have completely normal spinal fluid tau and amyloid levels, and brain scans. We will also include a group of subjects with AD. All participants will be recruited from ongoing studies, headed by the Partnering PI of this proposal, Dr. Robert Stern, at the Boston University Center for the Study of Traumatic Encephalopathy and the Alzheimer's Disease Center. We will use both a beta amyloid PET scan ([18F]-florbetapir) and a tau PET scan ([18F]-T807) on consecutive days. With the beta amyloid scan we expect little or no evidence of amyloid in the NFL players with presumed CTE, and no evidence of amyloid in the control group of athletes with no history of repetitive brain trauma. In contrast we expect to see beta amyloid accumulation in the AD patient brains. With the new tau ligand, we expect that the NFL players with presumed CTE will show elevated levels of tau protein in the brain, which will not be observed in athletes without a history of brain trauma, but which will be seen in the AD patients' brains.

Another goal is to use the latest MRI technologies to develop specific tau imaging biomarkers that correlate with the PET and spinal fluid tau measures but without the radiation of PET or invasiveness of spinal taps. The development of these surrogate imaging markers of tau, is critically important to diagnosing CTE. This in turn will lead to studies relevant to treatment and prevention of this devastating disease. Finally, as an exploratory method of examining possible genetic risk for CTE, we will also use cutting edge genetic analysis of blood samples from subjects in this proposal and compare tau load, measured by PET tau ligand uptake and cerebrospinal fluid (CSF) p-tau level, with a measure of genetic susceptibility to tau load, referred to as the genetic risk score for tau.

Conditions

Chronic Traumatic Encephalopathy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Presumed CTE Group

Interventions administered to the Presumed CTE Group include: \[F-18\]-T807 PET Scan, \[F18\]-Florbetapir PET Scan, MRI/MRS Scans, and Genetic Analysis for Genetic Risk Score for Tau.

Group Type: EXPERIMENTAL

[F18]-T807

Intervention Type: RADIATION

\[F18\]-T807 PET Scan to measure tau deposition in the brain.

[F18]-Florbetapir

Intervention Type: RADIATION

\[F18\]-Florbetapir PET scan to measure Beta-amyloid deposition in the brain.

MRI/MRS

Intervention Type: DEVICE

Two scans (structural, diffusion tensor imaging, and susceptibility weighted imaging scanned as part of one MR protocol, and a one-dimensional and two-dimensional spectroscopy examination as part of the other MR protocol.

Genetic Analysis for Genetic Risk Score for Tau.

Intervention Type: GENETIC

DNA will be extracted from previously acquired and de-identified frozen blood specimens using a standard protocol (Gentra Puregene Kit, Qiagen 158422). Genotyping will be performed using the iPLEX Sequenom MassARRAY platform and samples will be genotyped for single nucleotide polymorphisms (SNPs) associated with the deposition of neurofibrillary tangles.

Control Group

Interventions administered to the Control Group include: \[F-18\]-T807 PET Scan, \[F18\]-Florbetapir PET Scan, and MRI/MRS Scans.

Group Type: EXPERIMENTAL

[F18]-T807

Intervention Type: RADIATION

\[F18\]-T807 PET Scan to measure tau deposition in the brain.

[F18]-Florbetapir

Intervention Type: RADIATION

\[F18\]-Florbetapir PET scan to measure Beta-amyloid deposition in the brain.

MRI/MRS

Intervention Type: DEVICE

Two scans (structural, diffusion tensor imaging, and susceptibility weighted imaging scanned as part of one MR protocol, and a one-dimensional and two-dimensional spectroscopy examination as part of the other MR protocol.

AD Dementia Group

Interventions administered to the AD Dementia Group include: \[F-18\]-T807 PET Scan, \[F18\]-Florbetapir PET Scan, MRI/MRS Scans

Group Type: EXPERIMENTAL

[F18]-T807

Intervention Type: RADIATION

\[F18\]-T807 PET Scan to measure tau deposition in the brain.

[F18]-Florbetapir

Intervention Type: RADIATION

\[F18\]-Florbetapir PET scan to measure Beta-amyloid deposition in the brain.

MRI/MRS

Intervention Type: DEVICE

Two scans (structural, diffusion tensor imaging, and susceptibility weighted imaging scanned as part of one MR protocol, and a one-dimensional and two-dimensional spectroscopy examination as part of the other MR protocol.

Interventions

[F18]-T807

\[F18\]-T807 PET Scan to measure tau deposition in the brain.

Intervention Type: RADIATION

[F18]-Florbetapir

\[F18\]-Florbetapir PET scan to measure Beta-amyloid deposition in the brain.

Intervention Type: RADIATION

MRI/MRS

Two scans (structural, diffusion tensor imaging, and susceptibility weighted imaging scanned as part of one MR protocol, and a one-dimensional and two-dimensional spectroscopy examination as part of the other MR protocol.

Intervention Type: DEVICE

Genetic Analysis for Genetic Risk Score for Tau.

DNA will be extracted from previously acquired and de-identified frozen blood specimens using a standard protocol (Gentra Puregene Kit, Qiagen 158422). Genotyping will be performed using the iPLEX Sequenom MassARRAY platform and samples will be genotyped for single nucleotide polymorphisms (SNPs) associated with the deposition of neurofibrillary tangles.

Intervention Type: GENETIC

Other Intervention Names

[F-18] AV-1451; Amyvid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Diffusion Tensor Imaging; Susceptibility Weighted Imgaging; One-dimensional Spectroscopy; Two-dimensional Spectroscopy

Eligibility Criteria

Inclusion Criteria

• significant cognitive impairment (and impairment in at least one of the following):
• behavioral (e.g., impulsivity, aggression),
• mood (e.g., elevated depression measures, elevated suicidality),
• and/or motor (e.g., impairments evidenced in neurological examination;
• demonstrated abnormalities on svMRI, DTI, or MRS

• no history of mTBI or exposure to repetitive brain trauma
• normal functioning on DETECT clinical measures
• no abnormalities on svMRI, DTI, or MRS

• diagnosis of Dementia due to AD using the NIA-AA (National Institute on Aging-Alzheimer's Association) criteria
• Clinical Dementia Rating Global Score of 1.0,
• a positive florbetapir PET study,
• CSF p-tau/Aβ consistent with AD.

Exclusion Criteria

• weight > 350 lbs
• known metallic implants preventing MRI
• history of stroke
• non-English speaking
• significant vision or hearing impairment
• unable to provide written informed consent

2. Control Group (comprised of 5 male participants selected from 50 control subjects in the DETECT study).

• weight > 350 lbs
• known metallic implants preventing MRI
• history of stroke or other neurological disease
• non-English speaking
• significant vision or hearing impairment

3. AD Dementia Group (comprised of 5 male participants recruited from the BU Alzheimer's Disease Center (ADC) Clinical Core Registry (Dr. Stern, PI).

• history of TBI, mTBI or or exposure to repetitive brain trauma
• weight > 350 lbs
• known metallic implants preventing MRI
• history of stroke or other neurological disease
• non-English speaking
• significant vision or hearing impairment

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

U.S. Army Medical Research and Development Command

FED

Sponsor Role: collaborator

Boston University

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Martha E Shenton

Director, Psychiatry Neuroimaging Laboratory

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Martha E. Shenton, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Boston University Medical Center

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

Zhang W, Arteaga J, Cashion DK, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C, Mocharla VP, Mu F, Sinha A, Szardenings AK, Wang E, Walsh JC, Xia C, Yu C, Zhao T, Kolb HC. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis. 2012;31(3):601-12. doi: 10.3233/JAD-2012-120712.

Reference Type: BACKGROUND

PMID: 22683529 (View on PubMed)

Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, Shankle WR, Elizarov A, Kolb HC. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis. 2013;34(2):457-68. doi: 10.3233/JAD-122059.

Reference Type: BACKGROUND

PMID: 23234879 (View on PubMed)

Other Identifiers

2014P000035

Identifier Type: -

Identifier Source: org_study_id