Tau Imaging of Chronic Traumatic Encephalopathy
Condition: Chronic Traumatic Encephalopathy
MeSH terms: Brain Diseases; Brain Injuries, Traumatic; Chronic Traumatic Encephalopathy
Intervention: [F18]-T807; [F18]-Florbetapir; MRI/MRS; Genetic Analysis for Genetic Risk Score for Tau.
Intervention description: [F18]-T807 PET Scan to measure tau deposition in the brain.; [F18]-Florbetapir PET scan to measure Beta-amyloid deposition in the brain.; 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: Male
Minimum age: 40 Years
Maximum age: 69 Years
Healthy volunteers: No
Keywords: CTE; Positron Emission Topography; Tau; Beta-amyloid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Diffusion Tensor Imaging

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.
    

Eligibility criteria:

        1. Presumed CTE Group (includes 20 former NFL players who will have already participated
             in the NIH-funded R01 "DETECT" (Diagnosis and Evaluation of Traumatic Encephalopathy
             with Clinical Tests) study (Stern, PI; Shenton, Neuroimaging Site PI). Eligibility
             criteria for presumed CTE group and the control group are based on findings from the
             DETECT study.

             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

             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).

             Inclusion Criteria:

               -  no history of mTBI or exposure to repetitive brain trauma

               -  normal functioning on DETECT clinical measures

               -  no abnormalities on svMRI, DTI, or MRS

             Exclusion Criteria:

               -  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).

        Inclusion Criteria:

          -  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:

          -  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