Tau Imaging of Chronic Traumatic Encephalopathy

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.

CTE, Positron Emission Topography, Tau, Beta-amyloid, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Diffusion Tensor Imaging

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.

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

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

Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Diffusion Tensor Imaging, Susceptibility Weighted Imgaging, One-dimensional Spectroscopy, Two-dimensional Spectroscopy

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.

Whole brain mean (and standard deviation) cortical value derived from standardized uptake value ratio (SUVr). Each [F18]-T807 tau scan consisted of a 60-minute dynamic acquisition after bolus intravenous injection of 10 mCi of [18F]-T807, followed by a second 20-minute dynamic imaging (list mode) acquisition from 80-100 minutes. SUVr images were constructed from the sum of the 80-100 minute frames resulting in late SUVr distribution maps.

Mean and standard deviation for standardized uptake value ratios (SUVr) for posterior cingulate, superior parietal, lateral frontal, medial frontal, lateral temporal, and occipital brain regions. Each [F18]-Florbetapir (Beta-Amyloid) scan consisted of a 70-minute dynamic acquisition after bolus intravenous injection of 10 mCi of [18F]-Florbetapir. SUVr images were constructed from the sum of the 50-70 minute frames resulting in late SUVr distribution maps.

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 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 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

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