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.