Antemortem diagnostic techniques

Antemortem diagnosis of CTE

Because the first description of CTE and subsequent studies depended upon autopsied brain sections, and microscopic pathologic findings, developing methods for antemortem diagnosis of CTE has proven elusive. Recent studies have attempted to use brain imaging modalities and plasma biomarkers to correlate symptoms of the disease in living persons with brain pathology. A recent study used PET scan imaging in combination with Florbetapir, a tracer that binds to aggregated tau in neurofibrillary tangles. The study examined a 39-year-old retired NFL football bplayer who had experienced 22 concussions throughout his playing career, and who was exhibiting neuropsychiatric symptoms associated with CTE. Logitunally acquired MRIs revealed cortical thinging in frontal and lateral temporal lobes, and volume loss in the basal ganglia. Florbetapir PET imaging revealed tau accumulations at the depths of corical sulci, which is the defining lesion of CTE in autopsied brains¹.

            This study established the possibility of using imaging modalities in antemortem diagnosis of CTE, but does not define a radiologic signature of CTE. Furthermore, this modality needs to be confirmed by postmortem examination of the brains of people imaged during life, to correlate these findings with confirmed cases of CTE.

            Efforts to develop more rapid tests that do not require expensive imaging modalities and radiation exposure have also expanded greatly in recent years. Tau levels in cerebrospinal fluid have been proposed as an appropriate biomarker for CTE, but the lumbar puncture required to retrieve CSF is viewed as invasive, and is often feared by patients. The search for blood-based markers of the disease is the newest frontier for diagnostic techniques.

            Direct measurement of tau, while possible, may not be representative of tau tangles within neurons as it is often released from damaged neurons. Nanovesicles, which are vesicles exocytosed by cells of the body, reflect the contents of their cell of origin. They are released into CSF, blood, and urine, are very stable, and are capable of crossing the blood-brain barrier, making them an ideal marker of disease. The technique of nanovesicle or exosome isolation has been used to successfully detect Alzheimer Disease pathology ten years prior to the onset of symptoms². Furthermore, Stern et al. recently applied this technique in measuring tau exosomes in symptomatic former NFL players, compared with non-contact athletes and raised levels of tau-positive plasma exosomes was significantly correlated with worse neuropsychological test performance³. This may represent a significant step forward in antemortem diagnosis of CTE, but further study correlating plasma levels with postmortem disease confirmation is required.

Sources

1)    Pullman MY, Dickstein DL, DeKoscky ST, Gandy S. Antemortem biomarker support for a diagnosis of clinically probable chronic traumatic encephalopathy. Mol Psychiatry 2017, Advance online publication.

2)    Goetzl et al., Altered Lysosomal Proteins in Neural-Derived Plasma Exosomes in Preclinical Alzheimer Disease. Neurology. 2015 July 7; 85(1):40-47

3)    Stern et al., Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. J Alzheimers Dis. 2016; 51(4):1099-1109