We're going to begin with a repeat speaker, Ross Puffer, who's going to be talking about CSF biomarkers correlate with results of neuropsychological testing in patients with chronic traumatic brain injury. Thank you. So, this is another project that I had the opportunity to work with Dr. Alconquah at Pittsburgh on. No financial relationships to disclose, so I think it's best to start off by just identifying a term here, a TBI-related neurodegeneration. Using that to describe as a clinical term for a neurodegenerative syndrome in patients with a history of repetitive concussive and subconcussive TBI. A lot of people would say, well, that's chronic traumatic encephalopathy, but in fact that's a diagnosis that currently can only be made at autopsy. Classically thought to be deposition of phosphorylated tau in specific cortical and subcortical regions. This is an example from one of the McKee papers of an advanced tauopathy with a phosphorylated tau present in the perivascular spaces and deep sulci associated with brain atrophy. So, beta amyloid isn't currently a defining feature of the diagnosis of CTE, but it is found to be detected in more than 50% of confirmed CTE cases when a tauopathy is advanced. And it's also thought that a single severe TBI can lead to beta amyloid deposition. So one of the research focuses of the group is to accurately define this TBI-related neurodegeneration syndrome, but also help to distinguish it from other conditions that might be present in that population. So Alzheimer's, dementia, Parkinsonism, et cetera. And as well as that, identifying clinical, radiographic, and biomarker tests that can accurately and reliably diagnose that syndrome in patients who are still alive. Only when we achieve all of those goals and when we get a valuable definition and in vivo diagnosis can we focus more on management and potential prognostication for these patients. So with that being said, the objectives of this study were to evaluate CSF, phosphorylated tau, and beta amyloid concentrations in a cohort of TBI subjects, and then correlate those biomarker levels with neuropsych testing. So the subjects were selected from a larger parent study. It was the team TBI study that was performed at Pittsburgh. And to be eligible for the CSF side, you had to have a history of TBI greater than six months prior with refractory clinical symptoms, a PCSS greater than 30, and evidence of clinical deficits. The range of ages were 18 to 60, included military and civilian subjects. And the mechanism of injury was blast injury, blunt injury, or a combination of both. The CSF was obtained via LP and then batch processed in an independent lab and analyzed for beta amyloid, total tau, and phosphorylated tau. The neuropsych testing was performed by trained technicians at Pittsburgh who were blinded to the patient's status in the team TBI trial. And the test battery included a lot of the common neuropsych tests listed there. Statistics were performed by an in-house statistician, included for this study focused on nonparametric correlation, Spearman correlation. So getting into the results, there were 20 subjects with a mean age of 40 years old. Eighty-five percent were male. Almost 50 percent were military veterans. And the mechanism of injury was blunt trauma and 60 percent, blast trauma and 30 percent, and a combination in 10 percent. So just looking at the first correlation, the CSF beta amyloid had an inverse correlation with short delay free recall memory testing. So it was a strong inverse correlation that was significant even after age was controlled for. So as the concentration of beta amyloid decreases, the score on the short delay free recall improves. There's a lot of dispersion on this graph for the correlation, but it still remains significant. Again, the beta amyloid concentration in the CSF had a strong inverse correlation with long delay free recall as well. So a strong correlation that was significant when age was controlled for. And then the last finding was that phosphorylated tau in the CSF was also inversely correlated with running memory CPT, which is a test evaluating sustained and selective attention. Again, this was a moderate inverse correlation that was significant to decrease phosphorylated tau in the CSF and improvement in scores. So putting this together, the concentrations of phosphorylated tau and beta amyloid in the CSF seemed to correlate with specific neuropsychological tests. These were just a couple of the tests that were performed. There was a large battery that occurred, but these were the correlations in these subjects. There's an inverse correlation with free recall as well as sustained and selective attention testing. So this highlights a potential role in the comprehensive evaluation of TBI-related neurodegeneration, which really would include neuropsychological testing, volumetric imaging, PET imaging, actually biomarkers including CSF and blood studies, really trying to get a comprehensive evaluation so we can best define this syndrome before moving on to management, as I mentioned. So the limitations of this study, it's a very small cohort, only 20 subjects. And then some difficulty actually defining the diagnosis. How do we parse out the difference between TBI-related neurodegeneration compared to someone who's demonstrating early signs of Alzheimer's dementia? Those studies are very active and ongoing, trying to find the best way to differentiate these syndromes, just as I mentioned. So the next steps really here are to expand this cohort, but also to include healthy controls and, importantly, chronic TBI subjects with no evidence of clinical neurodegeneration. That way you have a normal healthy control group, a chronic TBI group that does not demonstrate neurodegeneration, so you can see what the levels of the phosphorylated tau and beta amyloid are in those patients, and then compare that to the group that we have here, which is chronic TBI subjects with clinical neurodegeneration. So the take-home points for this talk would be that CSF biomarkers, phosphorylated tau and beta amyloid inversely correlate with specific neuropsych tests in chronic TBI subjects. And they may play a role in this comprehensive evaluation in vivo of clinical neurodegeneration in these patients. But further studies really need to focus on achieving, A, a consensus definition of the clinical syndrome, as well as identifying and validating in vivo diagnostic testing, which as I previously mentioned would include volumetric MRI, PET imaging, biomarker testing, and neuropsychiatric evaluation. So thanks for listening. I'd be happy to answer any questions. Yeah? I think I missed it, but at what point post-injury did you get the CSF, and was it just one draw? So it was just one draw. It had to be, it was a wide range of timing from post, from the last injury. Some of these subjects were military veterans that reported 100 subconcussive injuries during a deployment, and so that could range from six months out to several years. Everyone in this study had clinical neurodegeneration, and that's how they became a part of the study. And so I apologize I didn't report that, but it's a fairly wide range, anywhere from six months out to several years. All right, thank you, Dr. Parfor, that's very important work.

CSF biomarkers

neuropsychological testing

TBI-related neurodegeneration

phosphorylated tau

beta amyloid