PT/MR evaluation of athletes with postconcussion syndrome

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1 PT/MR evaluation of athletes with postconcussion syndrome Niklas Marklund of Clinical Sciences Lund, Neurosurgery, Lund University, Sweden

2 Sports-related concussions- basic facts Recovery after concussion < first month in ca 90% of athletes Longer recovery periods in young/adolescents and female (?) athletes, key prognostic factor related to the severity of early symptoms Ca 10 % of athletes have prolonged symptoms > months post-injury

3 Definition of PostConcussion Syndrome (PCS)

4 Common symptoms of post-concussion syndrome (PCS)

5 PCS-persisting in a subset of athletes.. are they at risk for long-term problems?

6 Long-term consequences of (repeated) concussions (many, 3+?) Repeated concussions may result in an increased risk for mild cognitive impairment (MCI) an earlier onset of Alzheimer s disease Depression Cortical thinning, hippocampal atrophy A systematic review of potential long-term effects of sport-related concussion Manley et al., BJSM 2017

7 One basic hypothesis- A concussion results in White matter injury AND Neuroinflammation Which then triggers...

8 ....neurodegeneration including an increased risk of MCI/Alzheimer s disease - and the taopathy of CTE (?) found at autopsy McKee AC et al., Brain 2013

9 How to test this hypothesis of white matter injury, inflammation and tau accumulation?

10 Patients/Athletes/controls Healthy controls: 6 individuals (30+/-6 years) without prior history of concussion, CNS disorder or TBI Moderate- severe TBI patients 6 patients (age 29 +/- 8 years) with moderate-severe TBI (median 18 months before scanning). Three diffuse axonal injury (DAI), three mixed/focal TBI. All good recovery. Four males, two females. Athletes w. postconcussion syndrome (PCS) 6 athletes (age 28 +/-7 years, range 21-41) fulfilling the criteria for PCS. Last concussion (median 23 months (range months) before scanning). Median 6 concussions (3-10); 5 male hockey players, one female skier.

11 Patients and Methods Clinical examination, DSM IV for defining the diagnosis of postconcussion syndrome (PCS) Neuropsychological test-rbans (cognitive screen) Biomarkers from blood and CSF at time of PET/MRI evaluation

12 Sweden s first PET/3T MR scanner SIGNA PET/MR, Uppsala 2014 Image from Prof. Elna-Marie Larsson

13 Rationale for simultaneous PET/MR? Study of dynamic processes, e.g. neurotransmitter activity compared with fmri, blood flow Single imaging session, advantage e.g. in dementia MR based motion correction improves quality of PET images

14 Dual PET tracers- used the same day [ 11 C]PK11195 (neuroinflammation; microglial activation ), 5 MBq/kg i.v. [ 18 F]THK5117 (neurodegeneration, tau), 3 MBq/kg i.v. Scan time: 60 minutes for each tracer 2 different sessions

15 MRI 8ch head coil T2 3D FLAIR sag (CUBE) T1 3D gre sag (BRAVO) T2 3D tse sag (CUBE) SWI tra (SWAN) DTI tra (32 dir) 3D pcasl (x 2) Courtesy of Prof. Elna-Marie Larsson, Dept. of Radiology, Uppsala Univ.

16 Arterial Spin Labelling (ASL) CBF maps

17 Results-MRI Morphological sequences and SWI Healthy controls normal Moderate/severe TBI DAI and microhemorrhages on T2FLAIR and SWI PCS normal

18 ASL for the estimation of CBF Chronic reduction of global perfusion in grey matter AND white matter Vedung et al., manuscript

19 Reduced CBF in virtually all brain regions evaluated by MRI/ASL

20 Neuropsychology- cognitive screen

21 A b p g / m l T a u p g / m l A b p g / m l Biomarkers- reduced CSF amyloid-beta, normal TAU A b * * C o n t r o l s S R C T B I A b * T a u Collaboration; Drs Zetterberg, Blennow, Shahim C o n t r o l s S R C T B I C o n t r o l s S R C T B I

22 PET results- preliminary!

23 PET-tracers for tau in TBI/PCS/CTE

24 NFL Control 39-year old Retired NFL player 22 concussions

26 PET-tracers for tau in TBI/CTE/PCS

28 Moderate-severe TBI > one year post-injury Good outcome. MRI abnormalities Increased microglial reactivity -Binding of [ 11 C]PK11195 Increased tau signal for [ 18 F]THK5117 Marklund et al., manuscript

signal/binding TAU Last concussion ca 18 months

29 Sports-related concussion/ post-concussion syndrome Increased microglial reactivity Increased tau signal/binding TAU Last concussion ca 18 months previously (Mean age years) Marklund et al., manuscript

30 Careful analysis of all PET data Z-maps SPM8 T-maps VOI analyses SVCA Etc.

31 Limitations- ongoing work Careful analysis of variability crucial when interpreting the low signal of the tau PET Images Three more healthy controls are currently being analyzed for more robust statistical analyses [ 18 F]THK5117 is not specifik for phosphorylated tau and has a variable white matter binding also in healthy controls- sensitive for minor variations in binding [ 11 C]PK11195 supposedly binds to 18-kDA translocator protein (TSPO), elevated in activated microglia. Its specificity has been questioned. This is not diagnostic of CTE

32 Conclusions Postconssusion syndrome in athletes with repeated concussions is associated with Reduced amyloid-beta peptides, not tau, in CSF Impaired cognitive performance Global reduction, chronically, in cerebral blood flow Normal standard 3T MRI Increased irregular binding of [ 11 C]PK11195 indicating reactive microglia (?) Increased signal intensity/binding potential for tau in cortical regionspreliminary findings Follow-up scans are planned- is this a progressive disorder or will it resolve over time?

33 Acknowledgements Dept. Neuroscience, Neurosurgery Fredrik Vedung PET center Anders Wall Gunnar Antoni Marc Lubberink Neuroradiology Markus Fahlstrom, MR physics Sven Haller, Neuroradiology Elna-Marie Larsson Sports physicians Jakob Johansson Yelverton Tegner Isabella Björkman-Burtscher Oskar Hansson David Cederberg Helené Pessah Rasmussen -- and many more Funded by: Uppsala University Hospital Bissen Brain Walk ERA-NET Neuron,EU Center for Sports Injury Research

Treatments = 0 10/19/2018. Concussion is not a diagnosis!!! Multiple Clinical Trials for Traumatic Brain Injury (TBI) Treatment

Treatments = 0 10/19/2018. Concussion is not a diagnosis!!! Multiple Clinical Trials for Traumatic Brain Injury (TBI) Treatment Penn Center for Brain Injury and Repair Blood Biomarkers for Concussion Promises and Pitfalls Douglas H. Smith Center for Brain Injury and Repair, Dept. of Neurosurgery University of Pennsylvania Multiple