TABLE 3.
TES‐CTE diagnoses by CTE pathology status: frequencies, diagnostic validity, inter‐rater reliability, and characteristics of donors inaccurately diagnosed
| A. TES‐CTE consensus diagnosis by CTE pathology frequencies | ||||
|---|---|---|---|---|
| CTE pathological diagnosis | ||||
| TES‐CTE clinical consensus diagnosis | Yes | No | Total | |
| Yes | 236 (70.2%) | 73 (21.7%) | 309 (92.0%) | |
| No | 8 (2.4%) | 19 (5.7%) | 27 (8.0%) | |
| Total | 244 (72.6%) | 92 (27.4%) | 336 | |
| B. Diagnostic validity and inter‐rater reliability (95% CI) of TES‐CTE diagnosis | ||
|---|---|---|
| Pre‐consensus | Consensus | |
| Sensitivity | 0.94 (0.91, 0.97) | 0.97 (0.94, 0.99) |
| Specificity | 0.21 (0.12, 0.29) | 0.21 (0.12, 0.29) |
| Positive likelihood ratio | 1.18 (0.77, 1.82) | 1.22 (0.82, 1.82) |
| Negative likelihood ratio | 0.30 (0.18, 0.50) | 0.16 (0.08, 0.32) |
| Inter‐rater reliability | 0.75 (0.66‐0.84) | 0.98 (0.96‐0.99) |
| C. Neuropathological characteristics of donors without CTE neuropathology, who were diagnosed with TES‐CTE (i.e., false positives) | |
|---|---|
| Neuropathological characteristics | Frequency (N = 73) |
| Neurodegenerative pathology without cerebrovascular pathology | 20 (27.4%) |
| Cerebrovascular pathology without neurodegenerative pathology | 9 (12.3%) |
| Both neurodegenerative and cerebrovascular pathology | 36 (49.3%) |
| No neurodegenerative or cerebrovascular pathology | 8 (11.0%) |
| D. Characteristics of donors who were diagnosed with TES‐CTE, but did not have CTE, other neurodegenerative, or cerebrovascular pathology | ||||
|---|---|---|---|---|
| Age | Repetitive head impact (RHI) exposure | Other consensus diagnoses | Other observed pathology | Why TES‐CTE criteria were met |
| 14 | Youth football, youth wrestling, and youth lacrosse | Depression, anxiety, OCD, ASD, medication‐induced impairment | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Apathy, depression, irritability, explosivity, anxiety, impulsivity, hallucinations, hopelessness, suicidality |
| 22 | High school football and lacrosse | Depression, PTSD, PPCS, substance use disorder | Global segmental loss of Purkinje cells throughout the cerebellum; hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, irritability, explosivity, impulsivity, anxiety, physical and verbal violence |
| 33 | Youth football, military combat, concussions from a fall and a blast injury | PTSD, depression, substance use disorder, impairment due to hepatic encephalopathy | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, anxiety, irritability, explosivity impulsivity, hallucinations, headaches, motor impairment |
| 35 | High school football, concussions from MVA, work‐related blast injury, and physical fights | Depression, social anxiety disorder, PPCS, IED, ADHD, substance use disorder | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, anxiety, headaches, cognitive impairment (judgment, attention), impulsivity, apathy, irritability, explosivity, paranoia, hopelessness, suicidality, physical and verbal violence |
| 42 | High school football | Bipolar disorder, PTSD, substance use disorder | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, anxiety, mania, psychosis, motor impairment, impulsivity, suicidality, physical and verbal violence |
| 53 | College football, high school wrestling, concussion from MVA | Substance use disorder | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, irritability, explosivity, anxiety, impulsivity, hopelessness |
| 53 | Professional football | Bipolar disorder, generalized anxiety disorder | Hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Depression, anxiety, irritability, apathy, mania, paranoia, suicidality, headaches, physical and verbal violence |
| 57 | Professional football | Substance use disorder, chronic pain syndrome | Features suggestive of CTE without pathognomonic lesion; PART, ARTAG, white matter degeneration; global segmental loss of Purkinje cells throughout the cerebellum; hemosiderin‐laden macrophages around white matter vessels in the frontal cortex | Cognitive impairment (memory, judgment, attention, visuospatial), apathy, depression, irritability, explosivity, physical and verbal violence |
| E. Characteristics of donors with CTE neuropathology, but not diagnosed with TES‐CTE (i.e., false negatives) | ||||
|---|---|---|---|---|
| Age | Repetitive head impact (RHI) exposure | Clinical characteristics | CTE stage (I‐IV) | Why TES‐CTE criteria were not met |
| 22 | College football, amateur boxing, amateur wrestling | PPCS, symptoms of depression, anxiety, irritability, explosivity, physical/verbal abusiveness | I | PPCS were thought to account for entire syndrome |
| 24 | High school football, amateur wrestling | Symptoms of anxiety, depression, irritability, alcohol/substance use disorder, gait abnormality | I | Lack of a progressive course |
| 26 | High school football, high school basketball | Symptoms of depression, PPCS, apathy | I | Symptoms present < 1 year |
| 26 | Professional football, amateur wrestling | Asymptomatic | II | No core clinical feature |
| 48 | Professional football | Asymptomatic | I | No core clinical feature |
| 49 | High school football, amateur boxing, amateur mixed martial arts | PPCS, headaches, symptoms of anxiety, depression, irritability, explosivity, apathy, verbal abusiveness | II | Lack of a progressive course |
| 52 | College football | ALS, subtle symptoms of depression and anxiety | II | Lack of progressive course for mood/behavior symptoms |
| 88 | College and semi‐professional soccer, high school ice hockey | Life‐long, stable explosivity, physical/verbal abusiveness, mild symptoms of depression | I | Lack of a progressive course |
Notes: Pre‐consensus refers to individual diagnoses made by consensus panel members prior to discussion. Consensus refers to the group consensus diagnoses after discussion, except for inter‐rater reliability for which consensus refers to individual diagnoses made after discussion. Sensitivity: Among donors with a CTE neuropathological diagnosis, the frequency with which a TES‐CTE clinical diagnosis was made. Specificity: Among donors without a CTE neuropathological diagnosis, the frequency with which a TES‐CTE clinical diagnosis was not made. Positive likelihood ratio: Ratio of the frequency with which a TES‐CTE clinical diagnosis was made among donors with a CTE neuropathological diagnosis to the frequency with which a TES‐CTE clinical diagnosis was made among donors without a CTE neuropathological diagnosis. Negative likelihood ratio: Ratio of the frequency with which a TES‐CTE clinical diagnosis was not made among donors with a CTE neuropathological diagnosis to the frequency with which a TES‐CTE clinical diagnosis was not made among donors without a CTE neuropathological diagnosis. Inter‐rater reliability: A measure of agreement (range: 0 to 1) among consensus panel members that accounts for varying identity and number of raters.
Abbreviations: ALS, amyotrophic lateral sclerosis; ARTAG, age‐related tau astrogliopathy; ASD, autism spectrum disorder; CI, confidence interval; CTE, chronic traumatic encephalopathy; IED, intermittent explosive disorder; MVA, motor vehicle accident; OCD, obsessive compulsive disorder; PART, primary age‐related tauopathy; PPCS, persistent post‐concussion symptoms; PTSD, post‐traumatic stress disorder; TES, traumatic encephalopathy syndrome.