Association between contact sports participation and chronic traumatic encephalopathy: a retrospective cohort study.

Chronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non-athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records-linkage system of care providers in southern Minnesota and western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non-athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P-value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports-related repetitive head trauma.

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains.

TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with "typical" TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-ß). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-ß (n = 110, 46%). Type-α cases were older than type-ß at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-ß cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4-6) while in type-ß cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1-3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-ß cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (- 10.6% [- 17.6%, - 3.5%]; p = 0.003) and hippocampal (- 14.4% [- 21.6%, - 7.3%]; p < 0.001) volumes on MRI at death compared to type-ß cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (- 7.77%, - 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia.

BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.