Table 2.

Key studies of long-term neurodegenerative and other neurological diseases after traumatic brain injury

Study	Study design	Sample	Follow-up*	Outcomes	Covariates	Main findings
Crane et al (2016)16 Adult Changes in Thought study, Religious Orders Study, and Memory and Aging Project, USA	Pooled data from three prospective cohort studies	7,130 participants of whom 865 reported a lifetime history of TBI with loss of consciousness; aged ≥65 years at enrolment.	0 – to ≥ 40 years	Diagnosis of MCI, dementia, AD, and PD; abnormalities on neuropathology.	Age at enrolment, sex, education level, and cohort	No association between TBI and dementia or AD was observed; TBI was associated with PD in the three datasets (HR 3·56 for patients with LOC >1 h in Adult Changes in Thought study; pooled OR 1·65 for patients with LOC >1 h and 2·23 for patients with LOC >1 h in the Religious Orders Study and Memory and Aging Project) after adjustment. TBI was associated with dementia with Lewy bodies (pooled RR 1.59–5.73) and microinfarcts (pooled RR 1.58–2.12).
Nordstrom et al (2014)61 Military conscript study, Sweden	Retrospective population-based cohort, record linkage study	81,1622 men of whom 45,249 had at least one diagnosis of TBI over the follow-up interval; mean age 18 years at enrolment	0 – 43 years	ICD-8, ICD-9, and ICD-10 codes for TBI, AD, dementia, and selected other diagnoses.	Age, place and year of conscription, cognitive function at conscription, alcohol intoxication, weight, height, knee strength, TBI or dementia in parents, income, education level, blood pressure, drug intoxication, depression, and cerebrovascular disease	TBI was not associated with risk of AD, but was associated with risk of other types of dementia (adjusted HR 1.7 for a single mild TBI; 1.7 for at least two occurrences of mild TBI; 2.6 for a single severe TBI).
Gardner et al (2014)62 California state databases, USA	Retrospective population-based case-controlled, record linkage study	51,799 patients admitted to hospital for TBI (all severities); 112,862 patients admitted to hospital for non-TBI trauma (eg fractures); aged ≥ 55 years at injury without baseline dementia	5–7 years	ICD-9 diagnosis of dementia ≥1 year after TBI	Age, sex, race or ethnicity, income, comorbidities, healthcare use, and trauma severity	TBI was associated with a diagnosis of dementia (8.4% of patients with TBI vs 5.9% without TBI adjusted HR 1.26). Moderate or severe TBI was significantly associated with dementia in all age groups (HR 1.72 for 55–64 years; 1.46 for 65–74 years), whereas mild TBI was associated with an elevated risk (1.25) only in those aged ≥65 years.
Gardner et al (2015)63 California state databases, USA	Retrospective population-based case-controlled, record linkage study	52,393 patients admitted to hospital for TBI (all severities); 113 406 patients admitted to hospital for non-TBI trauma (fractures); aged ≥ 55 years at injury without baseline dementia or PD. trauma.	5–7 years	ICD-9 diagnosis of Parkinson’s Disease one year or more after TBI	Age, sex, race or ethnicity, income, comorbidities, healthcare use, and trauma severity	TBI was associated with diagnosis of PD (1·7% of patients with TBI vs 1·1% without TBI; adjusted HR 1.44); There was a dose-response relationship with both severity (HR 1.24 for mild TBI; 1.50 for moderate/severe TBI) and frequency of TBI (1.45 for single TBI; 1.87 for more than one TBI)
Wang et al (2012)64 Longitudinal Health Insurance Database, Taiwan	Retrospective population-based case-controlled, record linkage study	44,925 patients who received outpatient or hospital care for TBI; 224,625 patients who received outpatient or hospital care without TBI, matched for sex, age, and year of index use of health care; mean age 41 years at injury	5 years	ICD-9 diagnosis of dementia	Region and selected comorbidities (stroke, diabetes, hypertension, hyperlipidaemia, and heart disease)	TBI was associated with an increased risk of dementia at 5 years (adjusted HR 1.68).
Chen et al (2011)22 Longitudinal Health Insurance Database, Taiwan	Retrospective population-based case-control, record linkage study	23,199 patients who received outpatient or hospital care for TBI; 69,597 patients who received outpatient or hospital care without TBI, matched for sex, age, and year of index use of health care; mean age 42 years at injury	3 months to 5 years	ICD-9 diagnosis of stroke	Income, region, and selected comorbidities (stroke, diabetes, hypertension, hyperlipidaemia, and heart disease)	TBI was associated with an increased risk of stroke at 5 years (adjusted HR 2.32).
Lehman et al (2012)18 National Football League pension fund database, USA	Retrospective cohort, record linkage study	3,439 retired male American football players; 62% of those alive were aged < 60 years at date last observed	19- to ≥ 48 years	Mortality and neurodegenerative causes of death.	Age, race, and calendar year	Overall mortality in players was lower than that of the general US population (adjusted SMR 0.53); overall neurodegenerative deaths were increased (SMR 2.83–3.26), and were elevated for AD (3.86), and ALS (4.31)
Guskiewizc et al (2005)60 study of National Football League players, USA	Retrospective cohort study	2,552 retired male American football players, of whom 61% reported at least one concussion, and 24% reported three or more concussions; mean age 54 years at follow-up.	Up to ≥ 60 years	Diagnosis of MCI, AD, memory complaints, and health-related quality of life.	Unadjusted comparison between groups	In 758 retired players, aged ≥50 years and who had completed memory questionnaires, recurrent concussion was significantly associated with MCI (p=0.02), self-reported memory impairments (p=0.001), and spouse or relative-reported memory impairments (p=0.04); in participants with three or more concussions there was a five-time increase in MCI diagnosis, and a three-time increase in reported memory problems compared to players who had not been concussed.
Chio et al (2005)65 study of Italian professional soccer players	Retrospective cohort, record linkage study	7,325 professional soccer players; aged 18 – 69 years at last date of follow-up.	0 – 31 years	Diagnosis of ALS	Age and sex	Five cases of ALS were identified, with a mean age of onset of 43.4 years; overall adjusted SMR was 6.5 and there was a dose-response relationship with length of career (adjusted SMR 15.2 for > 5 years = 15.2; 3.5 for ≤5 years).
McMillan et al (2016)66 study of Scottish Rugby Union players, UK	Retrospective case-controlled study	52 retired male international rugby players with a median of 7 concussions; 29 individuals who had not had concussion matched for sex, age, and social deprivation; mean age 54 at follow-up..	1 – 48 years	Cognitive assessment, reported concussion symptoms, emotional adjustment, functional status, health-related quality of life, alcohol use, chronic stress biomarkers.	Unadjusted comparison between groups.	Players had lower scores on tests of verbal learning and fine motor co-ordination than did the control group; persisting symptoms were more common in players with more than nine concussions. No other group differences were significant.

Abbreviations: ACT=Adult Changes in Thought, AD = Alzheimer’s disease, ALS = amyotrophic lateral sclerosis, HR = hazard ratio, MAP= Memory and Aging Project, MCI = mild cognitive impairment, NFL = National Football League, OR = odds ratio, PD = Parkinson’s Disease, ROS = Religious Orders Study, RR= relative risk, SMR = standardized mortality ratio.

^*Interval between exposure to TBI and study observation; in the case of lifetime reported TBI, this follow-up period can comprise long intervals and some studies do not always report the exact range, because of uncertainty around the timing of the TBI.