Traumatic brain injury has been an important focus at the American Academy of Neurology annual meeting, and new data are expected at AAN 2016 later this month in Vancouver.

There has been conflicting evidence over the years about the significance of traumatic brain injury (TBI) in the etiology of neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease. A Swedish analysis of data from the National Patient Registry reported that PD patients were more likely to be hospitalized for head injury, but hospitalizations typically occurred about one year before a PD diagnosis and did not indicate a causal relationship between TBI and PD (Fang et al. Mov Disord 2012;27:1632-1635). A limitation of using hospital records, however, is that hospitalization for head trauma may be a consequence of an evolving motor disorder rather than a causative factor of PD (Rugbjerg et al. Br Med J 2008;337:a2494). More recently, a Danish case-control study found no association between a history of head injury and development of PD, nor was there an association between loss of consciousness and PD (Kenborg et al. Neurology 2015;84:1098-1103).

However, two meta-analyses have concluded just the opposite. A review of 22 studies did find an association between head trauma and the development of PD (odds ratio 1.57) (Jafari et al. Mov Disord 2013;28:1222-1229). In addition, a recently-published review of 57 studies found significant associations between TBI and the subsequent development of neurological (OR 1.55) and psychiatric (OR 2.0) outcomes (Perry et al. J Neurosurg 2015; epublished August 28, 2015). Neurological outcomes included PD, Alzheimer’s disease, and mild cognitive impairment. Psychiatric outcomes included depression, mixed affective disorders, and bipolar disorder.

A subsequent study examined outcomes of patients aged >55 years hospitalized in California for TBI in the period 2005-2006, and followed-up to 2011 (Gardner et al. Ann Neurol 2015;77:987-995). Outcomes were compared to patients with non-TBI trauma, such as fractures. Overall, older TBI patients were more likely to be diagnosed with PD over the next 5-7 years compared to non-TBI trauma patients (1.7% vs. 1.1%; adjusted HR 1.44). PD risk was similar in patients with TBI due to a fall compared to other TBI causes. PD risk was higher following moderate/severe TBI compared to mild TBI (HR 1.50 vs. 1.24), and was increased with more frequent TBIs (HR 1.87 for >1 TBI vs. 1.45 for 1 TBI).

Also noteworthy is a recent case-control study that reported that early head trauma was associated with PD risk (Gao et al. Parkinsonism Relat Disord 2015;21:292-296). Head trauma was identified by patient self-report. Overall, there was a positive association between head trauma and PD risk (OR 1.39 for one TBI, 2.33 for >2 TBIs). Much of this risk was due to head injuries sustained before age 30 years. PD risk was highest for TBI before age 18 (OR 2.04) and between 18-30 years (OR1.39), in contrast to TBI after age 30 (OR 1.04).

Determining the level of risk faces a number of difficulties, such is the accuracy of patients’ recall of TBI events, and the challenge of diagnosing TBI in practice (Sundman et al. J Alzheimers Dis Parkinsonism 2014;4. pii: 137; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4196712/pdf/nihms590848.pdf). To assist in TBI recognition, a new tool, the  Retrospective Screening of Traumatic Brain Injury Questionnaire (RESTBI), has been developed and is free to clinicians (accessed at http://sites.duke.edu/restbi/access/).

For more on the neurological consequences of TBI, see the May 2015 supplement of Molecular and Cellular Neuroscience (www.sciencedirect.com/science/journal/10447431/66/supp/PB).

Comment
Dr. Susan Fox:  The issue of prior head injury and increased risk of developing PD continues to be debated and remains somewhat controversial. All studies tend to have some element of recall bias, or lack of confirmatory diagnosis. These recent studies lean toward a positive association, but again the real risk remains unclear. Thus, not all people who have head injuries develop PD or other neurodegenerative disease; and there does not seem to be an association with severity of head injury and earlier onset or severity of PD, thus reducing possible biological plausibility. It is likely that head trauma is an additional risk on top of other, as yet, unknown risks. Further prospective studies with new imaging ligands and ultimate post-mortem with good clinicopathological correlations are needed.