We found that the effect of head injury was highly dependent on SNCA Rep1 genotype, with ORs ranging from 2.3 to 8.4 in those carrying a long Rep1 variant, depending on the model and study population. In addition, PD diagnosis age averaged four to five years younger in those with both head injury and expanded Rep1 genotype. Finding similar relationships in two unrelated study populations supports our hypothesis of biological interaction between head injury and α-synuclein. In contrast, the modest, non-significant association between head injury and PD overall suggests heterogeneity at the SNCA Rep1 locus may be one factor underlying the inconsistency of prior epidemiologic studies.
Animal models of head injury recapitulate many fundamental pathophysiological processes relevant to PD etiology, including protein accumulation and aggregation,37-39
increased striatal levels of nitrated α-synuclein,25
and altered proteosomal function.40
In human post-mortem studies, α-synuclein accumulation was observed after severe head injury,30, 31
possibly due to impaired axonal transport or as a direct response to axonal sheer stress.25, 27, 41, 42
Because aggregated extracellular α-synuclein activates microglia,43
and activated microglia enhance α-synuclein aggregation,44
one could envision a self-perpetuating “feed-forward” cycle of synuclein upregulation, aggregation and microglial activation resulting from head injury. Enhanced production and accumulation of α-synuclein, the major component of Lewy bodies and Lewy neurites, is a risk factor for PD.19, 45-48
Expansion of SNCA
Rep1 increases striatal α-synuclein expression in transgenic mice,20
is associated with increased blood and brain levels in human post-mortem studies,21, 22
and increases PD risk.23, 24
Thus, our results are consistent with the hypothesis that a self-perpetuating neurodegenerative cycle initiated by head injury is more likely to occur and/or persist when levels of synuclein are high, and that head injury may aggravate degenerative processes in an environment already stressed by synuclein overexpression.
In addition to direct effects on synuclein, head injury could lead to a neurodegenerative process such as PD through a number of other biologically plausible mechanisms. Mild-to-moderate closed-head injury induces an inflammatory cascade that begins within minutes and may persist for months.49, 50
Blood-brain barrier breakdown is an early response, followed rapidly by altered blood flow, edema and leukocyte infiltration.51-53
Interleukin-1, interleukin-6, tumor necrosis factor-α, cyclooxygenase-2, and other inflammatory cytokines are upregulated,54
and microglia activated.55
Head injury also disrupts mitochondrial function, increasing free radical production and lipid peroxidation,56, 57
elevating cytosolic calcium and activating calpain,58
which may enhance accumulation of cytotoxic synuclein species.59, 60
Glutamate excitotoxicity and nitric oxide synthase (iNOS) induction simultaneously increase metabolic demands, further taxing already stressed neurons and glia.28, 61
Each of these mechanisms is thought to be important in PD pathogenesis.62-64
Consistent with the systemic pathology of PD, moderate to severe head injury can increase systemic inflammation and impact numerous organ systems outside of the central nervous system,65-67
although systemic effects of mild head injury are not well studied.
PD risk has been inconsistently associated with head injury in epidemiologic studies.2-17
In addition to genetic heterogeneity, possible explanations include different diagnostic methods, varying definitions of head injury, recall bias, confounding by other factors such as smoking, or other environmental exposures. Our reliance on retrospective data could have resulted in exposure misclassification. In particular, recall bias—the predilection of case subjects to report exposures due to heightened awareness or concern—has been suggested as an explanation for associations with head injury.16, 17
Bias could also result from differential access to medical care due to socioeconomic status or geographic location. However, because neither recall nor access to medical care would be expected to vary by Rep1 genotype, these potential biases are not likely to explain our findings.
Use of proxy respondents in FAME could also have introduced reporting bias, but results were not altered when these subjects were excluded from analyses. Furthermore, proxy respondents were less likely to report a head injury and, because proxy respondents were over-represented among cases, this would attenuate rather than inflate associations. Head injury was more frequently reported in SEARCH, especially among women, suggesting a systematic difference in head injury reporting between the studies. However, results were similar in both populations, and inclusion of a head injury × study interaction term in pooled models or restriction to men did not alter results. Another inherent limitation of this work is reliance on prevalent cases, potentially resulting in survival bias. Although this possibility cannot be fully excluded in FAME, survival bias is unlikely in SEARCH, in which disease duration averaged three years. Reverse causation (i.e., head injuries resulting from functional deficits in early pre-diagnosed PD) is another concern, but findings were unaltered in analyses that excluded injuries within five or 10 years of diagnosis. It is conceivable that expanded Rep1 could cause lifelong alterations in motor function predisposing to head injury, but we are not aware of animal or human data to support this. Finally, and most importantly, although the interaction was not statistically significant in SEARCH, the relationship between head injury, Rep1 and PD was similar in two unrelated study populations, arguing against a chance association.
We observed an average latency of 30 years between head injury and PD diagnosis, similar to prior studies. This lag suggests the passage of time may be required for the neurodegenerative cascade to unfold fully in susceptible individuals. At least 2.5 million head injuries occur annually in the U.S., resulting in 1.7 million healthcare visits.18
Because population variability in SNCA
Rep1 is also common—10% of controls carried the long Rep1 genotype in the present studies—if our results are confirmed, the proportion of PD risk attributable to the combination of head injury and Rep1 allele expansion in the general population could be substantial. For example, based on an observed frequency of head injury and L* genotype co-occuring in 1.2% of controls, and an OR of 6.8 in subjects with both risk factors relative to the remainder of the population, 7% of PD in the general population could potentially be attributable to co-occurrence of head injury and L* genotype.68
Although these observations require replication, this large “at-risk” population could be targeted for prospective study and potential therapeutic intervention.