Does TBI in Later Life Increase the Risk for Parkinson’s Disease?

Patients 55 and older who present to inpatient and emergency department settings with a traumatic brain injury (TBI) have a 44% increased risk of developing Parkinson’s disease over five to seven years, compared with patients in the same age group who present with non-TBI trauma (NTT), according to research published online ahead of print February 27 in Annals of Neurology. In addition, the risk of developing Parkinson’s disease doubles following more severe or more frequent TBI, compared with mild or single TBI. This finding supports a causal association between TBI and Parkinson’s disease.

Raquel C. Gardner, MD, Clinical Instructor and Behavioral Neurology Fellow at the University of California, San Francisco, and colleagues analyzed International Classification of Diseases, Ninth Revision code data collected at California hospitals from 2005 to 2006 to evaluate the risk of developing Parkinson’s disease after TBI in older adulthood. Because of the theoretical possibility that patients with incipient Parkinson’s disease are more likely to fall and sustain a TBI than healthy controls, the researchers examined patients with NTT—defined as fracture, excluding fractures of the head and neck—to reduce possible confounding and reverse causation. To reduce the chance of reverse causation further, researchers excluded cases in which Parkinson’s disease was diagnosed less than a year after the injury.

Researchers identified 52,393 patients with TBI and 113,406 patients with NTT who survived hospitalization and did not have Parkinson’s disease or dementia at baseline. Using Kaplan–Meier estimates and Cox proportional hazards models adjusted for age, sex, race or ethnicity, income, comorbidities, health care use, and trauma severity, they estimated the risk of Parkinson’s disease after TBI during follow-up ending in 2011.

Patients With TBI Were Diagnosed Sooner
Patients with TBI were significantly more likely to be diagnosed with Parkinson’s disease, compared with NTT patients (1.7% of patients vs 1.1% of patients), and patients with TBI were diagnosed with Parkinson’s disease slightly sooner than those with NTT (at 3.1 years, compared with 3.3 years). Researchers found that risk of Parkinson’s disease was similar for TBI sustained via falls and for TBI sustained through other mechanisms.

Researchers also assessed the effect of TBI severity and TBI frequency and found a significant dose response. Patients with mild TBI were 24% more likely to develop Parkinson’s disease, and patients with moderate to severe TBI were 50% more likely to develop Parkinson’s disease, compared with those with NTT. “The evidence for a dose response for increasing TBI severity and TBI frequency, and our persistently significant results despite multiple additional analyses, all enhance causal inference,” the authors said.

A causal association between TBI and Parkinson’s disease may be explained by several possible mechanisms, the researchers said. TBI may reduce motor reserve, thus leading to an earlier diagnosis of Parkinson’s disease in susceptible patients. TBI also may accelerate or augment a pre-existing neurodegenerative cascade or trigger a de novo neurodegenerative cascade. The question of whether typical Parkinson’s disease neuropathologies or unique TBI-specific neuropathology causes post-TBI syndromes deserves further study, they said.

Studies using animal models support a causal mechanism for post-TBI Parkinson’s disease. For example, a progressive loss of dopaminergic neurons and abnormal accumulation of α-synuclein in the substantia nigra have been found in rats after experimentally induced TBI. Other research has begun to replicate these findings in humans.

Information About Patients Was Limited
The study’s limitations include the use of administrative diagnostic codes, which may be poorly sensitive or specific to Parkinson’s disease diagnoses. The researchers lacked information regarding patients’ medical histories and other data about patients’ treatments and outcomes. Also, post-traumatic motor or behavioral abnormalities may complicate the diagnosis of Parkinson’s disease, and diagnoses were not verified by expert review. In addition, the use of a trauma control group essentially controlled for any additional harmful effects of trauma on the nervous system that potentially could increase risk of Parkinson’s disease independently. It is important for large-scale prospective studies, ideally with autopsy confirmation, to confirm these findings, the investigators said.

The results are in line with a 2013 meta-analysis of 22 studies that reported a pooled odds ratio of 1.57 for the association between Parkinson’s disease and head trauma, the authors said. When considered with other studies, including prior research by Dr. Gardner’s team that identified a 26% increased risk of dementia after TBI versus NTT in this population, the results “suggest that TBI is an important independent risk factor for a variety of neurodegenerative syndromes.”

The findings also highlight the importance of preventing falls, which caused approximately 66% of trauma in the TBI and NTT groups. “As the cause of trauma in this study was overwhelmingly due to falls, there is critical importance for fall prevention in middle-aged and older adults, not only as a means to prevent bodily injury, but potentially as a means to prevent neurodegenerative diseases such as dementia and Parkinson’s disease,” the authors concluded.

Patients 55 and older who present to inpatient and emergency department settings with a traumatic brain injury (TBI) have a 44% increased risk of developing Parkinson’s disease over five to seven years, compared with patients in the same age group who present with non-TBI trauma (NTT), according to research published online ahead of print February 27 in Annals of Neurology. In addition, the risk of developing Parkinson’s disease doubles following more severe or more frequent TBI, compared with mild or single TBI. This finding supports a causal association between TBI and Parkinson’s disease.

Raquel C. Gardner, MD, Clinical Instructor and Behavioral Neurology Fellow at the University of California, San Francisco, and colleagues analyzed International Classification of Diseases, Ninth Revision code data collected at California hospitals from 2005 to 2006 to evaluate the risk of developing Parkinson’s disease after TBI in older adulthood. Because of the theoretical possibility that patients with incipient Parkinson’s disease are more likely to fall and sustain a TBI than healthy controls, the researchers examined patients with NTT—defined as fracture, excluding fractures of the head and neck—to reduce possible confounding and reverse causation. To reduce the chance of reverse causation further, researchers excluded cases in which Parkinson’s disease was diagnosed less than a year after the injury.

Researchers identified 52,393 patients with TBI and 113,406 patients with NTT who survived hospitalization and did not have Parkinson’s disease or dementia at baseline. Using Kaplan–Meier estimates and Cox proportional hazards models adjusted for age, sex, race or ethnicity, income, comorbidities, health care use, and trauma severity, they estimated the risk of Parkinson’s disease after TBI during follow-up ending in 2011.

Patients With TBI Were Diagnosed Sooner
Patients with TBI were significantly more likely to be diagnosed with Parkinson’s disease, compared with NTT patients (1.7% of patients vs 1.1% of patients), and patients with TBI were diagnosed with Parkinson’s disease slightly sooner than those with NTT (at 3.1 years, compared with 3.3 years). Researchers found that risk of Parkinson’s disease was similar for TBI sustained via falls and for TBI sustained through other mechanisms.

Researchers also assessed the effect of TBI severity and TBI frequency and found a significant dose response. Patients with mild TBI were 24% more likely to develop Parkinson’s disease, and patients with moderate to severe TBI were 50% more likely to develop Parkinson’s disease, compared with those with NTT. “The evidence for a dose response for increasing TBI severity and TBI frequency, and our persistently significant results despite multiple additional analyses, all enhance causal inference,” the authors said.

A causal association between TBI and Parkinson’s disease may be explained by several possible mechanisms, the researchers said. TBI may reduce motor reserve, thus leading to an earlier diagnosis of Parkinson’s disease in susceptible patients. TBI also may accelerate or augment a pre-existing neurodegenerative cascade or trigger a de novo neurodegenerative cascade. The question of whether typical Parkinson’s disease neuropathologies or unique TBI-specific neuropathology causes post-TBI syndromes deserves further study, they said.

Studies using animal models support a causal mechanism for post-TBI Parkinson’s disease. For example, a progressive loss of dopaminergic neurons and abnormal accumulation of α-synuclein in the substantia nigra have been found in rats after experimentally induced TBI. Other research has begun to replicate these findings in humans.

Information About Patients Was Limited
The study’s limitations include the use of administrative diagnostic codes, which may be poorly sensitive or specific to Parkinson’s disease diagnoses. The researchers lacked information regarding patients’ medical histories and other data about patients’ treatments and outcomes. Also, post-traumatic motor or behavioral abnormalities may complicate the diagnosis of Parkinson’s disease, and diagnoses were not verified by expert review. In addition, the use of a trauma control group essentially controlled for any additional harmful effects of trauma on the nervous system that potentially could increase risk of Parkinson’s disease independently. It is important for large-scale prospective studies, ideally with autopsy confirmation, to confirm these findings, the investigators said.

The results are in line with a 2013 meta-analysis of 22 studies that reported a pooled odds ratio of 1.57 for the association between Parkinson’s disease and head trauma, the authors said. When considered with other studies, including prior research by Dr. Gardner’s team that identified a 26% increased risk of dementia after TBI versus NTT in this population, the results “suggest that TBI is an important independent risk factor for a variety of neurodegenerative syndromes.”

The findings also highlight the importance of preventing falls, which caused approximately 66% of trauma in the TBI and NTT groups. “As the cause of trauma in this study was overwhelmingly due to falls, there is critical importance for fall prevention in middle-aged and older adults, not only as a means to prevent bodily injury, but potentially as a means to prevent neurodegenerative diseases such as dementia and Parkinson’s disease,” the authors concluded.

Patients 55 and older who present to inpatient and emergency department settings with a traumatic brain injury (TBI) have a 44% increased risk of developing Parkinson’s disease over five to seven years, compared with patients in the same age group who present with non-TBI trauma (NTT), according to research published online ahead of print February 27 in Annals of Neurology. In addition, the risk of developing Parkinson’s disease doubles following more severe or more frequent TBI, compared with mild or single TBI. This finding supports a causal association between TBI and Parkinson’s disease.

Raquel C. Gardner, MD, Clinical Instructor and Behavioral Neurology Fellow at the University of California, San Francisco, and colleagues analyzed International Classification of Diseases, Ninth Revision code data collected at California hospitals from 2005 to 2006 to evaluate the risk of developing Parkinson’s disease after TBI in older adulthood. Because of the theoretical possibility that patients with incipient Parkinson’s disease are more likely to fall and sustain a TBI than healthy controls, the researchers examined patients with NTT—defined as fracture, excluding fractures of the head and neck—to reduce possible confounding and reverse causation. To reduce the chance of reverse causation further, researchers excluded cases in which Parkinson’s disease was diagnosed less than a year after the injury.

Researchers identified 52,393 patients with TBI and 113,406 patients with NTT who survived hospitalization and did not have Parkinson’s disease or dementia at baseline. Using Kaplan–Meier estimates and Cox proportional hazards models adjusted for age, sex, race or ethnicity, income, comorbidities, health care use, and trauma severity, they estimated the risk of Parkinson’s disease after TBI during follow-up ending in 2011.

Patients With TBI Were Diagnosed Sooner
Patients with TBI were significantly more likely to be diagnosed with Parkinson’s disease, compared with NTT patients (1.7% of patients vs 1.1% of patients), and patients with TBI were diagnosed with Parkinson’s disease slightly sooner than those with NTT (at 3.1 years, compared with 3.3 years). Researchers found that risk of Parkinson’s disease was similar for TBI sustained via falls and for TBI sustained through other mechanisms.

Researchers also assessed the effect of TBI severity and TBI frequency and found a significant dose response. Patients with mild TBI were 24% more likely to develop Parkinson’s disease, and patients with moderate to severe TBI were 50% more likely to develop Parkinson’s disease, compared with those with NTT. “The evidence for a dose response for increasing TBI severity and TBI frequency, and our persistently significant results despite multiple additional analyses, all enhance causal inference,” the authors said.

A causal association between TBI and Parkinson’s disease may be explained by several possible mechanisms, the researchers said. TBI may reduce motor reserve, thus leading to an earlier diagnosis of Parkinson’s disease in susceptible patients. TBI also may accelerate or augment a pre-existing neurodegenerative cascade or trigger a de novo neurodegenerative cascade. The question of whether typical Parkinson’s disease neuropathologies or unique TBI-specific neuropathology causes post-TBI syndromes deserves further study, they said.

Studies using animal models support a causal mechanism for post-TBI Parkinson’s disease. For example, a progressive loss of dopaminergic neurons and abnormal accumulation of α-synuclein in the substantia nigra have been found in rats after experimentally induced TBI. Other research has begun to replicate these findings in humans.

Information About Patients Was Limited
The study’s limitations include the use of administrative diagnostic codes, which may be poorly sensitive or specific to Parkinson’s disease diagnoses. The researchers lacked information regarding patients’ medical histories and other data about patients’ treatments and outcomes. Also, post-traumatic motor or behavioral abnormalities may complicate the diagnosis of Parkinson’s disease, and diagnoses were not verified by expert review. In addition, the use of a trauma control group essentially controlled for any additional harmful effects of trauma on the nervous system that potentially could increase risk of Parkinson’s disease independently. It is important for large-scale prospective studies, ideally with autopsy confirmation, to confirm these findings, the investigators said.

The results are in line with a 2013 meta-analysis of 22 studies that reported a pooled odds ratio of 1.57 for the association between Parkinson’s disease and head trauma, the authors said. When considered with other studies, including prior research by Dr. Gardner’s team that identified a 26% increased risk of dementia after TBI versus NTT in this population, the results “suggest that TBI is an important independent risk factor for a variety of neurodegenerative syndromes.”

The findings also highlight the importance of preventing falls, which caused approximately 66% of trauma in the TBI and NTT groups. “As the cause of trauma in this study was overwhelmingly due to falls, there is critical importance for fall prevention in middle-aged and older adults, not only as a means to prevent bodily injury, but potentially as a means to prevent neurodegenerative diseases such as dementia and Parkinson’s disease,” the authors concluded.