Traumatic Brain Injury-Induced 
Parkinson's Disease:
An Analysis of the Potential Correlation
�Ρॸ��ǦƺΚƺǿƺ�^ȖǓǓȒƺǏॹ�EƺǹǩǦƺ�?Ǧƺǿॹ�[ȅljǦǓǹǹǓ�^ǦȠȣȠǩǿॹ�^ȅЙƺ�XǩǓǏȖƺЙȠƺেKȖȠǩΦॹ� 
Tejaswini Govindaraman, Neha Ramachandran, Danielle McMillion, 
Ariana Samimi and Diego Sandoval

Abstract
Research findings on the correlation between Traumatic Brain Injury (TBI) 
and the onset of Parkinson’s Disease (PD) are inconclusive. With PD affecting 
thousands of individuals, it is imperative to determine a potential causal link. 
The purpose of this literature review is to under-stand the validity and extent of 
the relationship between TBI and PD by examining population demographics, 
biological, sociological, and cognitive factors, as well as therapeutic treatments. 
Previous research has found that the incidence of TBI can occur during the 
prodromal period of PD, which is the period when symptoms of the disease begin to 
show, though the directionality of the correlation between TBI and the onset of 
PD requires a more in-depth investigation. Other findings include the over-
accumulation of alpha-synuclein in the substantia nigra—a protein that 
regulates vesicle trafficking—which is prominent in both patients with TBI and 
those with PD. The presence of Tyrosine Hydroxylase from TBI has also been 
proven to contribute to the decrease in dopamine seen in PD. Hippocampal 
damage is present in patients who experience either PD or TBI, which leads to 
cognitive decline. These findings indicate a positive correlation between TBI and 
the subsequent onset of PD, and confirm the need for additional research to 
develop new therapies for PD.

Berkeley 
Pharma Tech
Journal of Medicine

Correspondence: 
bhavana.sreepad@gmail.com

Keywords:
Parkinson’s Disease 
Traumatic Brain Injury   
Alpha-synuclein 
Tyrosine hydroxylase 
Dopamine

Submitted July 7, 2021 
Accepted August 28, 2021 
Published December 17, 2021

Full Open Access

Creative Commons 
Attribution License 4.0

Image Credits: N/C



Introduction
Parkinson’s disease (PD) a ects movement and is the second most common 
progressive neurodegenerative disorder after Alzheimer’s disease. Symptoms 
include slow movement, rigidity, shu ing gait, postural instability, and 
imbalance [1]. This neuronal imbalance is followed by the degeneration of 
dopamine neurons in the substantia nigra of the basal ganglia tissue in the 
brain, and the development of Lewy bodies, which interfere with brain 
activity [2]. PD was rst described by James Parkinson in 1817 [3]. The 
cause of neurodegeneration associated with PD has not been scienti cally 
proven and, only a small percentage of PD diagnoses are attributed to 
genetic factors. However, PD has been explored in association with 
non-genetic risk factors such as traumatic brain injury. Traumatic brain 
injury (TBI) typically results from blunt external force to the skull, which 
may result in cognitive and behavioral disruptions that could lead to brain 
pathologies [4]. Current research remains divided regarding the strength of 
the correlation between TBI and the onset of PD. As such, this review 
analyzes population demographics, biological and cognitive factors to 
elucidate the nature of this correlation.

Studies on the Risk Factors for TBI and Parkinson’s
Disease
TBI is traditionally organized into clinical categories that distinguish the 
levels of severity and each category’s potential to lead to neurodegeneration. 
Yet, most research serves to analyze the impact on only severe TBI. 
Insu cient research has been conducted on patients with moderate TBI, 
proving to be a challenge for researchers [6]. However, through research of 
mild and severe TBI, it has been determined that the majority of TBI cases 
in the United States result from falls and motor vehicle accidents.

Researchers analyzed demographics and the causes of injury using registry 
data from the National Trauma Data Bank (NTDB) between 2007 to 
2014 for patients over the age of 18 with mild TBI. It was determined that 
falls and motor vehicle-related injuries accounted for 43% and 34% of TBI 
cases, respectively. Furthermore, assessing TBI outcome severities 
demonstrated that adults in the 45-to-64-year age range had about a 
two-fold increased risk, while those over 80 years old had nearly a ve-fold 
increased risk of experiencing poor outcomes. Researchers de ned poor 
outcomes as in-hospital mortality, hospice, and long-term care. Similarly, a 
cross-sectional analysis conducted by Majdan et al. identi ed 1,375,974

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TBI-related hospital discharges and found the most prevalent causes of 
TBI to be falls and tra c incidents [5]. In recent years, however, there has 
been a shift from tra c accidents to falls as the most frequent cause of TBI 
[8].

On the other hand, there are many risk factors associated with the 
development of PD — one of which is genetic risk. A genome-wide linkage 
and sequencing study conducted from 2008 to 2017 aimed to identify 
genes involved in the onset of PD. The researchers rst conducted a 
genome-wide analysis on an Italian family whose members had PD through 
dominant inheritance. The identi ed gene was then analyzed and compared 
in a representative sample of international patients diagnosed with PD. 
Quadri et al. identi ed a mutation on LRP10 on chromosome 14 to be 
involved in the onset of PD. Out of the 11 patients identi ed with this 
mutation in the international cohort, 10 had a family history of PD. The 
LRP10 mutation was also found in the DNA of nine out of 10 relatives of 
the international cohort. These results suggest that there is a hereditary 
aspect of the increased risk of developing PD [9].

Other risk factors of PD include the consumption of dairy products, 
cancer, and exposure to pesticides [7]. Researchers conducting an 
observational study on nutritional factors and PD found that the higher 
intake of dairy was associated with an increased risk of PD development, 
with a larger risk in men compared to women [10]. An increased 
prevalence of malignant melanoma and skin carcinoma is also associated 
with a higher risk of PD. An epidemiological study in Denmark found the 
prevalence of malignant melanoma was 0.57% in PD patients compared to 
0.4% in control patients, while skin carcinoma prevalence was 4.24% in PD 
patients compared to 3.4% in controls [11]. Researchers have found similar 
patterns of increased relative risk when investigating the e ect of pesticides 
on patients who su ered from PD and/or TBI [12]. A controlled study 
researched the e ects of both TBI and paraquat exposure, which causes 
damage to the digestive system organs, in patients with PD. Researchers 
estimated a two-fold increase in the risk of developing PD in patients who 
experienced TBI, further supporting the correlation between the two 
diseases. In contrast, when examining the combined e ects of both 
paraquat exposure and TBI, researchers noticed a three-fold risk increase 
[13]. A study in rats further substantiated these ndings by demonstrating 
that TBI and paraquat exposure led to a loss in dopaminergic neurons and

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AppleofmyEye
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concurrently increased alpha-synuclein accumulation and in ammation in 
the brain, which are common characteristics of PD [14].

Demographics
Age and gender have proven to be signi cant factors in the incidence of TBI 
and in the development of PD [16, 17]. When researching the demographic 
data relating to these diseases, studies have been geared towards researching 
the demographics of TBI and PD individually rather than on their 
relationship to each other. A study analyzing the characteristics of patients 
with PD found that the age-adjusted incidence rate of PD was higher in 
men than in women, at 19.0 per 100,000 persons and 9.9 per 100,000 
persons, respectively. Incidence rates and the male to female ratio increased 
rapidly after 60 years of age. The mean age of diagnosis was 70.5 years for 
both men and women, yet women were diagnosed over a larger age range 
(31 to 93 years) than men (38 to 91 years). Further analysis found incidence 
rates of 0.50 per 100,000 persons in the 30-to-39-year group and 119.01 per 
100,000 persons in those over 89, suggesting that the risk of being 
diagnosed with PD increases dramatically with age. Researchers also sought 
to distinguish the prevalence of idiopathic PD among di erent racial 
groups. Non-Hispanic Whites were found to be diagnosed with PD at an 
older age than Hispanics and Asians/Paci c Islanders, and a slightly older 
age than African Americans. When adjusting for age and gender, incidence 
rates of PD were highest among Hispanics, followed by non-Hispanic 
Whites, Asians/Paci c Islanders, and African Americans. Pairwise 
comparisons among di erent groups found this data to be somewhat 
statistically signi cant. Prevalence of PD in the non-Hispanic White cohort 
compared to the Asian/Paci c Islander cohort was 13.6 and 11.3 per 
100,000 persons (p = 0.07) respectively, while the non-Hispanic White 
cohort compared to the African American cohort exhibited incidence rates 
of 13.6 and 10.2 per 100,000 persons (p = 0.11). Researchers also noted 
that in every group besides the Asian/Paci c Islander cohort, the incidence 
of PD was higher in men than in women by two-fold [18].

Researchers have found increasing evidence pointing to gender as an 
important factor in the development and expression of PD [19]. A case 
study conducted by Haaxma et al. found women to be 2.1 years older than 
men at their age of symptom onset, the mean ages being 53.4 and 51.3, 
respectively [20]. At symptom onset, women presented tremors, a symptom 
of PD, more frequently than men (67% and 48%), regardless of their age of

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onset. However, men presenting tremors at the age of onset were, on 
average, 3.6 years older than women. From this research, it was concluded 
that gender-based di erences in PD patients were signi cant. Women 
tended to be older at symptom onset, presented higher striatal dopamine 
a nity and tremor dominant symptoms, and experienced slower disease 
progression compared to men. Other studies have shown that women 
diagnosed with PD tend to present more benign phenotypic symptoms, 
but later tend to have an increased risk of treatment complications 
compared to men, further pointing to the biological and phenotypic 
di erences between male and female patients with PD [21]. Reviewing 
demographic factors relating to TBI reveals similar trends regarding data on 
the age and gender of patients.

A cross-sectional study analyzed data from the National Hospital 
Ambulatory Medical Case Survey (NHAMCS) and collected information 
on demographic characteristics of older patients who sustained mild TBI in 
the United States. The average age of patients diagnosed with mild TBI was 
79.1 years of age, 87.8% of whom were White, and 64.3% of whom were 
female.

Emergency department (ED) visits were also observed to increase with age. 
In patients aged between 65 to 74 years old, the rate was 386 per 100,000 
persons, while patients 85 years or older had an incidence rate of 1,205 per 
100,000 persons. Since the rates for those 85 and older triple the rates for 
those between 65 to 75 years of age, TBI has been found to be more 
prominent in older age groups. Researchers found that women visited the 
ED for TBI at a rate of 706 per 100,000 persons, while men visited at a rate 
of 516 per 100,000 persons. Another characteristic that researchers 
investigated was geographic region, nding that visits related to diagnosed 
TBI were more common than visits related to possible mild TBI in the 
northeastern and western regions of the United States. The diagnosis of 
TBI was more prevalent on the west coast and less prevalent in the south 
and Midwest, compared to the northeast regions of the United States. This 
data, however, should be interpreted with caution, as some have suggested 
that the CDC codes for detecting mild TBI have poor sensitivity and mild 
TBI can be underdiagnosed [22]. A retrospective cohort study analyzed 
data on older adults from the Ontario Association of Community Care 
Access Centers (OACCAC) home care database. In this experiment, 
incidence of TBI among patients of varying education levels, marital status, 
sex, race, and age groups were observed over a ten-year period from 2003 to

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2013. Investigators found that those who had sustained a TBI had an equal 
sex distribution. Overall, positive associations were found between 
sustaining TBI and several groups, including males, patients of aboriginal 
origin, increasing age, education level, being widowed, and having PD [23]. 
In another study on the medical data of Californian patients 55 years or 
older who were diagnosed with TBI but not PD, patients with TBI were 
slightly older, more likely to be male, have higher income, and higher 
severity scores when compared to patients with non-TBI trauma (NTT)
[24].

Moreover, patients with TBI were more likely to be diagnosed sooner with 
PD than patients with NTT. The average time until PD diagnosis was 3.1 
years for TBI patients versus 3.3 years for NTT patients, and 66% of the 
trauma for both the TBI and NTT group was caused by falls. Patients with 
PD had an average age of 76 years old, with 59% being female and 68%
being white. Data showed that incidence rates of TBI among racial groups 
was highest among Whites, followed by Hispanics, Asians, and African 
Americans. Cases of TBI were found to increase with wealth; there were 
10,276 incidents of TBI in the lowest quartile, while there were 14,132 
cases of TBI in the highest, wealthiest quartile. Researchers also noted that 
TBI was associated with a 44% increased risk of PD diagnosis after having 
adjusted for demographic variables (age, sex, race, income, etc.) This data 
suggested an increased risk of PD associated with TBI compared to NTT. 
Similarly, researchers found that the risk of being diagnosed with PD 
increases with the severity and frequency of TBI, providing support to a 
more causal association [24].

Prevalence of TBI in patients with PD
Contradicting evidence exists regarding the statistical signi cance of the 
association between TBI and the risk of developing PD [25]. TBI-related 
emergency visits have increased in recent years in the United States, with 
age-adjusted rates showing increases from 534.4 per 100,000 persons in 
2007 to 787.1 per 100,000 persons in 2013 [26]. Savica et al. similarly cites 
an increase in PD incidence in recent decades. With these increasing rates, it 
becomes even more pertinent to assess whether there is a correlation 
between PD and TBI [27].

Recent epidemiological studies have cited a lack of correlation between the 
development of PD and severe head injury. One study analyzed the medical

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records of the Danish population 20 years and older who were hospitalized 
for head trauma from 1981 to 1993. Of the 8769 cases requiring 
hospitalization, 107 patients developed PD, in which 55 of those cases were 
male and 52 cases were female. The mean age to sustain the injury was 39.7 
for males and 49.2 for females [28]. Regarding the severity of TBI, Raj et 
al. found that the mean age of sustaining moderate-to-severe TBI (39 
years) was less than that of patients diagnosed with mild TBI (46 years) 
[29]. In a study by Spangenberg et al., the expected number of 
participants who developed PD without sustaining a severe head 
injury was 112.14 per 100,000 persons [28]. Due to these results, the 
study concluded that there was no correlation between PD risk and 
severe head injury among adults. Similarly, Raj et al. found no signi cant 
pattern of correlation between TBI history and PD risk in the adult Finnish 
population [29].

Conversely, other studies have observed a correlation between PD risk and 
TBI. A case control study consisting of twins found that head injuries were 
associated with a three-fold increase in PD, while head injuries with amnesia 
and loss of consciousness were more strongly associated with the onset of 
PD. These results suggest that mild‐to‐moderate closed head injury may 
increase PD risk. It was also observed that the risk for PD increased with the 
frequency and severity of the head injury [30]. Similarly, a study by Bower 
et al. corroborated this as the researchers found that only moderate-severe 
diagnoses of TBI were correlated with an increased PD risk [31]. Similarly, 
White et al. found a 2.69-fold and 3.70-fold increase in PD risk in Veterans 
A airs healthcare facilities’ patients diagnosed with mild TBI and 
moderate TBI, respectively, indicating a correlation between increased 
incidence rate and the severity of TBI [32]. Bower et al. and White et 
al. also observed a possible association between PD risk and TBI in their 
studies [31, 32].

During our literature review regarding the prevalence and demographics 
of PD and TBI, some studies noted the possibility of attaining TBI due to 
PD. In a study conducted in Denmark, patients were found to have a 50%
higher risk of developing PD if they sustained a head injury less than 10 
years before the diagnosis, and an even higher risk if the TBI was sustained 
three months prior to PD diagnosis. Due to this lack of correlation over 
the l0-year study, Rugbjerg et al. concluded that there was no correlation 
between head injury and PD. In fact, Rugbjerg et al. mentioned the 
possibility of PD-induced TBI due to PD patients’ tendency to have a 
slower reaction time [33]. Delayed reaction time makes it di cult for PD

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patients to break their fall with their arms, resulting in a more severe injury 
which could lead to TBI. It is possible that head injury in the months 
preceding PD is not a cause of diagnosis, but rather a consequence due to 
decreased control of motor function. This could serve as a plausible 
explanation for the observed association between TBI and the subsequent 
PD diagnosis in the previous study. This reverse relationship could be 
mistaken for an association between TBI and increased PD risk and 
should be researched further to assess the nature and directionality of this 
association [33].

Cognition
PD and TBI can greatly a ect a patient's cognitive function. The 
association between the two suggests that cognition can be a ected from 
both physical and biological standpoints.

Cognitive dysf unction in PD and in TBI
Cognitive dysfunction appears as a common symptom among those 
diagnosed with PD, and numerous studies have examined the extent to 
which cognition is a ected by PD. In one study, 115 participants newly 
diagnosed with PD and 70 healthy control participants were given a 
neuropsychological assessment, which included tests for psychomotor 
speed, memory, language, attention, and executive and visuospatial 
functions. PD patients performed signi cantly worse than healthy controls 
for most of the cognitive measures. The results indicated that PD patients 
were cognitively impaired due to their dysfunctional performance on at 
least three neuropsychological tests. 24% of PD patients were determined to 
be cognitively impaired, whereas only 4% of healthy controls were 
cognitively impaired. The de cits in PD patients appeared in memory and 
executive functions. Apparent de cits may be misrepresented by the type of 
test given, as the tests may have favored assessment of immediate memory 
rather than cognitive dysfunction as a whole [34]. Further analysis is 
warranted to discern factors such as TBI and falls that may have 
contributed to performance.

Another study consisted of a population-based, case-control examination of 
cognitive function in early PD patients. The study consisted of 46 patients 
who were 65 years or older that presented PD within ve years. All these 
patients were enrolled in the Neurological Disorders in 

Berkeley Pharma Tech Journal of Medicine | 33



Central Spain (NEDICES) and matched with 138 controls for comparison. 
The Mini-Mental State Examination, a cognitive ability examination of the 
elderly, was administered and PD patients performed worse (p = 0.04) than 
controls. Subjective memory complaints were observed in 58.7% of PD 
patients compared to 37% in controls (p = 0.010). Results indicated that 
PD patients who were diagnosed within the last ve years did not perform 
well on global cognition tests, verbal uency tests, and memory tests. 
Additionally, 16 of the 46 PD patients with early PD were previously 
undiagnosed [35].

In addition, a study following cognitive change for ve years in newly 
diagnosed patients was done to explore the extent of cognitive dysfunction 
in PD patients. At zero, three, and ve years, a sample of PD patients (n = 
59) and a sample of healthy controls (n = 40) were given neuropsychological 
assessments in which six cognitive domains were tested. In all the domains 
except the assessment of attention, patients with PD showed a greater 
decline than the healthy controls over time. Individually, 53% of PD 
patients showed a greater decline in cognition than controls. Overall, 
cognitive impairment with varying levels of severity seems to be prevalent 
among PD patients, with memory and psychomotor speed being the most 
a ected [36]. Similarly, patients with TBI commonly exhibit cognitive 
impairment.

Furthermore, studies have researched areas of the brain in which cognitive 
impairment occurs in patients with PD. One study assessed the areas in 
which brain atrophy occurred in PD patients who also had Mild Cognitive 
Impairment (MCI), a cognitive impairment that does not interfere with 
daily activities. In comparison to PD patients without cognitive 
impairment, PD patients with cognitive impairment had hippocampal 
atrophy, a potential biomarker for initial cognitive decline in patients with 
PD [37]. As with PD, cognitive dysfunction in patients appears to be a 
common characteristic among patients with TBI. To better understand the 
association between cognitive dysfunction and TBI, a study was conducted 
in 2008 to investigate cognitive impairments ten years after participants 
experienced TBI (time range of initial injury was limited to the years of 
1992 and 1995). 60 TBI participants were gathered and compared to a 
group of 43 demographically similar participants. These groups underwent 
a series of tests that measured functions such as attention, processing speed, 
memory, and executive function. Results showed that the group of patients 
who had a TBI 10 years prior scored signi cantly lower than the control

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group on the Symbol Digit Modalities Test and the Digit Symbol Coding 
subtest, both of which measured information processing speed. These 
results strongly suggest that patients who su ered a TBI may experience 
long-term cognitive dysfunction [38].

In addition to long-term e ects, there appears to be a short-term e ect on 
cognitive function in TBI patients as well. A study from the University of 
Texas at Dallas in 2016 examined whether a history of TBI was associated 
with an increased risk of earlier onset of mild cognitive impairment (MCI). 
3,187 subjects with MCI and 3,244 normal-cognition subjects were selected 
from the National Alzheimer's Coordinating Center database and 
categorized based on severity and demographics. The results demonstrated 
that patients with MCI were diagnosed 2.3 years earlier in the TBI positive 
group than the subjects without TBI, showing TBI as a potential risk factor 
for MCI. Limitations are vast, as this association could be due to other 
factors such as gender or mental state. However, this opens the door for 
further studies to discover whether TBI and MCI can be associated with an 
increased risk of neurodegenerative diseases such as PD [39].

TBI and PD Cognition Studies
Cognitive impairment is a shared characteristic among patients with TBI 
and PD. Further exploration of cognitive impairment in recent studies has 
shown that there may be greater cognitive impairment in PD patients who 
experienced TBI, compared to PD patients who have not experienced TBI. 
Hence, there is a great need to investigate the role of TBI in inducing or 
exacerbating PD.

A research team at UCSF conducted a study to investigate the relationship 
between head injury and PD phenotype. Data collected from 267 patients 
in the Parkinson's Progression Markers Initiative (PPMI), it was found 
that individuals who experienced head injury prior to being diagnosed 
with PD had higher non-motor symptoms. PD patients with any report of 
head injury received a mean score of 7.73 on the Movement Disorders 
Society-Uni ed Parkinson's Disease Rating Scale, where lower scores 
indicate milder symptoms. By comparison, PD patients with no history of 
head injury had a mean score of 6.19 on the same scale (p = 0.035). Those 
with severe head injury had scores of 8.29, and those without a head injury 
report had a score of 6.19 (p = 0.051). Additionally, motor symptoms were

Berkeley Pharma Tech Journal of Medicine | 35



higher in those who had a severe head injury (score of 8.35) on the MDS 
assessment, whereas patients without a head injury history had a score of: 
6.19 (p = 0.042) [40].

Figure 1: PD with severe head injury has the highest score (8.29) on the Movement Disorders 
Society-Unified Parkinson’s Disease Rating Scale.

A separate longitudinal study took place over two years and consisted of 
cognitive testing on PD patients with and without a history of TBI. The 
study found that patients with a history of TBI faced more signi cant 
cognitive decline over the two years. After taking the Mattis Dementia 
Rating Scale test, which measures attention, initiation-perseveration, 
construction, memory, and conceptualization, PD patients without TBI 
had improved scores after two years, whereas PD patients with TBI had a 
decline in scores. However, both faced a similar decrease in motor function 
and a similar increase in depressive symptoms. The PD group with a history 
of TBI fare worse in both memory and initiation/preservation subscales 
[41]. This study demonstrated a potential correlation between TBI and PD 
symptoms. Another cross-sectional cohort study was conducted to 
investigate whether a patient's history of TBI could be associated with PD 
and cognitive, motor, and neuropsychiatric symptoms. 120 patients 
between the ages of 60 to 85 were assessed for demographic data, 
neuropsychological tests, motor evaluation, neuropsychiatric 
questionnaires, and a brain injury screening questionnaire. Of the 120 
patients, 69 had PD and 51 were healthy controls. Results from this study 
concluded there was a signi cant negative correlation between the number 
of TBIs in PD patients and mean z-scores for global cognition (rs (69) =
−0.338, p = 0.004) [42].

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Neurodegeneration in PD and TBI and its E ects on
Cognition
The e ects of TBI on the brain may increase the severity of cognitive 
impairment by exacerbating the neurodegeneration present in PD. 
Weintraub et al. [37] conducted a study to assess regions in which brain 
atrophy occurred in patients with PD with normal cognition, PD with 
mild cognitive impairment, and dementia-level cognitive decline. 84 PD 
patients (61 PD normal cognition, 12 PD mild cognitive impaired, and 11 
dementia-level cognitive impaired) and 23 healthy controls were assessed 
using magnetic resonance imaging of the brain. Results indicated that 
individuals who had PD and normal cognition did not have signi cant 
brain atrophy compared to the healthy controls. When comparing the PD 
patients with normal cognition and patients with mild cognitive 
impairment, PD patients with mild cognitive impairment demonstrated 
hippocampal atrophy (β = −0.37; P = .001), and PD patients with 
dementia had hippocampal (β = −0.32; P = .004) and medial temporal lobe 
atrophy (β = −0.36; P = .003) [37]. PD patients with mild cognitive 
impairment had a similar pattern to the patients with both dementia and 
PD. A correlation between memory-encoding performance and 
hippocampal volume was found in the PD groups not exhibiting dementia. 
From this study, it was concluded that hippocampal atrophy may serve as a 
biomarker of initial cognitive decline in PD [37].

PD patients with mild cognitive impairment also showed a faster rate of 
cortical thinning. According to the Montreal Cognitive Assessment, 
signi cant thinning of the temporal and medial occipital lobe was 
correlated with a decline in cognitive function [43]. To understand the 
genetic nature of cognitive impairment, researchers from North China 
University conducted an experiment to analyze the dysregulated expression 
of microRNA144 (miRNA) and its role in the pathogenesis of TBI in a rat 
model TBI. According to the researchers, miR-144 overexpression was a 
common characteristic of neurological diseases, as MiR-144 could alter 
gene expression in the hippocampus. After analyzing the miR-144 gene in 
TBI patients and TBI in rats in vivo and in vitro, researchers found that the 
inhibition of the gene led to a better neurological outcome after TBI in vivo 
and improved cognitive de cits. The researchers also found that 
overexpression of the miR-144 gene led to an inhibition of the ADAM10 
expression, which can modulate beta-amyloid formation, a common

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protein involved in the development of cognitive de cits. These results 
demonstrate the potential relationship between cognitive de cits in TBI 
and gene expression in the brain, which could lead to neurological diseases 
such as PD [44].

Previous research has investigated areas of the brain responsible for 
cognitive dysfunction commonly observed in TBI, PD, depression, and 
dementia. After analyzing magnetic resonance imaging (MRI) data from 
participants, researchers found frontoparietal and fronto-occipital networks 
and temporoparietal, inferior frontal cortices were the primary systems 
responsible for information processing speed and stimulus-driven attention 
of the brain [45].

Figure 2: The medial temporal lobe, highlighting the hippocampal area affected by TBI and 
PD.

Biological         Factors
Current literature has largely focused on the role of biological molecules 
such as alpha-synuclein, a presynaptic neuronal protein that regulates the 
tra cking of synaptic vesicles and the release of neurotransmitters, and 
enzymes such as tyrosine hydroxylase. Additionally, biological phenomena 
such as oxidative stress and neuroin ammation are possible conditions that 
may contribute to the loss of dopaminergic neurons.

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Alpha-Synuclein
The neurodegenerative e ects caused by TBI and PD have been correlated 
with speci c proteins in the brain. To understand pathological correlations 
between PD disease and TBI, the structure and signi cance of 
alpha-synuclein must be discussed. A dominant pathological characteristic 
of PD is the abnormal folding and accumulation of alpha-synuclein in 
protein deposits known as Lewy bodies. Aggregation and overexpression of 
alpha-synuclein have been shown to disrupt the cell membrane of 
dopaminergic neurons, causing neuronal damage [46].

Alpha-synuclein has di erent structural forms, such as the oligomer and 
brillar forms, which have varying e ects on PD pathology. A study 

conducted by Froula et al. investigated the stable β-amyloid–sheet oligomer 
form (secondary protein structure) of the alpha synuclein protein in 
comparison to the brillar form to identify their varying abilities to induce 
characteristics of PD [47]. The various well-de ned forms of alpha-
synuclein were injected into the striatum of mice, with a monomeric alpha-
synuclein injection serving as the control of the experiment. 
Neuropathological outcomes were monitored by performing 
immunohistochemistry using an antibody for alpha synuclein, 
phosphorylated at serine 129. Results showed that in comparison to the 
monomer-injected mice, brils, cellular components that provide stability, 
produced ~30% loss of dopaminergic neurons in the substantia nigra 
compacta and loss of dopamine terminals in the striatum. Injection of bril 
alpha-synuclein also yielded a higher concentration of alpha-synuclein–
positive inclusions. In contrast, injection of the β-sheet oligomer resulted in 
a smaller loss of dopamine neurons in the substantia nigra compacta but 
showed no signs of inclusion formation. In addition, the brillar form of 
alpha-synuclein led to notable motor defects, while oligomer-injected mice 
did not exhibit a decline in motor behavior. It was concluded that the 
brillar form of alpha synuclein had a more signi cant toxic impact than 

the β-sheet oligomers due to the brillar protein’s ability to recruit alpha-
synuclein monomers and spread more quickly in vivo. Overall, this research 
concluded that the brillar form of alpha-synuclein plays an important role 
in the induction of PD-related phenotypes, and interestingly, alpha-
synuclein has proven to be a characteristic of TBI.

In an in vivo study by Acosta et al., male rats underwent cortical impact to 
simulate TBI [46]. Sixty days after TBI surgery, the brain tissues of these

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rats were harvested for testing. Characterization of alpha-synuclein in 
TBI-induced brains was studied through immuno uorescent staining of 
sections of the substantia nigra. Performing this experiment showed that 
brain tissue exposed to TBI had an increased accumulation of 
alpha-synuclein in the ipsilateral substantia nigra pars compacta. TBI 
resulted in a three-fold upregulation of alpha-synuclein density around the 
soma and neurites of dopaminergic neurons, which triggered dopaminergic 
cell death. Researchers concluded that the alpha synuclein overexpression in 
TBI-exposed brains led to a loss of dopaminergic neurons and served as a 
connection between TBI and the development of PD pathology [46]. 
Furthermore, a study from Impellizzeri et al. con rmed this nding. This 
study analyzed alpha synuclein levels in male mice brains 30 days after the 
mice were exposed to induced TBI. Through dopamine transporter and 
alpha-synuclein staining, signi cant increases in alpha-synuclein expression 
and signi cant decreases in dopamine transporters were observed in 
comparison to controls. Impellizzeri et al. also found a reduction in 
neurotrophic factors after 30 days, which are biomolecules that support the 
growth and development of neurons [48]. Overall, ndings from these two 
studies suggest that alpha-synuclein may serve as a notable pathological link 
between TBI and Parkinson’s disease.

Tyrosine  Hydroxylase
In addition to alpha-synuclein, tyrosine hydroxylase, an enzyme that plays a 
key role in the synthesis of dopamine, has been researched as another 
biological marker in TBI and PD. Shin et al. investigated tyrosine 
hydroxylase levels in rat brain tissue to determine this enzyme’s e ect on 
dopaminergic activity. For this study, a set of rats was rst exposed to TBI 
using a controlled cortical impactor. Thirty days after exposure to TBI, the 
brain tissues of these rats were harvested for testing. Western blotting 
techniques were utilized to detect the phosphorylation of tyrosine 
hydroxylase. Between one and four weeks after exposure to TBI, tyrosine 
hydroxylase levels decreased signi cantly at the serine 40 sites. In addition, 
analysis of the striatal tissue revealed a decrease in potassium-evoked 
dopamine release. It was concluded that lower tyrosine hydroxylase levels 
after TBI negatively impacts dopamine concentration in the brain, 
suggesting a correlation between TBI and the development of PD 
pathology [49].

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Figure 3: Location of the Substantia Nigra--the site of the dopamine-producing neurons. A 
decrease in these neurons is implicated in the development of Parkinson's Disease.

Oxidative  Stress
Oxidative stress is a phenomenon in which neuronal damage can occur due 
to the overproduction and accumulation of reactive chemical species that 
cannot be readily detoxi ed [50] [51]. Typically, these chemicals are 
reactive oxygen species (ROS) that take on the form of oxygen containing 
radicals [50]. This may be because brain cells require and receive large 
amounts of oxygen. Current literature has discussed oxidative stress in 
the context of TBI and PD independently, and the similar pathology of 
both suggests that this is one biological aspect that may link these two 
a ictions.

Several studies have implicated oxidative stress in TBI pathology through a 
variety of mechanisms. Hill et al. observed, within hours of injury, an 
increase in ROS production and the accumulation of reactive aldehydes 
acrolein and 4-hydroxynonenal, which are indicative of oxidative damage. 
In addition, Hill et al. observed impairment of Complex I and II activity 
[50]. These e ects were more pronounced in the synaptic mitochondria 
compared to those that were nonsynaptic.

Another study focused on monitoring the synergistic e ects of 
mechanical strain induced-TBI and paraquat pesticide exposure. 
Research has been carried out through an in vitro model of 
undi erentiated SH-SY5Y cells, which are often used to model 
neuron-like activity in experiments. Cells that underwent a moderate 
degree of strain experienced greater and longer-lasting mitochondrial 
membrane depolarization and increased ROS mitochondrial

Berkeley Pharma Tech Journal of Medicine | 41



production, ultimately resulting in the death of dopaminergic neurons. 
These e ects were ampli ed when combined with exposure to paraquat 
[52]. Together, these studies suggest that oxidative stress plays a unique 
role in further propagating neuronal damage from TBI at the cellular 
level, likely by interfering with the cellular respiration processes in the 
mitochondria.

Gene-regulated expression may also play a role in oxidative stress. Wang et 
al. examined the role of protein-disul de isomerase-associated 3 (PDIA3) 
regulated oxidative stress in augmenting TBI damage [53]. Though this 
study focuses on the expression of ROS and antioxidant enzymes as a 
metric for gauging the level of oxidative stress rather than mitochondrial 
activity, it appears to con rm the ndings of Hill et al. While 
mitochondrial dysfunction and interference with neuronal function 
appear to be unifying themes connecting TBI and oxidative stress in these 
studies [50] [52] [53], further research is required to elucidate the exact 
mechanism to determine a causal relationship. Additional research has 
sought to characterize the potential role of oxidative stress in the 
development of PD — more speci cally, its impact on the decline of 
dopaminergic neurons. Paul et al. aimed to evaluate the e cacy of 
melatonin as an antioxidant capable of providing neuroprotective bene ts 
to mitigate the development of PD. Researchers showed that rats 
experiencing oxidative stress, as the result of a homocysteine injection in 
the brain, exhibited a decrease in the number of functioning 
dopaminergic neurons in the substantia nigra region [54]. The study 
concluded that melatonin was an e ective antioxidant and could prove 
promising as a treatment. Oxidative stress and the overexpression of alpha 
synuclein together have been found to possibly cause a synergistic e ect in 
inhibiting the function of cholinergic neurons in the vagus nerve [51]. 
This study, however, noted that not all cholinergic neurons within the 
brain were a ected by oxidative stress, suggesting that speci c regions of 
the brain and nervous system may be a ected di erently. A similar pattern 
has been observed for dopaminergic neurons, with the substantia nigra 
and striatum being the main regions of focus [54] [55] [56]. A causative 
relationship has to be made cautiously between oxidative stress and PD 
due to limited information.

If the aforementioned observations involving oxidative stress have any 
signi cant overall impact on dopaminergic neurons, then there may be a 
causal relationship between TBI and PD. Researchers from Purdue

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University used a mild-TBI rat model, immuno uorescence staining, and 
Western Blot analysis to demonstrate acrolein’s role in inducing 
aggregation and modi cation of alpha-synuclein, further corroborating 
the ndings from Hill et al. [55]. This study is one of the few that 
discusses the role of oxidative stress in the potential pathological link 
between TBI and PD. However, additional research is needed on the 
e ects of oxidative stress and how its association with TBI can in uence 
the development of PD. Speci cally, the mechanism of mitochondrial 
dysfunction and the accumulation of aldehyde byproducts in relation to 
its interaction with alpha-synuclein requires further research to determine 
its relation to the development of PD-related symptoms.

Figure 4: General Trends Associated with Oxidative Stress and its Potential Role in PD

Neuroin ammation
Neuroin ammation has been researched as another biological link 
between PD and TBI. As dopaminergic neurons are easily susceptible to 
in ammation, neuroin ammation has been found to be an important 
characteristic of PD. Impellizzeri et al. conducted a study in 2016 
analyzing neuroin ammation processes in the brains of male mice with

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induced TBI. Western blot analysis was utilized to analyze midbrain tissue 
of mice 30 days after exposure to TBI using IκB-α and NF-κB speci c 
antibodies. Performing this analysis showed a signi cant reduction in IκB-α 
expression and an increase in NF-κB translocation in mice exposed to TBI. 
Nuclear κB translocation plays a critical role in the transcriptional 
stimulation of pro-in ammatory target genes such as inducible nitric oxide 
synthase (iNOS) and cyclooxygenase-2 (COX-2). iNOS and COX-2 are 
both neurotoxic markers that can damage dopaminergic neurons. 
Evaluating iNOS expression revealed that there was a prominent increase in 
iNOS in the TBI-induced brains in comparison to the control brains. In 
addition, COX-2 expression increased in the midbrain of mice that 
su ered TBI [48]. Interestingly, increased COX-2 expression was also 
detected post-mortem in the substantia nigra of Parkinson's patients [57]. 
Based on these ndings, researchers concluded that neuroin ammatory 
processes resulting from TBI can lead to the development of PD pathology 
in the midbrain.

In a 2018 study, Yu et al. examined the role that the expression of the 
transcriptional factor early growth response-1 (Egr-1) played in inducing 
neuroin ammation and neurodegeneration in mouse models of PD [58]. 
Mice were injected with 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine 
(MPTP), induced expression and upregulation of Egr-1 in the substantia 
nigra pars compacta. Upon Egr-1 activation, researchers also noted an 
increase in interleukin 1-beta (IL-1b) and tumor necrosis factor-alpha 
(TNF-a), which are cytokines involved in in ammatory responses. 
Conversely, using Egr-1 knockout mice models, researchers noted that the 
extent of the in ammatory response and dopaminergic neuronal death was 
less than in non-knockout models, suggesting that Egr-1 could play a role in 
linking neuroin ammation to PD pathology. The researchers con rmed 
these ndings by administering mithramycin A, an antibiotic known to 
displace transcription factors such as Egr-1 from their binding sites. Yu et al. 
also noted that the protective e ects of Egr-1 knockout was largely limited 
to the substantia nigra, and that this protective e ect was not observed in 
the striatum. Thus, further investigation needed on the speci c molecular 
pathways in the substantia nigra and the striatum.

Other studies have focused on how the presence of pro-in ammatory 
cytokines a ects PD patients. Karpenko et al. quanti ed the prevalence of 
di erent cytokines present in blood samples from PD patient groups at 
various disease stages using immunosorbent assays. In particular, the

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researchers examined samples from the blood serum and cerebrospinal uid 
to determine if the presence of TNF-a and interleukin (IL)-type cytokines 
correlated with the severity and progression of PD [59]. Researchers found 
that higher levels of IL-1b in the serum and TNF-a in the cerebrospinal 
uid were correlated with increased severity and rapid disease progression, 

but the correlation between other cytokines such as IL-6 and PD was still 
unclear [59]. Another study in 2018 conducted by Li et al. employed 
similar methods to evaluate the correlation between cytokines in the blood 
plasma and PD-related pain found increased levels of IL-1 in the blood 
serum of PD patients [60]. Because IL-1b is contained within the IL-1 
family, these ndings appear to corroborate the ndings of Karpenko et al., 
further suggesting that proin ammatory factors may play a role in PD 
progression, though the exact role remains unclear.

While there is evidence that neuroin ammation, oxidative stress, 
alpha-synuclein, and tyrosine hydroxylase may provide a link between TBI 
and PD, these ndings are speculative and require further research to prove 
a causal relationship. Such research could prove useful in the development 
of new pharmaceutical treatments.

Treatment and  Therapeutic  Targets
Medical treatment of chronic disease is crucial in ameliorating symptoms, 
improving disease management, and prolonging life. Current research 
focuses on prescription drugs and non-invasive treatments for the 
management of PD, with a particular concentration on relieving motor 
symptoms such as lack of balance, slowness, or Parkinsonian gait, which is a 
distinctive change in the walk of a patient with PD [61]. Medications used 
to treat TBI, regardless of their extremity, have the goal of stabilizing 
complications that arose from the injury, preventing further symptoms, and 
minimizing pain to maximize the patient’s well-being.

Medication
Pharmaceutical drugs serve as a powerful, successful treatment strategy in 
combating the detrimental e ects of TBI and PD, despite the high 
prevalence of side e ects. Unlike non-invasive treatments such as exercise 
and behavioral therapy, prescription drugs work biologically to trigger body 
responses that mitigate and prevent the progression of symptoms.

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Rascol et al. discuss medications that have been proven to e ectively 
prevent the worsening of PD symptoms. Some treatments include 
Levodopa (in combination with Carbidopa), Pergolide, Pramipexole, 
Ropinirole, and Selegiline [62]. Levodopa is the strongest and most e ective 
treatment used in patients to delay disease progression, lessen persistent and 
long-term side e ects, and improve well-being. Levodopa is also vital in 
managing acute symptoms of PD relating to body movements such as 
sti ness, tremors, and slowness of motion. The development of these 
motor symptoms stems from the lack of dopamine in certain brain areas of 
patients with PD. Levodopa acts as a dopamine replacement agent to 
manage motor issues in patients [63]. Conversely, many have speculated 
that Levodopa can potentially be harmful and directly provoke motor 
complications. Studies have shown that Levodopa can be noxious to 
dopaminergic neurons, triggering the advancement of neuron degradation 
in the substantia nigra [63]. However, there have been few in vivo studies 
that support these ndings in PD patients. Nonetheless, the bene ts of 
Levodopa in mitigating PD symptoms may outweigh the negative 
controversies that have arisen regarding its e cacy. Much like most existing 
pharmaceutical drugs on the market, there are numerous side e ects of 
Levodopa, including drowsiness, nausea, and hallucinations. However, 
Gandhi and Saadabadi discuss that the key in administering Levodopa to 
Parkinson's patients is to integrate it with a decarboxylase inhibitor like 
Carbidopa [64]. Carbidopa is commonly prescribed with Levodopa, as it 
minimizes nausea and blocks Levodopa from being transformed to 
dopamine prior to moving into the brain, preventing side e ects such as 
vomiting.

Furthermore, Pergolide, Pramipexole, Ropinirole, and Selegiline are 
dopamine agonists that function by emulating the actions of dopamine. 
Studies have shown that dopamine agonists are e cacious as both 
monotherapies and adjunct therapies in treating motor abnormalities 
and dyskinesia, known as involuntary muscle disorder [62]. However, 
there is still insu cient research on the performance of these dopamine 
agonists in Levodopa-naive patients and a lack of veri cation that these 
promote neuroprotective mechanisms. Rascol et al. discuss that for many 
patients, dopamine agonists other than Levodopa have proven to be more 
e ective. However, as with Carbidopa, co-prescribing dopamine agonists 
has proved to signi cantly mitigate symptoms compared to 
monotherapies like Levodopa alone [65]. In their study, Rascol et al. 
examined the e cacy of both Levodopa and Ropinirole in alleviating PD

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symptoms. A patient's risk of developing dyskinesia was found to be 
almost three times lower while taking Ropinirole alone, as opposed to 
Levodopa alone. Ropinirole and Levodopa taken together more 
e ectively reduced the likelihood of worsening PD symptoms [65].

Numerous pharmaceutical medications serve to ease the pain of patients 
who have experienced TBI. Unlike PD, which is characterized by a speci c 
set of side e ects common to each patient, TBI symptoms are diagnosed on 
a case-by-case basis [37]. Therefore, diagnostic procedures di er with each 
patient and prescription dosages directly correlate to the severity of the TBI 
[66]. For milder forms of TBI such as brain damage that are blast-related 
(caused by air pressure changes), focal (caused by contact), di used (caused 
by force), or from concussions, the process of diagnosis involves examining 
solely the history of the incident and direct cause of injury [66]. However, 
for acute brain injuries such as skull fractures, bruising of brain tissue 
known as cerebral contusions, or hematomas, prognosis is determined via 
analysis of imaging tests and a patient’s clinical presentation. In most mild 
cases, recommended medications include over-the-counter pain relief drugs 
such as Naproxen and Acetaminophen [67].

Other prescription medications directly targeted to reduce both physical 
pain and emotional trauma experienced by TBI patients include 
anticonvulsants, antidepressants, antipsychotics, and medications relieving 
motor complications. Anticonvulsant medication is utilized in patients who 
experience epileptic episodes due to their TBI and works to prevent the 
occurrence of seizures [68]. Antiepileptic drugs, such as Gabapentin and 
Topiramate, inhibit excessive neuronal excitability and thus prevent the 
escalation of existing seizures. Used to treat many forms of neurological and 
mental illnesses, antidepressants and antipsychotics are common treatments 
for patients who su er from both PD and TBI. As both PD and TBI 
directly in uence the levels of neurotransmitter signaling in the brain, 
antidepressants and antipsychotics serve to combat any psychiatric disorders 
that may arise, such as depression and hallucinations [69].

Amantadine, an antiviral medication that was rst prescribed to combat the 
In uenza A virus, has increasingly been proven to signi cantly reduce 
prevalent symptoms of PD such as sti ness, tremor, and slowness of 
movement known as bradykinesia [70]. Amantadine has also been shown 
to stimulate the functional recovery of those who su er from motor 
dysfunction related to TBI. Furthermore, Chang and Ramphul point out

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that the primary advantage of Amantadine is its low side e ect pro le, 
which allows it to properly function without excessive harm. Though 
Amantadine has been prescribed to patients su ering from PD and to 
patients su ering from TBI, few studies have examined the e ect of 
Amantadine in treating PD and TBI simultaneously [70]. Thus, further 
research is needed to determine the drug’s e cacy in patients with both 
disorders. Acosta et al. demonstrate the possibility for a molecular 
mechanism that could be harnessed to create new medication for PD [55]. 
Newer and more advanced medications can target acrolein in the body to 
impede and moderate oxidative stress. With the existing research on the 
e ectiveness of prescription medications, many classes of drugs can be 
utilized to target symptoms of PD and TBI both individually and 
simultaneously.

Figure 5: Mechanism behind Levodopa, a PD dopamine agonists

Non-invasive  treatment (Cognitive  Therapies /Exercising)
Non-invasive treatments for PD and TBI have demonstrated e cacy in 
many studies. Such treatments center on physical and cognitive 
rehabilitation to ameliorate many of the common symptoms found in both 
PD and TBI, including motor weakness and stability. A common 
appearance of motor weakness in PD and TBI patients is an abnormal gait 
[71]. An abnormal gait is characterized by an asymmetric rhythm that 
a ects the ability of the patient to walk e ectively and can manifest as 
shu ing steps, gait initiation failure, or freezing of gait [72]. Another 
appearance of motor weakness is a lack of balance, which can be 
characterized by an unusually increased number of falls [73]. Many studies

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have been successful in their focus on exercise as a possible method of 
improving gait, balance, mobility, and overall motor symptoms of patients 
with Parkinson’s disease [74]. Furthermore, basic treadmill exercises have 
markedly improved most motor symptoms in comparison to other forms of 
movement, such as dance and yoga [75]. To maximize therapeutic bene t, 
other studies have coupled exercise with other forms of stimulation.

A new study found that combining rhythmic auditory stimulation (RAS) 
and treadmill training greatly improved the overall gait performance of the 
participants. RAS was implemented in this study through the use of music 
to capture their innate internal timing process and improve their gait 
parameters. All participants in the trial reported no side e ects during the 
entirety of the rehabilitation process. Overall, it was concluded that the 
addition of Rhythmic Auditory Stimulation to treadmill exercise o ers 
complementary advantages to PD patients’ balance, stride count, and 
overall gait performance [76]. Due to the loss of rhythmic movements that 
characterize gaits in PD patients, rhythmic auditory stimulation provides 
compensation for this loss.

A few studies have also researched the loss of rhythm in the movements of 
patients with PD and its correlation with the appearance of abnormal gait. 
A study conducted in 1997 focused on the e ect of rhythmic auditory 
stimulation on the gait velocity and cadence of PD patients. The study 
found that a faster RAS resulted in a signi cant improvement in gait 
velocity and cadence, indicating that rhythmic auditory facilitation could be 
a successful technique in gait rehabilitation [77]. Another study 
incorporated rhythmic auditory cues of a metronome beat to analyze the 
overall e ect PD patients’ performance on single and dual-motor tasks. No 
signi cant change in gait performance was observed when the metronome 
beat was implemented as a standalone; however, signi cant improvement 
was observed in patients who experienced a combination of a rhythmic 
auditory cue and an attentional cue (e.g., requiring patients to focus on 
taking big steps) [78]. This study corroborates the claim that some type of 
incorporation of rhythmic auditory stimulation can have a signi cant 
positive change in gait performance of Parkinson’s disease. Nevertheless, the 
topic of RAS and treadmill training as a therapeutic strategy to improve 
gait appearance lacks recent research and requires further investigation.

Other forms of exercise, such as aquatic exercise, may also provide 
therapeutic bene t to PD patients. A randomized controlled trial studied

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the e ects of aquatic exercise therapy on the improvement of Parkinsonian 
gait. The experimental group performed various exercises in a community 
pool setting for two 45-minute sessions per week for a total of six weeks, 
whereas the control group received their normal treatment, which only 
consisted of medication. Both the experimental and control groups 
demonstrated an improvement in gait, yielding inconclusive evidence for 
the bene ts of aquatic exercise as a potential therapeutic technique [79]. 
Another study sought to compare the e ectiveness of both on-land gait 
training and aquatic gait training to mitigate peripheral neuropathies, a 
common occurrence for PD patients. The study concluded that the 
improvements from the inclusion of aquatic-based gait training in 
conjunction with traditional on-land gait training were similar to the 
improvements of the control group that did not undergo any aquatic-based 
gait training [80]. Despite original postulates that aquatic-based therapies 
would provide bene t to PD patients, current research does not provide 
durable support for this claim.

As with PD, cognitive and physical therapy have received attention as a 
potential therapeutic avenue. Alberto Esquenazi et al. focused on speci c 
methods of locomotor therapy that targeted the gait velocity and 
spatiotemporal symmetry of TBI patients. Researchers tested the e ects of 
an end e ector robot, a robotic exoskeleton, and treadmill training with 
manual assisted partial-body weight-support (Lokomat). The 
Lokomat training method included a harness and a robotic orthosis, 
which were used on a treadmill. The partial-body weight-supported 
treadmill training method used a LiteGait body weight support system in 
tandem with a treadmill. Esquenazi et al. found signi cant 
improvement in the participants’ self-selected velocity with all three 
methods of intervention, as well as a signi cant improvement in maximal 
velocity with the exclusion of the group that used an end e ector robot 
[81]. Overall, improvements in gait speed, gait symmetry, and walking 
endurance were observed. Similarly, Peters et al. researched the impact of 
intensive mobility training on balance and gait speed of chronic TBI 
patients. Though various subjects reported fatigue and pain throughout 
the experiment, the researchers noted signi cant improvement within 
the three months of the trial. Thus, Peters et al. concluded that the high 
consistency with these pain and fatigue reports prove the possibility of 
using intensive mobility training to continue to be a possible therapeutic 
technique for the TBI patients [82]. While the aforementioned studies 
analyzed a variety of di erent techniques, both found a signi cant

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improvement in gait performance, pointing to their possible e ectiveness 
as a therapeutic intervention for patients with TBI.

Figure 6: Berg Balance Scale comparing the following Locomotor Therapy Interventions: 
Partial- Body Weight-Supported Treadmill, Lokomat, and gait velocity and spatiotemporal 
symmetry using an end effector robot (G-EO) Training in patients with TBI.

With the intersection between technology and medicine, additional studies 
have focused on the use of di erent forms of virtual reality simulations to 
improve the balance and overall motor symptoms of patients with 
Parkinson’s disease. When comparing virtual reality rehabilitation to 
conventional physical therapy, Hao Feng et. al. concluded that the use of 
virtual reality by patients with PD resulted in a greater improvement in 
their balance and gait. The study consisted of a 12-week rehabilitation 
program in which the experimental group received balance and gait training 
using virtual reality (VR) technology. While the experiment demonstrated 
that balance and gait signi cantly increased with VR therapy, the study did

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not control for variables such as age, time of onset, and level of interest with 
the VR therapeutic modality [83]. Despite this, the study demonstrated 
that the inclusion of exercises that use VR technology is a possible therapy 
to improve Parkinson’s balance and mobility. Another study researched 
VR-based balance rehabilitation in TBI patients. Through a randomized 
controlled trial, virtual reality therapy was compared to the traditional 
home-based exercise programs currently utilized to help improve the 
balance in TBI patients. There were 6-week, 12-week, and 24-week 
follow-ups, where both the experimental group and the control group saw 
signi cant improvements in balance [84]. Despite the improvement in the 
balance of TBI patients who participated in VR-based rehabilitation, this 
improvement did not exceed that of the home-based exercise programs. The 
conclusion of both studies suggests that virtual reality may be a plausible 
therapeutic technique that improves balance for both PD patients and TBI 
patients.

Although many of the studies mentioned above solely focused on either PD 
or TBI, these non-invasive treatments and therapies include a combined 
improvement of symptoms of both PD and TBI. Additionally, other 
treatments and therapies that may not be speci cally marketed towards PD 
or TBI, but include an improvement in their symptoms as well. As 
previously mentioned, many prescription medications that are used to 
combat symptoms of PD and TBI include mental health drugs, such as 
antipsychotics and antidepressants. Targeted to alleviate internal 
psychological disorders, these classes of medication aid in minimizing the 
mental pain and su ering that occurs as an accompaniment to neurological 
disorders such as TBI and PD.

Symptoms of both often include psychosis, depression, anxiety, and 
personality disorders [85]. Furthermore, a recent study found a correlation 
between depression and other psychiatric symptoms and increased motor 
severity [86]. Research done by Conrad et al. illustrates that the appearance 
of depression, anxiety, and various personality-related disorders have been 
statistically proven to be more prevalent in those who have PD and TBI. 
Many types of treatment, both non-invasive and in the form of prescription 
medication, such as psychotherapy, antidepressant drugs, and 
neuromodulation, are utilized to minimize the e ects of depression and 
anxiety that appear in both PD patients and TBI patients. Makio Takahashi 
and colleagues conducted a multicenter randomized study in which they 
analyzed the e ectiveness of pairing duloxetine, a serotonin and

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norepinephrine reuptake inhibitor (SNRI), with paroxetine and 
escitalopram, which are selective serotonin reuptake inhibitors (SSRIs), to 
improve depressive symptoms, apathy, and gait freezing in PD patients. The 
study concluded that the combination of SNRIs with SSRIs improved 
both the freezing of the gait and the depressive symptoms in PD patients. 
However, the study did not indicate any signi cant change in feelings of 
apathy in the participants [87]. Nevertheless, treatments that provide a 
combined improvement for both PD patients and TBI patients must 
continue to develop and improve.

Conclusion
While the incidence of Traumatic Brain Injury has demonstrated a positive 
correlation with the onset of Parkinson’s disease, further research is 
required to determine the biological and cognitive mechanisms of this 
association. The incidence of TBI, and thus PD, was found to 
disproportionately a ect certain age and gender groups, being more 
prevalent in men than women, with women experiencing slower disease 
progression and older age at symptom onset.

Studies regarding the in uence of gender and prevalence of TBI showed 
contradictory results, pointing to the importance of further research. When 
studying patients with both PD and TBI, researchers found the risk of 
developing PD and/or head injury to increase greatly with age [5].

Research has correlated PD with genetic and environmental risk factors 
(paraquat exposure, malignant melanoma, skin carcinoma, and increased 
dairy consumption) [10] [11] [13]. Further research is required to 
understand the impact of TBI on the onset of PD in greater depth. 
Furthermore, PD patients are more likely to experience TBI during the 
prodromal period of their disease. These results could indicate that with a 
decline in motor function due to aging, individuals are more likely to 
experience TBI from falling, which could increase their chances of 
developing PD. While the incidence of TBI can lead to an increased 
chance of developing PD, the prodromal period of PD can increase an 
individual’s chances of experiencing a TBI from incidents such as falls. 
Therefore, the direction of the correlation is unclear, and further research 
is required.

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When understanding the biological correlation between TBI and the onset 
of PD, it can be concluded that TBI leads to overaccumulation of 
alpha-synuclein in the substantia nigra; these accumulations are also a 
prominent characteristic of Parkinson’s disease. Decreased levels of tyrosine 
hydroxylase serve as another pathological link between TBI and PD. The 
presence of alpha-synuclein has been observed in patients with TBI as well 
as patients with PD, and thus serves as a potential link between both 
conditions. Signi cant decreases in tyrosine hydroxylase in TBI can result in 
a decrease in dopamine and potentially initiate the onset of Parkinson’s 
disease, which is also associated with a loss of dopaminergic neurons in the 
brain. While tyrosine hydroxylase and alpha-synuclein are good biological 
markers for understanding the link between TBI and the onset of PD, 
further experimental research is needed to validate their clinical value. 
Further research is also needed to supply the currently insu cient research 
on the role of oxidative stress and neuroin ammation as a biological 
correlate between TBI and the onset of PD.

Research on the cognitive e ects of TBI and PD demonstrate that PD 
patients who su ered from TBI had greater cognitive decline compared to 
patients who did not su er from TBI. Furthermore, hippocampal 
damage, a region correlated with subsequent cognitive decline, was 
present in patients who experienced either TBI or PD. However, it is 
unclear whether TBI could aggravate the symptoms of prodromal PD or 
directly lead to PD.

The discussion on therapeutic targets and prescriptions determined 
e ective medications that treat the symptoms of PD and TBI 
independently. These include antidepressants, muscle relaxants, and even 
over the counter treatments. However, more research is needed to 
understand medications and therapeutic targets that can alleviate 
symptoms of TBI-induced PD.

In addition to therapeutic targets, non-invasive treatments have been 
identi ed to potentially target symptoms from both PD and TBI. Both 
PD patients and TBI patients present similar motor symptoms; therefore, 
non-invasive treatments such as the incorporation of treadmill activity and 
virtual reality therapy can potentially target these symptoms for 
improvement. The combination of invasive and non-invasive treatments 
could possibly treat patients who experience TBI-induced PD. Therefore, 
while TBI can be understood as a potential non-genetic risk factor for the

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development of PD, more research is required to understand the extent of 
this correlation and the implications of current research. Understanding 
the causal link between Traumatic Brain Injury and the incidence of 
Parkinson’s Disease would allow for more precise treatment plans that 
could potentially prevent the onset of PD.

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