Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson’s disease

Jenkins, Peter O; Roussakis, Andreas–Antonios; Simoni, Sara De; Bourke, Niall; Fleminger, Jessica; Cole, James H.; Piccini, Paola; Sharp, David J.

doi:10.1136/jnnp-2019-321759

Cited by 10 publications

(5 citation statements)

References 30 publications

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“…Despite strong parallels between PD and TBI that implicate striatum-mediated learning dysfunction (Jenkins et al, 2020) and consistent previous evidence of learning impairments in TBI (DeLuca et al, 2000;Vanderploeg et al, 2014;Wright, Schmitter-Edgecombe, & Woo, 2010), no studies have directly examined the functioning of the striatum in individuals with TBI and whether individuals with TBI exhibit de cits in learning through feedback. To address this gap, we investigated 1) whether individuals with TBI are able to learn from feedback and 2) the role the striatum plays in feedback learning.…”

Section: Introductionmentioning

confidence: 94%

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation

Dobryakova

Zuckerman

Sandry

2021

Brain Imaging and Behavior

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Objective: Outcome processing, the ability to learn from feedback, is an important component of adaptive behavior and rehabilitation. Evidence from healthy adults implicates the striatum and dopamine in outcome processing. Animal research shows that damage to dopaminergic pathways in the brain can lead to a disruption of dopamine tone and transmission. Such evidence thus suggests that persons with TBI experience de cits in outcome processing. However, no research has directly investigated outcome processing and associated neural mechanisms in TBI. Here, we examine outcome processing in individuals with TBI during learning. Given that TBI negatively impacts striatal and dopaminergic systems, we hypothesize that individuals with TBI exhibit de cits in learning from outcomes.Methods: To test this hypothesis, individuals with moderate-to-severe TBI and healthy adults were presented with a declarative paired-associate word learning task. Outcomes indicating performance accuracy were presented immediately during task performance and in the form of either monetary or performance-based feedback. Two types of feedback provided the opportunity to test whether extrinsic and intrinsic motivational aspects of outcome presentation play a role during learning and outcome processing.Results: Our results show that individuals with TBI exhibited impaired learning from feedback compared to healthy participants. Additionally, individuals with TBI exhibited increased activation in the striatum during outcome processing. Conclusions:The results of this study suggest that outcome processing and learning from immediate outcomes is impaired in individuals with TBI and might be related to ine cient use of neural resources during task performance as re ected by increased activation of the striatum.

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Section: Introductionmentioning

confidence: 94%

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation

Dobryakova

Zuckerman

Sandry

2021

Brain Imaging and Behavior

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“…34 Moreover, a greater reduction in the Putamen dopaminergic binding in relation to the caudate has been shown to be specific for the PD compared to the traumatic brain injury. 35 Therefore, the increase in the Caudate/Putamen ratio is an indication of the progression of the dopaminergic neurodegeneration in the brains of PD patients. In this study, genetic variations in at least 150 TE elements were found to be related to the faster degeneration of the Putamen and faster progression of PD.…”

Section: Discussionmentioning

confidence: 99%

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease

Kõks

Pfaff

Singleton

et al. 2022

Exp Biol Med (Maywood)

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The pathophysiology of Parkinson’s disease (PD) is a complex process of the interaction between genetic and environmental factors. Studies on the genetic component of PD have predominantly focused on single nucleotide polymorphisms (SNPs) using a cross-sectional case–control design in large genome-wide association studies. This approach while giving insight into a significant portion of the genetics of PD does not fully account for all the genetic components resulting in missing heritability. In this study, we approached this problem by focusing on the non-reference genome transposable elements (TEs) and their impact on the progression of PD using a longitudinal study design within the Parkinson’s progression markers initiative (PPMI) cohort. We analyzed 2886 Alu repeats, 360 LINE1 and 128 SINE-VNTR-Alus (SVAs) that were called from the whole-genome sequence data which are not within the reference genome. The presence or absence of these non-reference TE variants is known as a retrotransposon insertion polymorphism, and measuring this polymorphism describes the impact of TEs on the traits. The variations for the presence or absence of the non-reference TE elements were modeled to align with the changes in the 114 outcome measures during the five-year follow-up period of the PPMI cohort. Linear mixed-effects models were used, and many TEs were found to have a highly significant effect on the longitudinal changes in the clinically important PD outcomes such as UPDRS subscale II, UPDRS total scores, and modified Schwab and England ADL scale. In addition, the progression of several imaging and functional measures, including the Caudate/Putamen ratio and levodopa equivalent daily dose (LEDD) were also significantly affected by the TEs. In conclusion, this study identified the overwhelming effect of the non-reference TEs on the progression of PD and is a good example of the impact the variations in the “junk DNA” have on complex diseases.

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“…Loss of dopaminergic neurons in the substantia nigra, which underlies akinesia, rigidity, and postural tremor in PD, is also thought to be a potential mechanism by which TBI increases the risk of PD. For example, dopamine transporter imaging revealed that human patients with TBI show a similar reduction in dopamine transporter levels in the caudate compared with PD [ 162 ]. Complementary to this, TBI in rodents leads to reduced expression of tyrosine hydroxylase and dopamine transporter in the substantia nigra [ 157 ], as well as reduced dopamine transporter in the cortex ipsilateral to the injury site [ 163 ].…”

Section: Tbi and Pdmentioning

confidence: 99%

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

2023

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Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.

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Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson’s disease

Cited by 10 publications

References 30 publications

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

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