The Role of Inflammation in Parkinson’s Disease and Atypical Parkinsonian Disorders

Conducted by Piotr Alster, PhD Hab., from the Department of Neurology, the project titled “The significance of inflammatory factors in the pathophysiology of Parkinson’s disease and its atypical Parkinsonian disorders” has received a grant of PLN 47,520 from the National Science Centre.

Neurodegenerative Diseases – an Increasingly Common Problem

The most common neurodegenerative diseases are said to be Alzheimer’s disease, which affects nearly 500,000 residents of Poland, and Parkinson’s disease, which occurs in 150 to 300 out of 100,000 people globally. As life expectancy increases and more people are affected by neurodegenerative diseases, so does the importance of optimal diagnostics. 

Characteristics of Parkinson’s Disease

Parkinson’s disease is a movement disorder. In 90% of cases, the root cause of the disease cannot be determined unequivocally (the disease is sporadic and idiopathic). In Parkinson’s disease, bradykinesia plays a key role. Other symptoms include stiffness, and resting tremor. In contrast to atypical Parkinsonian disorders, the disease responds well to treatment with levodopa. 

Atypical Parkinsonian Disorders – What Are They?

Atypical Parkinsonian disorders are less common. Similarly to Parkinson’s disease, they are idiopathic (at a much higher percentage). Estimates suggest between one and seven out of 100,000 people are affected. Atypical Parkinsonian disorders are characterized by a much less favorable course than Parkinson’s disease, and there are no verified treatment methods. 
Atypical Parkinsonian disorders are a diverse group of conditions. It includes a range of disease entities, such as progressive supranuclear palsy, corticobasal syndrome, and multiple system atrophy. Those conditions are related to a group of symptoms referred to as the Parkinsonism (which includes bradykinesia, muscle stiffness, resting tremor, and abnormal posture), yet they differ significantly in terms of accompanying dysfunctions. Progressive supranuclear palsy and the corticobasal syndrome come with dementia, behavioral changes, abnormal eye movements, and problems with balance. Multiple system atrophy is related to the dysfunction of the autonomous system, and includes symptoms caused by damage to the cerebellum.

Pathophysiology of Neurodegenerative Diseases – What Do We Know So Far?

Neurodegeneration is a process whereby neurons die due to the accumulation of pathological protein. The pathophysiology of neurodegenerative diseases has not been explored in depth yet. However, the definition of neurodegeneration has evolved over the last few decades. The factors related to the process that have been listed include disrupted mitophagy (a process whereby a cell removes its damaged mitochondria to keep its “internal powerhouses” in good condition), oxidative stress (too many free radicals in the body, which may damage cells and speed up ageing), or disrupted mechanisms that control inflammation (which in itself is the body’s natural defensive reaction that helps fight an infection or repair damaged tissue). Neurodegeneration is sometimes also seen as related to vascular factors, infection, and may result from repetitive injuries as well as other causes.   

Potential Role of Inflammation in the Pathophysiology of Parkinsonisms

Inflammation is a process that involves many factors. It is meant to provide a defensive reaction to damage to the tissues caused by pathogens such as bacteria, fungi or viruses. The end result of inflammation is the removal of that factor and restored homeostasis.

Theories on the role of inflammation in the pathophysiology of neurodegenerative diseases point to disruptions in that process. Once it is launched, homeostasis is not restored.

Research by McGeer has shown that the factor that may contribute to the disruption of the inflammatory process are brain phagocytes – “hunter” cells in the brain, which may produce large amounts of superoxide anions and other neurotoxins. However, the profile of inflammation in neurodegenerative diseases has not been described yet, and the data we do have are often superficial. This is mostly due to the pace of progression in those diseases, which often prevents follow-up assessments. 
Another aspect that has not been explored yet is the reason why some cases evolve into Parkinson’s disease, and others – into atypical Parkinsonian disorders. The cause behind the course of the disease being milder for some people but more aggressive for others is not known yet either.

My analysis may allow for assessing the role inflammation plays in the pathophysiology of atypical Parkinsonian disorders. It will also allow for exploring why, within the individual disease entities, some cases evolve into more and some into less burdensome subtypes. The study may also contribute to verifying the diseases without any effective treatment methods, including progressive supranuclear palsy, for factors that could be modifiable by treatment.

Results from Previous Research on the Role of Inflammation in Parkinsonisms

The research so far has indicated the potential role of inflammation in terms of differential diagnostics for the specific disease entities. The results of previous studies, based on the analysis of interleukins (i.e. proteins involved in immune system communications) associated with activating the microglial – interleukins 1 and 6, have shown different profiles in the two most common subtypes of progressive supranuclear palsy, i.e. Richardson’s (PSP-RS), and Parkinsonian (PSP-P). Blood serum and cerebrospinal fluid tests showed higher levels of interleukins 1 and 6 for PSP-P. In another paper on the significance of testing hepcidin levels in serum, a significantly higher level was found in PSP-RS, with results for PSP-P and the control group at comparable levels. 

Tests have shown an interesting correlation not only in terms of differentiating between the diseases, but also in terms of understanding clinical deterioration (i.e. the patient’s condition deteriorating as their deficits get more serious). PSP-P is a subtype with significantly milder progression; however, as evolution progresses, also less invasive subtypes finally transform into PSP-RS, with the duration and progression of symptoms varying widely. The causes of the variation in the nature of those diseases have not been verified. 

Research based on evaluating the levels of individual factors has demonstrated the potentially protective role, e.g. for interleukin-1 – in the atrophy of the midbrain in progressive supranuclear palsy, on the one hand, and correlation with the stage of Parkinson’s disease, on the other. In multiple system atrophy, the factor that triggers inflammation remains unknown. Neuropathological studies have shown extensive microglial activation and neuroinflammation with diffuse infiltration of T cells. Analyses of interleukin 6 and TNF-alfa levels present contradictory data on the role of inflammatory factors in neurodegenerative diseases, which is related to the small number of patients involved in the research, as well as the low incidence of some of the diseases, such as the atypical Parkinsonian disorders. Yet another factor may be the potentially different pathology that underlies the clinical syndrome. For some atypical Parkinsonian disorders such as the corticobasal syndrome, the underlying cause is very heterogenous and based on pathologies of corticobasal degeneration, Alzheimer’s disease, or frontotemporal dementia. Another difference may lie in the protein that determines neurodegeneration, as apart from the tau protein involved in the corticobasal syndrome, also cases related to the TDP-43 protein have been observed. Furthermore, one significant limitation is the fact that most studies evaluating inflammatory parameters are verified only once. This prevents the assessment of how the processes evolve over time.

Methods Applied So Far to Study Inflammation in Parkinsonisms

The evaluation of the cytokine profile in Parkinsonisms is being studied but limited in terms of methodology, due to the availability of methods and the costs of evaluation. Furthermore, the number of papers evaluating inflammatory parameters in the cerebrospinal fluid is relatively low, which is related to the invasive nature of the sampling procedure, as well as to the significant number of procedures whose diagnostic significance has been better verified for this group of diseases.

The widely available methods for the evaluation of Parkinsonisms, which have been described increasingly often, include non-specific parameters derived from peripheral blood morphology indicators, such as the neutrophil to lymphocyte ratio (NLR). Research has shown that it is potentially significant in differentiating Parkinson’s disease and atypical Parkinsonian disorders such as the progressive supranuclear palsy or multiple system atrophy, for which the values of that parameter were higher. Another parameter that has been attracting increased attention is the ratio of the number of neutrophils to the level of high-density lipoprotein (NEUT/HDL=NHR). This involves HDL, a parameter related to the permeability of the blood-brain barrier. For the corticobasal syndrome, there have been reports of the negative correlation between the perfusion of the encephalon, assessed using single-photon emission computed tomography (SPECT) in the thalamus and the insular cortex, with the NHR. 
In isotope diagnostics, inflammation markers in positron emission tomography (PET) have also been described. The markers mentioned include 11C-PK11195, for example. Inflammation parameters in PET as well as isotope markers of the tau protein are correlated with atrophy lesions within the cerebellum or the brain stem. However, those methods are not very broadly available; paired with the rarity of atypical Parkinsonian disorders, this makes it even more difficult to interpret the analyses more broadly. This also limits the possibilities of implementing those tests in clinical diagnostics. The concept for improving the specificity of diagnostic tests for atypical Parkinsonian disorders will most likely involve a multi-dimensional analysis using biochemical and imaging assessments as well as other types of investigations. 

Goal of the Project Funded by the National Science Centre Miniatura 9 Program

The goal of the project titled “The significance of inflammatory factors in the pathophysiology of Parkinson’s disease and its atypical Parkinsonian disorders” is to verify the parameters for their significance in differentiating between the disease entities, which are often clinically similar. Another goal is to explore the changes in the values of disease factors depending on the nature of Parkinsonism. 

The project involves testing 40 patients with a clinical diagnosis of Parkinson’s disease, 40 patients with progressive supranuclear palsy, and 40 healthy volunteers. For the patients, the duration of symptoms is expected to be 3 to 6 years.

As part of the project, I will analyze cytokines related to inflammatory and anti-inflammatory action. Patients will be tested twice within approximately 8 months, with serum samples taken on study enrollment and during follow-up assessment, while cerebrospinal fluid will only be sampled at the first visit, due to the invasive nature of lumbar puncture. 

Exclusion criteria include autoimmune disorders, infectious diseases, neoplasms, history of ischemic and hemorrhagic strokes, immunomodulatory treatment, as well as counterindications for or limited possibility of performing the lumbar puncture, e.g. infections in the puncture area or coagulation disorders. For the groups with the diagnosis of Parkinson’s disease and progressive supranuclear palsy, the study will involve verifying the significance of inflammatory parameters in determining the specific subtypes of the disease. The results will hopefully allow for defining the directions for further research into the pathophysiology and diagnostics of neurodegenerative diseases. 

Expected Project Outcomes

The results of analyses will allow for comparing the levels of inflammatory markers in the course of PD and PSP, which have distinct pathogenetic mechanisms, and will allow for identifying the potential factors that differentiate between those disease entities. 

The changes observed in the inflammatory parameters may serve as a starting point for further analyses aimed at identifying the possible targets for modifying the course of those diseases. Furthermore, analyzing the dynamics of those changes may reveal their relationship with the exacerbation of clinical deterioration.