Inflammation in noncommunicable diseases

A movie and a reflection

30th of March 2020

Ever since I have Parkinson’s the focus of my work has been shifting. I am so utterly interested in the complex disease that is my fate, that I have noticed I am using all the time I can spare for researching ‘all things Parkinson’s’. It is exactly this curiousity which is helping me find new assignments which I can do in the focused way my brain needs nowadays.
One of these assignments was for the division of pharmacology at Utrecht University, the Netherlands. After having interviewed prof. dr. Aletta Kraneveld earlier about diet as a medicine in Parkinson’s disease, she asked me whether I would want to make a movie about their translational research into promoting immune fitness.

Hell, yes!

So, here it is. The movie, followed by some explanatory notes of used concepts and an in-depth reflection on what targeting inflammation has to do with Parkinson’s.

According to the WHO, noncommunicable diseases (NCDs) “tend to be of long duration and are the result of a combination of genetic, physiological, environmental and behavioural factors”.

The diseases supposedly aren’t transmissible directly from one person to another, although there is at least a ‘socially transmissible component’. This component points to our shared environment, including diet and lifestyle, as well as the composition of our microbiota. Because families share diets and environments, the composition of their gut microbiota is more similar than that of genetically similar siblings living separately (Finlay, 2020).

NCDs account for more than 70% (41 million) of all deaths globally.

The skin and our mucosal surfaces (amongst others the cell linings of our lungs and gut) form the protective barrier between our body and the external environment. When a pathogen – bacteria, a virus or parasites which can make us ill – enters, an inflammatory response to get rid of the pathogen is rapidly initiated by our immune system.

The immune system is categorized into innate and adaptive immunity:

  • Innate immunity is already present at birth. It is a nonspecific response to defend the body from pathogens.
  • Adaptive immunity is when the first line of defense fails and the body needs a more sophisticated approach to fight off the attack. It then turns to its T-cells and B-cells, which are types of white blood cells also called lymphocytes. On the surface of pathogens so called antigens are located. To target these antigens, antigen-specific T-cells proliferate and our B-cells produce Y-shaped antibodies. These T- and B-cells lock onto the antigen on the surface of invading pathogens. In this way they sort of put a marker on it which says ‘destroy me’. Some specialized T-cells as well as innate immune cells such as macrophages and Natural Killer cells, recognize the ‘flagged cells’ and help destroy them. T- and B-cells can remember past pathogen encounters, which results in a faster inflammatory response upon secondary infection.

The heightened inflammatory state following the resolution of pathogen infection lasts some time. Chronic inflammation is when this heightened state lasts so long that it has negative side effects.

A wealth of epidemiological, immunohistological, biofluid, and genetic evidence supports a role for the innate and adaptive immune system in the pathophysiology of PD  | Tansey, 2018

A failing resolution of inflammation is associated with the presence of Parkinson’s Disease (PD). Some examples from literature:

  • In people with Parkinson’s (PwP), systemic innate immune changes are present (e.g. Wijeyekoon, 2020).
  • One of the most common genetic risk factors for PD is having a mutated GBA1 gene which encodes for the lysosomal enzyme glucocerebrosidase (also called GCase). GCase helps with the digestion and recycling of various proteins inside lysosomal cells. PwP with such a mutation in the GBA1 gene, show elevated plasma concentrations of the cytokines IL-1β and TNFα. Cytokines are small secreted proteins released by cells with a role in orchestrating the immune response. (Miliukhina, 2020). 
  • Another common genetic risk factor for PD is a mutation in the LRRK2 gene. The LRRK2 gene provides instructions for making a protein called Leucine-rich repeat kinase 2, or dardarin in short. This protein has been implicated in multiple processes critical for immune cell function. In PwP with a LRRK2-mutation the ones with the highest levels of pro-inflammatory proteins IL-8, MCP-1 and MIP-1-b progressed more rapidly. (Brockmann, 2017).

Neuroinflammation via the gut

A process of gut dysbiosis accompanies at least a subgroup of patients with Parkinson’s (Scheperjans, 2015; Bullich, 2020). An increase of microbiota with exotic names such as Verrucomicrobiaceae and Akkermansia, and a decrease of Prevotellaceae was observed in various studies (Uyar, 2019). This dysbiosis supposedly leads to an increase of exposure of toxins and metabolic products to the central nervous system. First by passage through a leaky gut and second through an impaired blood-brain-barrier (BBB) (Baizabal-Carvallo, 2020), which – in turn – may lead to low-grade chronic neuroinflammatory processes.

There is currently no consensus on PD specific changes in microbiome composition, possiby due to differences in methodologies and unaddressed confounders (Boertien, 2019; Bullich, 2020). For example, low Prevotellaceae levels alone are not specific for PD. Also, whether/when inflammatory processes are a cause and/or a preventive mechanism – which possibly goes rogue at some point in time – remains to be seen. Inflammation could also signify a response to underlying pathoghenic mechanisms still to be discovered.

Neuroinflammation via the olfactory bulb

Whereas in the movie I’ve made, inflammation derived from the gut is taking the stage, other ways of entry exist. Environmental toxins and pathogens – and possibly also COVID-19 pathogens – can enter the brain via the olfactory epithelium and induce inflammatory responses and PD-like neuropathology (Doty, 2012; Baig, 2020) For all of you who have seen the movie Awakenings: In it we see how encephalitis lethargica which spread through Europe after WW I leads to subjects developing Parkinsonian symptoms which are relieved to some extent after taking levodopa (Hofmann, 2017).

Ultimately, the only way you will know whether the immune response is good or bad is by intervening in patients | Roger Barker, in a webinar on infllammation from Cure Parkinson’s Trust.

In literature, you see several approaches to reduce a supposedly overactive inflammatory response:

  • Inhibiting particular molecular pathways in inflammation
    E.g. there are numerous biotech companies actively developing clinical programs around the so called NLRP3 inflammasome. The NLRP3 inflammasome is a multi-protein complex that detects a wide range of pathogens and subsequently initiates an inflammatory form of cell death. Agents are being developed which block NLRP3 thereby dampening inflammation.
  • Targeting inflammation through dietary interventions
    Diet is a potential factor that may prevent the development or slow the progression of PD. There is a growing body of experimental evidence strongly suggesting that diet impacts the development/progression of multiple neurodegenerative diseases including PD  (Jackson, 2019). Several proof-of-concept studies have been or are being undertaken:

    • There is some evidence that adherence to a Mediterranean diet may be protective for Parkinson’s disease risk (Alcalay, 2019), presumably via a process of reducing oxidative stress and inflammation. Also, a Mediterranean diet has recently been shown to improve cognitive function in PwP (Paknahad, 2020). Further studies, with a larger sample size and longer duration, are required to confirm the results of this study.
    • Researchers at King’s College London are starting a world-first clinical trial to test if a probiotic drink could help with motor and non-motor symptoms of Parkinson’s. Some caution with taking probiotics is necessary. Some gut bacteria are able to convert levodopa, the medication most PwP take to relieve their symptoms. This process reduces the availability of levodopa to the brain. Probiotic strains exist which have this ability too (van Kessel, 2019).
    • In a case-control study, researchers assessed the gut microbiome of 54 PD patients and 32 healthy controls. In a proof-of-concept study they saw that a vegetarian dietary intervention and additional physical colon cleaning lead to a greater diversity of the gut microbiome in PD, possibly leading to a beneficial effect on the course of the disease. (Hegelmaier, 2020).

Even though ‘on average’ persons with Parkinson’s seem to benefit from dietary interventions, the average person with PD does not seem to exist. We still need loads of data to tells us what may work for one, and not for another.

Because it is still unclear how the microbiome might be modulated to affect disease expression, measuring intestinal microbiota in observational and interventional studies is imperative to better define its role across PD subtypes | Espay, 2020

Parkinson’s disease continues to be a relentlessly progressive disorder. The failure of previous clinical trials investigating putative neuroprotective compounds for PD may be due to differences between patients in the underlying pathogenic mechanisms. Precision medicine is increasingly advocated as a promising strategy in the pursuit of neuroprotection in PD but would require the identification of distinct pathomechanisms in individual patients | Carling, 2020

It’s been more than two centuries since James Parkinson first medically described what would be called Parkinson’s disease years later. Along the way, we have come to realise that a clinical manifestation of Parkinson’s disease – what it looks like from the outside –  isn’t enough to tell us what genes, environmental triggers, and pathogenic mechanisms were and are at play in each individual. So far, it’s mostly what we currently don’t see yet that defines a person with Parkinson’s. That defines his or her chance a given treatment will have success.

Understanding how to subdivide the population to define more homogeneous subgroups for the purpose of studying the causes of disease is a challenge we are accepting (Alcalay, 2019). Several approaches of subdividing populations are already being pursued, e.g.:

  • Genetic
    Subdividing populations isn’t always as easy as isolating the persons with a specific gene mutation assuming it caused PD. Several pathways are enriched for genes associated with multiple neurodegenerative diseases and a ‘disease–disease overlap’ exists. (Arneson, 2018). Also, shared pathways may exist between patients who don’t share a mutation. E.g, in the clinical trial with ambroxol it was found that a subgroup of PwP without a known genetic mutation associated with PD, had the same dysfunctional biological pathways associated with PwP who carry a mutation in the GBA1 gene. Both subgroups had reduced levels of Glucocerebrosidase (GCase). GCase –  which is encoded by the GBA1 gene – is an enzyme that helps with the digestion and recycling of various proteins in our lysosomes.
  • Mechanistic
    Researchers used patient tissue from skin biopsy samples from PwP and managed to discern two groups with distinct differences in the functioning of either their mitochondria – the power houses of our cells – or their lysosomes – the organelles responsible for recycling and disposal of waste products (Carling, 2020).

It might be interesting to add an ‘exposome based’ stratification layer if possible. We could try to find out which infections people have lived through. In my blood, for example, it was found that I had antibodies to the Epstein-Bar virus without me knowing I had suffered from the disease. Such tests could be supplemented with questions about possible assaults on the immune system people have lived through. In my case notable events were exposure to pesticides and an antrum perforation where mouth bacteria enter the nasal cavities and trigger inflammation.

Also, stratification based on symptoms in stead of ‘disease label’ may be of interest. E.g. people with anosmia – a loss of a sense of smell such as I have myself – may have developed PD via a different mechanism than PwP with constipation. And even though machine-learning cannot yet predict which persons with anosmia will progress into PD (Lötsch, 2020) this might become feasible as we add more parameters to the algorithm.

I find it remarkable that in the clinical trials I have enrolled so far, questions about one’s exposome fingerprint and specific symptoms such as side of onset, anosmia, etc. are not added to the data we could mine later on …

We know that inflammation plays a role in several noncommunicable diseases such as Parkinson’s, but we don’t know yet what to prevent in whom. With all perspectives combined we can eventually find out how confounding variables overlap and differ across and within diseases.

In order to find out, we will need lots of eyeballs with different perspectives watching this space. We will especially need to uncover hidden patterns and connections in the vast amount of data we have been, are and will be collecting. New questions and new knowledge is to be found at the intersections.

In my opinion, not one experiment has been done in vain as long as we share the underlying (positive and negative) data.

Challenging times lie in front of us.  But the dream is worth pursuing.

Would it not be great if neurologists could add an individual’s intestinal microbiome, the panel of neuron-specific proteins in the cerebrospinal fluid and the density of this patient’s social network into the overall equation that would lead to the decision whether or not to start with dopaminergic treatment in a given individual with PD?  | Van den Heuvel, 2020

Alcalay, R. N., Gu, Y., Mejia-Santana, H., Cote, L., Marder, K. S., & Scarmeas, N. (2012). The association between Mediterranean diet adherence and Parkinson’s disease. Movement Disorders, 27(6), 771–774. https://doi.org/10.1002/mds.24918 (Closed Access)

Arneson, D., Zhang, Y., Yang, X., & Narayanan, M. (2018). Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks. Journal of genetics, 97(3), 795–806. https://doi.org/10.1007/s12041-018-0963-3 (Open Access)

Baizabal-Carvallo, J. F., & Alonso-Juarez, M. (2020). The Link between Gut Dysbiosis and Neuroinflammation in Parkinsońs Disease. Neuroscience. https://doi.org/10.1016/j.neuroscience.2020.02.030 (Closed Access)

Baig, A. M., Khaleeq, A., Ali, U., & Syeda, H. (2020). Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS chemical neuroscience, 11(7), 995–998. Advance online publication. https://doi.org/10.1021/acschemneuro.0c00122 (Temporarily Open Access in times of COVID-19)

Boertien, J. M., Pereira, P. A. B., Aho, V. T. E., & Scheperjans, F. (2019). Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson’s Disease: A Systematic Review. Journal of Parkinson’s Disease, 1–15. https://doi.org/10.3233/jpd-191711 (Open Access)

Bullich, C., Keshavarzian, A., Garssen, J., Kraneveld, A., Perez-Pardo, P. (2019). Gut vibes in Parkinson’s disease: the microbiota-gut-brain axis. Mov Disord Clin Pract 6:639–651. https://doi.org/10.1002/mdc3.12840 (Closed Access)

Brockmann, K., Schulte, C., Schneiderhan-Marra, N., Apel, A., Pont-Sunyer, C., Vilas, D., … Maetzler, W. (2017). Inflammatory profile discriminates clinical subtypes inLRRK2-associated Parkinson’s disease. European Journal of Neurology, 24(2), 427–e6. https://doi.org/10.1111/ene.13223  (Closed Access)

Carling, P.J., Mortiboys, H.,Green, C., Mihaylov, S., Sandor, C., Schwartzentruber, A., Taylor, R., Wei, W., Hastings, C., Wong, W., Lo, C., Evetts, S., Clemmens, H., Wyles, M., Willcox, S., Payne, T. (2020). Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease. Progress in neurobiology. https://doi.org/10.1016/j.pneurobio.2020.101772 (Closed Access).

Cronkite, D. A., & Strutt, T. M. (2018). The Regulation of Inflammation by Innate and Adaptive Lymphocytes. Journal of Immunology Research, 2018, 1–14. https://doi.org/10.1155/2018/1467538 (Open Access)

Doty, R. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol 8, 329–339 (2012). https://doi.org/10.1038/nrneurol.2012.80 (Closed Access)

Espay, A.J., Schwarzschild, M.A., Tanner, C.M., et al. Biomarker-driven phenotyping in Parkinson’s disease: A translational missing link in disease-modifying clinical trials. Mov Disord. 2017;32(3):319–324. https://doi.org/10.1002/mds.26913 (Closed Access)

Espay, A.J., e.a.  (2020). Disease modification and biomarker development in Parkinson disease. Revision or reconstruction? Neurology Mar 2020, 94 (11) 481-494; https://doi.org/10.1212/WNL.0000000000009107

Finlay, B.B. (2020). Are noncommunicable diseases communicable? Science 367 (6475), 250-251. https://doi.org/10.1126/science.aaz3834 (Closed Access)

Hegelmaier, T.; Lebbing, M.; Duscha, A.; Tomaske, L.; Tönges, L.; Holm, J.B.; Bjørn Nielsen, H.; Gatermann, S.G.; Przuntek, H.; Haghikia. (2020) Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson’s Disease. Cells 9, 376. https://doi.org/10.3390/cells9020376 (Open Access)

Hoffman, L.A., Vilensky, J.A., Encephalitis lethargica: 100 years after the epidemic, Brain, Volume 140, Issue 8, August 2017, Pages 2246–2251, https://doi.org/10.1093/brain/awx177 (Open Access)

Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., & Keshavarzian, A. (2019). Diet in Parkinson’s Disease: Critical Role for the Microbiome. Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.01245 (Open Access)

Kudlicka, A., Hindle, J. V., Spencer, L. E., & Clare, L. (2018). Everyday functioning of people with Parkinson’s disease and impairments in executive function: A qualitative investigation. Disability and Rehabilitation. Volume 40, issue 20, https://doi.org/10.1080/09638288.2017.1334240 (Closed Access)

Marras, C., Canning, C. G., & Goldman, S. M. (2019). Environment, lifestyle, and Parkinson’s disease: Implications for prevention in the next decade. Movement Disorders. https://doi.org/10.1002/mds.27720 (Closed Access)

Miliukhina, I.V., Usenko, T.S., Senkevich, K.A. et al. Plasma Cytokines Profile in Patients with Parkinson’s Disease Associated with Mutations in GBA Gene. Bull Exp Biol Med (2020). https://doi.org/10.1007/s10517-020-04723-x (Closed Access)

Novellino, F., Saccà, V., Donato, A., Zaffino, P., Spadea, M. F., Vismara, M., Donato, G. (2020). Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases. International Journal of Molecular Sciences, 21(3), 1115. https://doi.org/10.3390/ijms21031115 (Open Access)

Özata Uyar, G., Yildiran, H. (2019). A Nutritional approach to microbiota in Parkinson’s disease. Bioscience of Microbiota, Food and Health. https://doi.org/10.12938/bmfh.19-002 (Open Access)

Scheperjans, F., Aho, V., Pereira, P. A. B., Koskinen, K., Paulin, L., Pekkonen, E., Auvinen, P. (2015). Gut microbiota are related to Parkinson’s disease and clinical phenotype. Movement Disorders, 30(3), 350–358. https://doi.org/10.1002/mds.26069 (Closed Access)

Tansey, M. G., & Romero-Ramos, M. (2018). Immune system responses in Parkinson’s Disease: early and dynamic. European Journal of Neuroscience. https://doi.org/10.1111/ejn.14290 (Closed Access)

van den Heuvel, L., Dorsey, R. R., Prainsack, B., Post, B., Stiggelbout, A. M., Meinders, M. J., & Bloem, B. R. (2020). Quadruple Decision Making for Parkinson’s Disease Patients: Combining Expert Opinion, Patient Preferences, Scientific Evidence, and Big Data Approaches to Reach Precision Medicine. Journal of Parkinson’s disease, 10(1), 223–231. https://doi.org/10.3233/JPD-191712 (Open Access)

van Kessel, S.P., Frye, A.K., El-Gendy, A.O. et al. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat Commun 10, 310 (2019). https://doi.org/10.1038/s41467-019-08294-y (Open Access)

Wijeyekoon, R. S., Kronenberg-Versteeg, D., Scott, K. M., Hayat, S., Kuan, W.-L., Evans, J. R., Williams-Gray, C. H. (2020). Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson’s disease. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2020.01.018 (Open Access)

Sparks

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