Saturday 9 September 2017

How neuro-inflammation makes our brain ill

In scientific research into brain disorders, neuro-inflammation is increasingly identified as a cause. Alzheimer’s disease, depression, Parkinson’s disease, MS and OCD: today’s sensitive PET scanner ruthlessly exposes brain inflammation. But what is the cause of the cause?


Take Alzheimer’s disease. In the past, this neurodegenerative disease was described as an accumulation of neurofibrillary tangles and beta-amyloid plaques, but recent research has revealed that the real culprit is chronic neuroinflammation of the brain [1]. The build-up of plaques and tangles only occurs after, as we will show below. But this isn’t where the effect of neuroinflammation stops.


Neuroinflammation also plays a role in depression, Parkinson’s and multiple sclerosis [2,3]. New research using brain scans published in JAMA Psychology adds obsessive-compulsive disorder (OCD) to this list [4]. In this latter disorder, cognitive behavioural therapy – sometimes in combination with medications – is used with reasonable success [5]. But shouldn’t we first work out where that neuroinflammation comes from, and then choose a therapy that deals directly with the cause and for which as little medication as possible is used?   


Where neuroinflammation starts

A fascinating example of how the process of neuroinflammation works is given by Braak’s hypothesis of the progression of Parkinson’s disease. This is the best hypothesis in this discipline, which is also endorsed in a review published this year in Parkinson’s Disease [3] a Nature related journal. According to the researchers, as many as 53-82 percent of all cases of Parkinson’s were found to go through the four Braak stages. And what does Braak tell us about the cause of the cause?


Intestinal problems. In stage one, inflammation occurs in the intestine, for example, as a response to a microbiological stimulus. This inflammation causes the protein alpha-synuclein to change shape. Provided that the good and bad gut flora are in balance, this protein cannot escape from the intestinal environment. However, in the event of dysbiosis, this can lead to leaky gut and alpha-synuclein can migrate up through the central nervous system. The body doesn’t recognise the deviant protein, resulting in an inflammatory response. The protein continues its way to the brain and the inflammation continues to spread.


In stage two the brainstem becomes inflamed and early Parkinson’s symptoms occur, such as disturbed sleep and depression. In stage three, the dopamine-producing cells become inflamed, which explains the characteristic motor symptoms of Parkinson’s. In stage four, the areas of the brain associated with executive functioning also become affected, as a result of which cognitive problems, such as impulsivity, can occur.


Brain scans clearly show that the inflammation really takes place before the symptoms of Parkinson’s become manifest [2]. Isn’t this process identical in MS and OCD?    


Underlying process is the same

Although the exact details differ between disorders, they have one thing in common: they all start with an inflammation in an unfavourable intestinal environment of susceptible individuals. This results in neuroinflammation and then the entire microbiome-gut-brain axis becomes deregulated.


Chronic low-grade inflammations in the intestines are initially responsible for the breakdown of the gut wall and other tissues. The blood-brain barrier – the ‘gatekeeper’ that protects the brain from toxins – is compromised by an influx of cytokines. Proteins and/or other substances then migrate effortlessly along, for example, the nerves to the brain, where they leave behind a trail of inflammations. Immune cells in the brain, such as microglia are then activated and produce reactive oxygen species (ROS). These damage the areas of the brain. Cytokines, such as interleukine-6 (IL-6), interleukine-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α) then promote the inflammation and this spreads further still.


What then happens? In the presence of these cytokines, microglia are no longer able to carry out phagocytosis properly. For example, they are no longer able to clean up amyloid [6]. Whilst the low-grade inflammation is active, the plaque continues to accumulate. When this is not inhibited or corrected at source in the intestine, the syndrome continues to develop.


A focus on neurodegeneration

The foregoing also applies to other neurodegenerative disorders. That is because the essential difference is not the underlying process, that is almost always a form of neuro-inflammation. Equally, the difference is not in how migration is possible along the nerves, i.e. dysbiosis and leaky gut. The difference between the disorders lies primarily in the nature of the intruder(s) and the (combinations of) areas of the brain that ultimately become inflamed. But why hasn’t that been ‘discovered’ in the past?


It is now much easier to measure brain inflammations using the current generation of sensitive PET scans. That is why there is a growing body of research on this inflammatory component. For example, in OCD, the basal ganglia are affected and perhaps even the entire cortico-striato-thalamo-cortical circuit, as shown by very recent research using PET scans [5]. But in this case too, it all starts in the intestine.


Cocktail of risk factors

In our current Western society, the intestine has to cope with a cocktail of risk factors. Deregulation of the gut-microbiome-brain axis can occur as a result of ageing, brain trauma or auto-immunity. But mainly the interaction between external factors and the body’s internal intestinal environment plays a role: toxins and unfavourable microbes, viruses and bacteria in the food, the wrong diet, a lack of exercise, air pollution and, for example, passive smoking. Each of the foregoing harm our healthy flora and therefore undermine our health.


A certain genetic susceptibility also plays a role, but always in combination with the quality of the epigenetic environment. And this again is affected by the diet, exercise, stress, social contacts, dealing well with emotions and a whole range of other parameters which can be influenced without medicines.


Good treatment (and prevention) therefore always starts with the intestinal immune system. Even with (the early stages of) traditionally difficult to treat neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. Conclusion? If you want to tackle the actual cause of the cause, choose a psycho-neuro-immunological treatment.



[1] Meraz-Rios, Marco (August 2013). "Inflammatory process in Alzheimer's Disease". Frontiers in Integrative Neuroscience. 7.

[2] Tansey, Malu (May 2012). "Neuroinflammation and Non-motor Symptoms: The Dark Passenger of Parkinson's Disease?". Curr Neurol Neurosci Rep. 12: 350–358

[3] Madelyn C. Houser & Malú G. Tansey, The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? Nature PJ Parkinson's Disease 3, Article number: 3 (2017)

[4] Sophia Attwells, HBSc; Elaine Setiawan, PhD; Alan A. Wilson, PhD; et al., Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder, JAMA Psychiatry. 2017;74(8):833-840.

[5] McKay D, Sookman D, Neziroglu F, Wilhelm S, Stein DJ, Kyrios M, Matthews K, Veale D, Efficacy of cognitive-behavioral therapy for obsessive-compulsive disorder, Psychiatry Res. 2015 Feb 28;225(3):236-46.

[6] Tansey, Malu; Tamy C Frank-Cannon (November 2009). "Does neuroinflammation fan the flame in neurodegenerative diseases?". Molecular Neurodegeneration. 4: 47.