Science



What’s Driving Parkinson’s Disease? The Role of Chronic Gastrointestinal Infection.



In 1817, James Parkinson described the ‘shaking palsy’, characterized by slowness and poverty of movement (brady/hypokinesia), muscle stiffness (rigidity), and a stooped posture, as well as the distinctive tremor. Subsequent therapeutic milestones have been few and far between.

A team of researchers at King’s College London, Drs R John & Sylvia Dobbs (clinical neuropharmacologists/physicians), Dr Clive Weller (biomedical engineer) and André Charlett (statistician), together with Professor Ingvar Bjarnason (gastroenterologist) have published a comprehensive overview of their work on the role of infection in causing and propagating Parkinson’s Disease (PD). André Charlett is also Head of the Statistics Unit at the Health Protection Agency’s Centre for Infections.

Medical problems are often approached in an opinionated rather than an exploratory manner. For example, the constitutional nature of Parkinson’s Disease has been ignored as a basis for therapeutic intervention. Indeed, the dogma of a ‘cold’ neurodegeneration demands that constitutional illness is attributed to other causes, and has led to the a priori classification of PD as a non-communicable disease. In contrast, the team uses investigational medicine to yield clinical clues to elucidating processes and mechanisms, and pinpointing potential causal agents. Consequent observational and experimental studies provide raw data for a sound, statistically based, hypothesis. Assessment of parkinsonism by ‘global subjective scores’ is ubiquitous. (This is analogous to studying diabetes mellitus without measuring blood glucose.) We have pioneered the obvious methodological approach, for a multi-step, multi-factorial disease, of objective quantitative assessment of its individual facets. Traditional funding has favoured the laboratory-to-clinic approach of arbitrary selection of conjectured disease-producing mechanisms for detailed examination. It has been directed to patching up damage, rather than removing the (ongoing) cause.

Exploration led to an infection hypothesis, implicating the gut. The initial therapeutic target was colonization of the (usually almost sterile) small-intestine by bacteria from the large-intestine, as a result of sluggishness of the bowel. The immune system treats this as harmful. Constipation features even in James Parkinson’s essay. The team found that people with PD notice it, on average, three decades before the median age of neurological diagnosis. This finding is upheld prospectively by others, who showed an association of infrequent bowel movements and subsequent diagnosis of PD.

As a collateral hypothesis, the team described the epidemiological fit to PD of stomach infection with Helicobacter pylori, the bacterium causally related to peptic ulcer. They proposed an ‘autoimmune’ basis: that the organism evokes an immune response which is also directed against the host. The way to the Helicobacter causal hypothesis was paved, before the discovery of its association with gastric inflammation (1983), by observation of an excess of previously-documented peptic ulcer in PD (1965), and speculation that an infectious agent was involved in both (1979). By 2005, the team had proof-of-principle that infection contributes to PD, through case-studies of anti-Helicobacter therapy, and a formal hypothesis-testing trial of treatment. The benefit was irrespective of whether patients were receiving stable long-acting symptomatic treatment for PD, or had never been treated. Neither does improvement depend on the infection being florid. The review illustrates (in frames from serial videos) that walking can change from tentative, stilted, wooden and doll-like to relaxed free-flowing and, finally, vigorous, following eradication of infection detected only by finding the organism’s DNA in the stomach lining. However, the team stress that they are describing disease-modification, not cure. Nonetheless, the research programme is at the interface of disciplines, where further discoveries are more likely. The cause of a disease is, of course, no respecter of which medical discipline ‘owns’ it!

Some key background references