Filip Scheperjans

Linking Smoking, Coffee, Urate, and Parkinson’s Disease – A Role for Gut Microbiota?

While the etiology and pathogenesis of Parkinsons disease (PD) is still obscure, there is evidence for lifestyle factors influencing disease risk. Best established are the inverse associations with smoking and coffee consumption. In other contexts there is evidence that health effects of lifestyle factors may depend on gut microbiome composition. Considering the gastrointestinal involvement in PD, it was recently speculated, that the associations between smoking, coffee, and PD risk could be mediated by gut microbiota. Here we review such a possible mediatory role of gut microbiota taking into account recent findings on microbiome composition in PD and extending the scope also to urate.

More than constipation – bowel symptoms in Parkinson's disease and their connection to gut microbiota

The majority of Parkinsons disease (PD) patients suffer from gastrointestinal symptoms of which constipation is considered the most prominent. Recently, in addition to constipation, a diagnosis of irritable bowel syndrome (IBS) was also found to be associated with increased PD risk. Gut microbiota alterations have been reported in IBS and recently also in PD. IBS‐like bowel symptoms in PD and their possible connection to other non‐motor symptoms and faecal microbiota were assessed.

The prodromal microbiome

In human microbiome research, reproducibility is crucial because the microbial ecosystem is heavily influenced by environmental factors and highly variable between individuals. This poses challenges when designing such studies and recruiting suitable subjects. Furthermore, the employed methodology of data acquisition and analysis can be highly customized, and differences in the work flow may introduce biases and hamper comparisons between studies. In the last 2 years, the gut microbiome has gained increasing attention in the Parkinson’s disease research community because of its possible implication in the prominent gastrointestinal disturbances frequently present from the earliest stages of PD and the ascension hypothesis of PD-related neuropathology. So far, 9 original publications have reported gut microbiota alterations in PD. As could be expected, the subject selection criteria, laboratory protocols, and bioinformatical and statistical pipelines differed considerably between studies. Sample size ranged from 38 to 327 subjects. Most studies used 16S ribosomal RNA amplicon sequencing to assess the community structure of the gut microbiota, whereas 2 studies relied on qPCR analysis of preselected bacterial taxa. These approaches are relatively cost effective and allow a description of differences in the relative abundances of bacterial taxa between study groups (ie, the community structure). Despite the above-mentioned limitations and considerable differences in their methodology and results, it is encouraging that the abovementioned studies showed clear overlaps with respect to the bacterial taxa differentially abundant between PD patients and control subjects. Increased abundance of Akkermansia and Lactobacillus and decreased abundance of Prevotella in PD subjects were reported in 5 studies. Other reproducible findings were reduced abundance of Faecalibacterium (4 studies) and Blautia (3 studies) and increased abundance of Bifidobacterium (3 studies) in PD. So by now, that the gut microbial community structures of PD patients and controls differ seems to be reasonably well established, with several bacterial genera showing consistent abundance alterations in multiple studies. However, it was not known whether these alterations precede the development of PD or whether they are rather a consequence of a dysfunctional gut associated with PD. In this issue of Movement Disorders, HeintzBuschart et al add an important piece of evidence to the field by demonstrating that indeed gut microbiome alterations may precede the motor symptoms of PD. In addition to patients with established PD, they studied a group of subjects suffering from a well-defined prodromal syndrome of PD, namely, rapid eye movement sleep behavior disorder (RBD). Because RBD is associated with an up to 90% risk of developing a neurodegenerative disorder later on (mostly synucleinopathies), it is considered a promising criterion for selection of patients for premotor trials of diseasemodifying treatments. In their study, Heintz-Buschart et al employed stateof-the-art analytical pipelines to assess microbiome community structure in nasal and fecal samples and aimed to account for potential confounders such as constipation and medications. The rationale for the analysis of nasal microbiota was that, like the gastrointestinal tract, the nasal cavity has been suggested to constitute a port of entry for a possible pathogenic agent. For the first time, in this study, nasal microbial communities were directly compared with fecal communities. As has been previously described, the nasal bacterial community was sparse and showed high interindividual variation. Operational taxonomic units (OTUs) common to the nasal and gastrointestinal microbiota were found, likely attributable to nasal discharge being swallowed. However, none of these OTUs differed significantly between study groups. -----------------------------------------------------------*Correspondence to: Filip Scheperjans, Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland; filip.scheperjans@hus.fi

Hypoperfusion of an Entire Cerebral Hemisphere – Stroke or Postictal Deficit

The clinical differential diagnosis between ischemic stroke and postictal deficit is sometimes challenging. If the clinical presentation is inconclusive, perfusion imaging can help to identify stroke patients for thrombolysis therapy. However, also epileptic phenomena may alter cerebral perfusion. Hypoperfusion spreading beyond the borders of cerebrovascular territories is usually considered suggestive of an etiology other than stroke. We present a patient whose clinical symptoms suggested a postictal deficit rather than an acute stroke. CT perfusion imaging showed hypoperfusion of the entire left cerebral hemisphere covering all vascular territories. CT angiography revealed occlusions in the ipsilateral internal carotid artery and in the circle of Willis as the cause of the global hypoperfusion. The patient was treated with i.v. thrombolysis and recovered with moderate disability. This is the first description of hyperacute ischemia of an entire cerebral hemisphere and its treatment with thrombolysis. It demonstrates the potential of modern neuroimaging in identifying atypically presenting strokes and shows that i.v. thrombolysis can be effectively and safely used to treat such potentially fatal insults.

Emergency computed tomography in patients with first seizure

PURPOSE To determine the frequency of emergent imaging findings on head computed tomography (CT) in an adult population of first seizure (FS) patients presenting to an emergency department (ED); and to search for associations between clinical features and emergent imaging findings among these patients. METHODS For this retrospective registry-based study, adult FS patients presenting to Helsinki University Hospital ED in 2006 were identified based on ICD-10 diagnosis. Clinical parameters were extracted from patient records. A neuroradiologist blinded to clinical information reviewed the CT scans for emergent imaging findings prompting changes in acute treatment, predefined as intracranial haemorrhage, acute ischemia, central nervous system infection, mass effect, midline shift, obstructive hydrocephalus and/or brain oedema. RESULTS 449 FS patients were identified, of which 416 (93%) had undergone emergency CT imaging. Of these, 49 (12%) had emergent imaging findings on non-contrast CT. Logistic regression suggested that headache (odds ratio (OR) 3.62, 95% confidence interval (CI) 1.30-10.12), focal motor sign in the ED (OR 3.23, 95% CI 1.58-6.62), history of malignancy (OR 3.05, 95% CI 1.17-7.92), and altered mental state in the ED (OR 2.27, 95% CI 1.15-4.49) were associated with emergent imaging findings on NCCT. Presence of at least one of these factors had 84% sensitivity for emergent imaging findings. CONCLUSION In FS patients, clinical information can be used to guide imaging decisions in the ED. However, if emergency imaging is not performed, urgent outpatient imaging and pre-imaging follow up should be secured.

Motor outcome and electrode location in deep brain stimulation in Parkinson's disease

To evaluate the efficacy and adverse effects of subthalamic deep brain stimulation (STN‐DBS) in patients with advanced Parkinsons disease (PD) and the possible correlation between electrode location and clinical outcome.

Reply to letter to the editor by Assoc. Prof. Yusuf Ozgur Cakmak, MD, PhD

A recent article by Scheperjans et al. reported that the gut microbiome is altered in Parkinson’s disease (PD) patients. In their detailed analysis, Provotella was found to be decreased in PD patients. The researchers explained that the negative effect of a reduced Provotella population on PD is owing to decreased levels of health-promoting neuroactive short-chain fatty acids and vitamins, such as thiamine and folate, which are synthesized with the aid of Provotella. However, the researchers failed to note a much stronger link between Provotella and the protection of dopaminergic neurons in PD: hydrogen sulfide. Hydrogen sulfide is a gaseous gut neurotransmitter that is secreted by Provotella and that exerts a protective effect on dopaminergic neurons in rat PD models. In the case of a reduced Provotella population, both the increase in gut permeability and constipation symptoms of PD can be explained by altered hydrogen sulfide levels. In the case of a reduced Provotella population in PD patients, it can be assumed that hydrogen sulfide levels are decreased and that the human body may lose the ability to initiate neuroprotective mechanisms in response to hydrogen sulfide. As the researchers stated, it has been shown that the Provotella abundance is positively associated with gut permeability. Moreover, the researchers reported that increased gut permeability may lead to local and systemic exposure to bacterial endotoxins. Considering that hydrogen sulfide is a gaseous neurotransmitter that exerts protective effects on dopaminergic neurons, it may be theorized that the human body increases gut permeability to enhance the benefits of a decreased level of gut hydrogen sulfide under the conditions of a reduced Provotella population. Additionally, in PD patients, constipation is one of the first signs of disease. Constipation may represent a conjoint mechanism underlying the increase in gut permeability to increase hydrogen sulfide absorption. In conclusion, considering the decreased levels of hydrogen sulfide in the PD patient gut in combination with the data showing increased gut permeability and constipation in PD patients and the neuroprotective effects of hydrogen sulfide on dopaminergic neurons in rat PD models, hydrogen sulfide may act as a sole or contributing factor with vitamins and short-chain fatty acids to mediate the mechanisms underlying the link between the reduction in the Provotella population and PD.