Effects of Resistant Starch on Symptoms, Fecal Markers, and Gut Microbiota in Parkinson's Disease - The RESISTA-PD Trial.

The composition of the gut microbiota is linked to multiple diseases, including Parkinson's disease (PD). Abundance of bacteria producing short-chain fatty acids (SCFAs) and fecal SCFA concentrations are reduced in PD. SCFAs exert various beneficial functions in humans. In the interventional, monocentric, open-label clinical trial "Effects of Resistant Starch on Bowel Habits, Short Chain Fatty Acids and Gut Microbiota in Parkinson'sDisease" (RESISTA-PD; ID: NCT02784145), we aimed at altering fecal SCFAs by an 8-week prebiotic intervention with resistant starch (RS). We enrolled 87 subjects in three study-arms: 32 PD patients received RS (PD + RS), 30 control subjects received RS, and 25 PD patients received solely dietary instructions. We performed paired-end 100 bp length metagenomic sequencing of fecal samples using the BGISEQ platform at an average of 9.9 GB. RS was well-tolerated. In the PD + RS group, fecal butyrate concentrations increased significantly, and fecal calprotectin concentrations dropped significantly after 8 weeks of RS intervention. Clinically, we observed a reduction in non-motor symptom load in the PD + RS group. The reference-based analysis of metagenomes highlighted stable alpha-diversity and beta-diversity across the three groups, including bacteria producing SCFAs. Reference-free analysis suggested punctual, yet pronounced differences in the metagenomic signature in the PD + RS group. RESISTA-PD highlights that a prebiotic treatment with RS is safe and well-tolerated in PD. The stable alpha-diversity and beta-diversity alongside altered fecal butyrate and calprotectin concentrations call for long-term studies, also investigating whether RS is able to modify the clinical course of PD.

Striatal dopamine transporters and cognitive function in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. METHODS: Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. RESULTS: In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. CONCLUSIONS: The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.

Gastric Motility in Parkinson's Disease is Altered Depending on the Digestive Phase and Does Not Correlate with Patient-Reported Motor Fluctuations.

BACKGROUND: Altered gastric motility is a frequent non-motor symptom of Parkinson's disease (PD). It has been hypothesized that disturbed gastric motility contributes to motor fluctuations in PD due to an erratic gastro-duodenal transport and an unpredictable absorption of drugs. OBJECTIVE: We investigated whether patient-reported fluctuations are associated with parameters of gastric motility visualized by real-time magnetic resonance imaging (MRI) of the stomach. METHODS: We analyzed real-time MRI-scans of the stomach after an overnight fasting period in 16 PD patients and 20 controls. MRI was performed 1) in the fasting state, 2) directly after a test meal, and 3) 4 hours postprandially. Gastric motility indices were calculated and compared between groups. RESULTS: MRI showed an attenuated gastric motility in PD patients compared to controls. The difference was most obvious in the early postprandial phase. Gastric motility was not associated with patient-reported motor fluctuations. Using an iron-containing capsule we were able to retrace retention of drugs in the stomach. CONCLUSION: The results of this study stress the importance of considering the phase of digestion when investigating gastric motility in PD. Despite theoretical considerations, we did not find robust evidence for an association between MRI parameters of gastric motility and patient-reported motor fluctuations. For future studies that aim to investigate gastric motility in PD by MRI, we suggest multiple short-time MRIs to better track the whole gastro-duodenal phase in PD. Such an approach would also allow to retrace the retention of drugs in the stomach as shown by our approach using an iron-containing capsule.

Third ventricular width assessed by transcranial ultrasound correlates with cognitive performance in Parkinson's disease.

INTRODUCTION: Cognitive impairment and dementia are common in PD; however, no stable marker of cognitive dysfunction is available. Transcranial sonography can evaluate global and focal brain atrophy and has been widely used in the differential diagnosis of parkinsonism. METHODS: 225 consecutive PD patients were recruited in a two-center cross sectional study and underwent a standardized sonographic protocol assessing the third ventricle's width and substantia nigra hyperechogenicity. All subjects were evaluated with an extensive motor and cognitive battery. RESULTS: 222 PD patients were included and classified as PD with normal cognition (PDNC; n = 130), mild cognitive impairment (PD-MCI; n = 61) and dementia (PDD; n = 31). Ventricular width correlated strongly with cognitive performance in all cognitive domains (p < 0.001) while SN size did not. PDD patients had significantly wider ventricles than PD patients without dementia (p < 0.001) while differences between PD-MCI and PDNC or PDD were less strong (p < 0.05). There were no group differences in SN size. ROC analyses resulted in age-related cut-offs of third ventricular diameter for the prediction of PDD (6.0 and 7.5 mm for subjects < and ≥70 years of age, respectively). These cut-offs significantly differentiated PDD from PDNC (p < 0.001) and from all patients without dementia (PDNC + PD-MCI; p < 0.001). CONCLUSIONS: The third ventricular diameter correlated with cognitive performance in all domains and was able to differentiate PDD patients from those without dementia. Longitudinal studies are warranted to evaluate whether transcranial sonography could identify PD patients at risk for a rapid cognitive decline.

MIBG scintigraphy of the major salivary glands in multiple system atrophy.

We applied MIBG scintigraphy to measure the sympathetic innervation of the major salivary glands in 28 patients with multiple system atrophy (MSA) and 15 controls. MIBG uptake did not differ significantly between MSA patients and controls. This normal MIBG uptake correlates with predominantly intact postganglionic sympathetic innervation in MSA.

Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease.

BACKGROUND/OBJECTIVE: Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD. METHODS: In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors. RESULTS: Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation. CONCLUSIONS: Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD.

Reduced MIBG accumulation of the parotid and submandibular glands in idiopathic Parkinson's disease.

INTRODUCTION: Alpha-synuclein pathology (ASP) is a characteristic histopathological finding in idiopathic Parkinson's disease (PD). The ASP involves not only the brain but also extracranial structures. In the present study we utilized MIBG scintigraphy to measure the sympathetic innervation of the major salivary glands. We were interested in whether MIBG uptake in the major salivary glands represents a potential biomarker for ASP in PD. METHODS: We investigated 77 PD patients (age 61 ± 10 years, mean ± SD), while 15 non-PD patients (age 58 ± 15 years) with arterial hypertension, who underwent MIBG scintigraphy to exclude pheochromocytoma, served as age-matched controls. The MIBG uptake of the parotid glands and the submandibular glands was quantified by means of a region of interest technique. The sublingual glands were too small for an exact measurement. We applied Generalized Estimating Equations (GEE) to identify and remove factors which may bias the statistical correlation analysis. RESULTS: The PD patients showed a significantly lower MIBG uptake in the parotid and submandibular glands than the controls (p < 0.0001). MIBG uptake in the PD patients did not correlate with clinical severity (Hoehn and Yahr stage, motor part of the UPDRS) or disease duration. CONCLUSION: MIBG uptake in the parotid and submandibular glands might be a candidate biomarker for PD. The missing correlation between MIBG uptake and clinical PD parameters suggests that ASP of the extracranial sympathetic superior cervical ganglion, which innervates the major salivary glands, develops independently from the cerebral dopaminergic nigrostriatal ASP.

Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls.

BACKGROUND: Patients with Parkinson's disease (PD) frequently have gastrointestinal symptoms (e.g. constipation) and exhibit the PD-typical pathohistology in the enteric nervous system (ENS). Both, clinical symptoms and pathohistological changes in the ENS occur at early stages and can precede the motor manifestations of PD. Two recent studies reported an association between changes in gut microbiota composition and PD. We hypothesized that alterations in gut microbiota might be accompanied by altered concentrations of short chain fatty acids (SCFA), one main metabolic product of gut bacteria. METHODS: We quantitatively analyzed SCFA concentrations (using gas chromatography) and microbiota composition (using quantitative PCR) in fecal samples of 34 PD patients and 34 age-matched controls. RESULTS: Fecal SCFA concentrations were significantly reduced in PD patients compared to controls. The bacterial phylum Bacteroidetes and the bacterial family Prevotellaceae were reduced, Enterobacteriaceae were more abundant in fecal samples from PD patients compared to matched controls. CONCLUSIONS: Our study confirms the recently reported association between PD and the abundance of certain gut microbiota and shows a reduction in fecal SCFA concentrations (one main metabolic product of certain gut bacteria). The reduction in SCFA might, theoretically, induce alterations in the ENS and contribute to gastrointestinal dysmotility in PD. Prospective longitudinal studies in subjects at risk for PD are required to further elucidate the causal role of gut microbiota and microbial products in the development of PD and PD-associated dysmotility.

Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease.

We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.

Performance of repetitive alternating elbow movements in Parkinson's disease.

BACKGROUND: Bradydiadochokinesia is one main clinical symptom in idiopathic Parkinson's disease (IPD). The pathogenesis of bradydiadochokinesia is not completely clear. METHODS: Fifteen patients with IPD and 15 age-matched healthy volunteers had to perform rhythmic alternating flexion and extension movements in the elbow joint. The rhythm was provided auditorily by a click tone stimulator. Six maneuvers (spatial extents of 48 and 83° at frequencies of 0.45, 0.75 and 1.25 Hz) had to be absolved. The potentiometer converted the horizontal forearm movements into a variable voltage. RESULTS: The duration of single movements varied more significantly in patients than in controls (p < 0.05; Mann-Whitney U test). Patients executed all conditions more slowly than controls, but this difference was only significant at the most difficult condition (83° at 1.25 Hz; p < 0.01). The movement amplitudes or their variability were not significantly different at any condition. No parameter correlated significantly with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) or with the duration of disease. CONCLUSION: An insufficient temporal coordination contributes to bradydiadochokinesia in IPD. This deficit occurs independently of other parkinsonian cardinal motor symptoms.

Principal Component Analysis of gait in Parkinson's disease: relevance of gait velocity.

Principal Component Analysis (PCA) is a method to estimate the relation between data points. We used PCA to analyse movements of the upper and lower extremities during treadmill walking in healthy subjects and two groups of Parkinsonian patients. Healthy subjects (n=35) showed a typical pattern with high values of PC1 and low values in a descending order of PC2-PC4. Increase of speed resulted in a significant increase of PC1 and a significant decrease of the following PC's. In more severely affected patients (n=19, UPDRS>20), PC1 was significantly decreased and PC2-PC4 were significantly increased compared to healthy subjects. Speed could be increased only within a small range without corresponding changes of the PC's. In less severely affected patients (n=17), significant differences of the PC's were only found with fast pace. Separate analysis of arms and legs revealed that these changes are only due to altered movements of the arm. Analysis of the pattern of PC's in response to changes of gait velocities reveal alterations even in less severely affected Parkinsonian patients. The changes of the PC's with higher gait velocities in healthy subjects are suggestive of an increase of intersegmental coordination. This is impaired even in less severely affected Parkinsonian patients.

Is reduced myocardial sympathetic innervation associated with clinical symptoms of autonomic impairment in idiopathic Parkinson's disease?

Patients with idiopathic Parkinson's disease (IPD) have a reduced myocardial MIBG uptake in MIBG scintigraphy, indicating myocardial sympathetic denervation. We were interested whether this myocardial sympathetic denervation coincides with clinical symptoms of autonomic impairment in IPD patients. We performed MIBG scintigraphy, the SCOPA-AUT scale, a standardized medical history (developed in our clinic) and autonomic nervous system testing in 47 IPD patients (21 female, 26 male patients). We correlated myocardial MIBG uptake with the results of the SCOPA-AUT scale, the standardized medical history and the autonomic nervous system testing through the use of Spearman's correlation. Myocardial MIBG uptake correlated significantly (p < 0.05) with several items of the SCOPA-AUT scale (in female patients: perspiration during the night, in male patients: sum score, saliva dribbling of the mouth, difficulty swallowing, fainting, constipation), of the standardized medical history (in male patients: swollen ankles) and of the autonomic nervous system testing (all patients: sum score, Ewing orthostasis test). Remarkably, we found more significant correlations in male than in female patients. Reduced myocardial sympathetic innervation-as revealed by MIBG scintigraphy-is associated with clinical symptoms of autonomic impairment. This association is more pronounced in male than in female patients. The cause for this gender-specific phenomenon is unclear.

Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease.

The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SN(contra)) was compared to myocardial (123)I-MIBG uptake. SN(contra) did not correlate with the myocardial MIBG uptake (r = -0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = -0.03; p = 0.87 and r = -0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD.

Long-term course of substantia nigra hyperechogenicity in Parkinson's disease.

A hyperechogenicity of the (SN+) in transcranial sonography corroborates the diagnosis of idiopathic Parkinson's disease (iPD). Although it is thought to represent a biomarker of the disease that is independent of disease severity and progression, differing results have been reported describing a positive correlation of the size and advancing clinical stage. In 50 parkinsonian patients, transcranial ultrasound and clinical examination was performed twice with a mean time interval of 6.4 years. SN+ did not change in size significantly between the first and second examination, whereas clinical parkinsonian symptoms--as determined by the motor part of the UPDRS--significantly worsened (P < 0.001). We found a highly significant intraindividual correlation in SN+ sizes between both examinations (P < 0.001). The size of SN+ did not correlate with the UPDRS part III at the time of first or second ultrasound examination. Progression of motor symptoms between the first and second investigation did not correlate with the size of SN+ at baseline. Furthermore, even in the subgroup of patients with an interval of ≥ 8 years between examinations, there was no significant change in SN+ size. SN+ represents a largely stable biomarker in iPD and does not reflect disease progression. The size of SN+ does not predict the further course of the disease.

Response of Toll-like receptors in experimental Guillain-Barré syndrome: a kinetic analysis.

Guillain-Barré syndrome (GBS) is an autoimmune disorder caused by the interaction between cellular and humoral immune responses in the peripheral nervous system. Toll-like receptors (TLRs) are key players in innate and have regulatory functions in adaptive immunity. In this study, we systematically examined expression patterns of TLRs in sciatic nerve and lymphoid organs during the disease course of murine experimental autoimmune neuritis and in blood from Guillain-Barré patients. A kinetic response pattern was identified, characterized by a pronounced up-regulation of TLR2, 6 and 11 on T cells and TLR4 and 6 on APCs, while TLR1 expression was decreased. Moreover, an enhanced expression of the disease promoting cytokine Interleukin-(IL)17A was detected. Additional analysis of GBS patients revealed an up-regulation of TLR2, TLR4 and TLR6 mRNA, negatively correlated with disease severity. This first systematic analysis of TLR expression pattern may contribute to elucidating the role of TLRs in GBS pathophysiology.

Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons.

OBJECTIVE: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN: Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS: Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE: Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS: There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS: In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Myocardial MIBG scintigraphy may predict the course of motor symptoms in Parkinson's disease.

BACKGROUND: The metaiodobenzylguanidine (MIBG) scintigraphy is a well established nuclear medicine method to support the clinical diagnosis of Parkinson's disease. In this study we examined the predictive value of the MIBG scintigraphy concerning the severity and progression of the parkinsonian motor symptoms. PATIENTS AND METHODS: This study included 40 patients with idiopathic Parkinson's disease (age 56 ± 9 years, Hoehn and Yahr stage 1.4 ± 0.7, mean ± standard deviation). All patients underwent a baseline visit and a follow-up visit 3-8 years (5.3 ± 1.6 years) after the baseline visit. (123)I-MIBG scintigraphy was performed only once at the baseline visit. At both visits the motor symptoms bradykinesia, rigidity, resting tremor, postural tremor and axial symptoms were quantified by means of the motor part of the Unified Parkinson's disease rating scale. RESULTS: The myocardial MIBG uptake correlated significantly with the annual progress of rigidity (r=-0.41, p<0.05; Pearson's correlation) and axial symptoms (r=-0.49, p<0.01). There was no significant correlation (p>0.05) between the initial myocardial MIBG uptake and the annual progress of the other motor symptoms. CONCLUSION: The MIBG scintigraphy may predict the velocity of progress of rigidity and axial symptoms in the following 3-8 years. Such a prediction is not possible for the other motor symptoms resting tremor, postural tremor and bradykinesia.

Doxepin concentrations in plasma and cerebrospinal fluid.

Doxepin--like other antidepressant drugs (ADs)--shows a variable antidepressant effect in clinical practice. The cause for this variability is as yet unclear; however, pharmacokinetic factors such as the variable permeability of doxepin into the cerebrospinal fluid (CSF), may contribute to the difference in therapeutic efficacy. We measured and correlated the concentration of doxepin and its active metabolite nordoxepin in both the plasma and CSF. Plasma and CSF samples were taken simultaneously from 21 patients who were treated with doxepin due to different clinical indications. The plasma concentration of both doxepin and nordoxepin correlated significantly with the oral dosage of doxepin (doxepin: r = +0.66, p < 0.001; nordoxepin: r = +0.78, p < 0.0001; Spearman's correlation). Furthermore, we found significant correlations between the plasma and CSF concentrations of both doxepin (r = +0.71; p < 0.001; Pearson's correlation) and nordoxepin (r = +0.74; p < 0.001). These highly significant correlations between the plasma and CSF concentrations indicate a constant CSF permeability of doxepin and its active metabolite nordoxepin.