Fecal Calprotectin in Parkinson's Disease and Multiple System Atrophy.

Faecal intestinal permeability and intestinal inflammatory markers in older adults with age-related disorders: A systematic review and meta-analysis

Parkinson’s disease (PD) is characterized by alpha-synuclein misfolding with subsequent intraneuronal amyloid formation and accumulation, low grade neuroinflammatory changes, and selective neurodegeneration. Available evidence suggests that the pathology usually begins in the gut and olfactory mucosa, spreading to the brain via the vagus and olfactory nerves, by a prion-like mechanism. A causal relationship has not been established, but gut dysbiosis is prevalent in PD and may lead to intestinal inflammation and barrier dysfunction. Additionally, epidemiological data indicate a link between inflammatory bowel diseases and PD. Calprotectin and zonulin are markers of intestinal inflammation and barrier permeability, respectively. We evaluated their serum and fecal levels in 22 patients with sporadic PD and 16 unmatched healthy controls. Mean calprotectin was higher in PD, both in serum (14.26 mcg/ml ± 4.50 vs. 5.94 mcg/ml ± 3.80, p = 0.0125) and stool (164.54 mcg/g ± 54.19 vs. 56.19 mcg/g ± 35.88, p = 0.0048). Mean zonulin was also higher in PD serum (26.69 ng/ml ± 3.55 vs. 19.43 ng/ml ± 2.56, p = 0.0046) and stool (100.19 ng/ml ± 28.25 vs. 37.3 ng/ml ± 13.26, p = 0.0012). Calprotectin was above the upper reference limit in 19 PD serums and 6 controls (OR = 10.56, 95% CI = 2.17–51.42, p = 0.0025) and in 20 PD stool samples and 4 controls (OR = 30, 95% CI = 4.75–189.30, p = 0.000045). Increased zonulin was found only in the stool samples of 8 PD patients. Despite the small sample size, our findings are robust, complementing and supporting other recently published results. The relation between serum and fecal calprotectin and zonulin levels and sporadic PD warrants further investigation in larger cohorts.

Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers.

MicroRNAs are reportedly involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy. We previously identified 7 differentially expressed microRNAs in Parkinson's disease patients and control sera (miR-30c, miR-31, miR-141, miR-146b-5p, miR-181c, miR-214, and miR-193a-3p). To investigate the expression levels of the 7 serum microRNAs in Parkinson's disease and multiple system atrophy, 23 early Parkinson's disease patients (who did not take any anti- Parkinson's disease drugs), 23 multiple system atrophy patients, and 24 normal controls were recruited at outpatient visits in this study. The expression levels of the 7 microRNAs in serum were detected using quantitative real-time polymerase chain reaction. A receiver operating characteristic curve was used to evaluate whether microRNAs can differentially diagnose Parkinson's disease and multiple system atrophy. Clinical scales were used to analyze the correlations between serum microRNAs and clinical features. The results indicated that miR-214 could distinguish Parkinson's disease from the controls, and another 3 microRNAs could differentiate multiple system atrophy from the controls (miR-141, miR-193a-3p, and miR-30c). The expression of miR-31, miR-141, miR-181c, miR-193a-3p, and miR-214 were lower in multiple system atrophy than in Parkinson's disease (all P < 0.05). Combinations of microRNAs accurately discriminated Parkinson's disease from multiple system atrophy (area under the receiver operating characteristic curve = 0.951). For the correlation analysis, negative correlations were discovered between the expression of miR-214 and the Hamilton Anxiety Scale and Parkinson's Disease Non-Motor Symptom scores (all P < 0.05). Our results demonstrate that the distinctive characteristics of microRNAs differentiate Parkinson's disease and multiple system atrophy patients from healthy controls and may be used for the early diagnosis of Parkinson's disease and multiple system atrophy.

Faecal calprotectin and IgA have been suggested as non-invasive markers of gut health. Faecal calprotectin is a marker of intestinal inflammation in adults, whereas IgA has been suggested as a marker of intestinal immunity. The purpose of the present study was to evaluate the effect of gestation, lactation and age on faecal concentrations of these biomarkers. Thirty puppies, nineteen pregnant or lactating bitches and eighty-nine healthy control adult dogs were included in the study. Faeces were collected from the fourth week of gestation until the eighth week of lactation in pregnant and lactating bitches, and between 4 and 9 weeks of age in puppies. Faeces from the eighty-nine healthy control adult dogs were also collected. Faecal calprotectin and IgA concentrations were measured. Faecal calprotectin concentrations in control dogs were significantly lower than faecal calprotectin concentrations in puppies between 4 and 6 weeks of age (P<0·001) or between 7 and 9 weeks of age (P=0·004). Puppies between 4 and 6 weeks of age had significantly higher faecal IgA concentrations compared with puppies between 7 and 9 weeks of age (P=0·001). Bitches during their second month of lactation had significantly lower faecal IgA concentrations compared with their first month of lactation (P=0·049). Faecal calprotectin and IgA have been suggested as non-invasive and easily measured biomarkers of gut health in adults. However, the present study underlines that faecal IgA and calprotectin concentrations vary markedly depending of physiologic factors such as gestation, lactation and age. These factors need to be considered when these faecal biomarkers are used for evaluation of intestinal immunity or inflammation.

A Quantitative Analysis of NSAID-Induced Small Bowel Pathology by Capsule Enteroscopy

Background: Fecal calprotectin (FC) has become a promising noninvasive indicator for identifying intestinal inflammation in inflammatory bowel diseases (IBD). Nevertheless, the accuracy of FC as a diagnostic tool, especially within the context of an endoscopy clinic in Sana'a, Yemen, has not been thoroughly investigated. Aim: To assess the level of fecal calprotectin as a marker for intestinal inflammation in the Sana'a population of IBD at endoscopic clinics. Methods: A hospital-based, cross-sectional study was done from January 2022 to March 2024. Patients with suspected or known IBD who were undergoing gastrointestinal endoscopy were included in the study. Stool samples were gathered from patients before undergoing colonoscopy, and FC levels were assessed through enzyme-linked immunosorbent assays (ELISAs). Colonoscopic and histological results were obtained to establish a correlation with FC levels. Statistical analysis was conducted to evaluate diagnostic accuracy. Results: A total of 165 patients, with 78.2% being male and 21.8% female, and the mean age was 41.3 years. Among the patients, 59 (35.8%) who tested positive for FC displayed intestinal inflammation related to IBD, while 67 (40.6%) who tested negative for FC also showed signs of intestinal inflammation in IBD. FC demonstrated a diagnostic precision of 1.3 for predicting IBD, although this finding was non-significant, p &gt; .05. The sensitivity measured at 46.8% and specificity at 46.2%. Conclusion: FC does not serve as a reliable marker for diagnosing intestinal inflammation in individuals with IBD. Logistic regression indicated that FC was a non-significant predictor for IBD, and the area under the curve (AUC) was 0.535, signifying poor discrimination ability..

This study was designed to assess the role of fecal lactoferrin and calprotectin as markers of intestinal inflammation in patients with Crohn's disease who have undergone ileocolonic resection. Sixty-three patients who had undergone ileocolonic resection for Crohn's disease with a median follow-up of 40.5 (range, 5-102) months were enrolled. Clinical examination and blood test were performed, and fecal lactoferrin and calprotectin levels were dosed. The predictors for fecal lactoferrin and calprotectin levels that resulted to be significant at the univariate analyses were included in two multiple regression analysis models. The mean lactoferrin level was 21 +/- 3.9 microg/g and the mean calprotectin fecal level was 247 +/- 22.7 ng/ml. C-reactive protein levels (P < 0.01), calprotectin levels (P < 0.01), and the presence of clinical recurrence (P = 0.04) resulted to be independent predictors of lactoferrin levels. Only lactoferrin levels resulted to be an independent predictor for calprotectin fecal levels (P < 0.01). Crohn's disease patients maintain high fecal levels of lactoferrin and calprotectin at long-term follow-up after resection of the diseased bowel even in case of clinical remission. The significant correlation between the two fecal markers may be the expression of the ongoing intestinal inflammation. Only lactoferrin significantly correlated with C-reactive protein and showed a reliable threshold value for systemic inflammation. Lactoferrin fecal levels may be a reliable indicator for intestinal inflammation influencing the systemic inflammatory status. The third predictor of lactoferrin fecal level was the presence of episodes of clinical recurrence during the postoperative follow-up.

JOURNAL/nrgr/04.03/01300535-202512000-00025/figure1/v/2025-01-31T122243Z/r/image-tiff In clinical specialties focusing on neurological disorders, there is a need for comprehensive and integrated non-invasive, sensitive, and specific testing methods. Both Parkinson's disease and multiple system atrophy are classified as α-synucleinopathies, characterized by abnormal accumulation of α-synuclein protein, which provides a shared pathological background for their comparative study. In addition, both Parkinson's disease and multiple system atrophy involve neuronal death, a process that may release circulating cell-free DNA (cfDNA) into the bloodstream, leading to specific alterations. This premise formed the basis for investigating cell-free DNA as a potential biomarker. Cell-free DNA has garnered attention for its potential pathological significance, yet its characteristics in the context of Parkinson's disease and multiple system atrophy are not fully understood. This study investigated the total concentration, nonapoptotic level, integrity, and cell-free DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants, comprising 76 normal controls, 62 patients with Parkinson's disease, and 33 patients with multiple system atrophy. In our cohort, 75.8% of patients with Parkinson's disease (stage 1-2 of Hoehn & Yahr) and 60.6% of patients with multiple system atrophy (disease duration less than 3 years) were in the early stages. The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic (ROC) analysis, and their association with disease prevalence was examined through logistic regression models, adjusting for confounders such as age, sex, body mass index, and education level. The results showed that cell-free DNA integrity was significantly elevated in both Parkinson's disease and multiple system atrophy patients compared with normal controls ( P < 0.001 for both groups), whereas cell-free DNA relative telomere length was markedly shorter ( P = 0.003 for Parkinson's disease and P = 0.010 for multiple system atrophy). Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson's disease and multiple system atrophy from normal controls. Specifically, higher cell-free DNA integrity was associated with increased risk of Parkinson's disease (odds ratio [OR]: 5.72; 95% confidence interval [CI]: 1.54-24.19) and multiple system atrophy (OR: 10.10; 95% CI: 1.55-122.98). Conversely, longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson's disease (OR: 0.16; 95% CI: 0.04-0.54) and multiple system atrophy (OR: 0.10; 95% CI: 0.01-0.57). These findings suggest that cell-free DNA integrity and cell-free DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson's disease and multiple system atrophy, potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders.

While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.

Parkinson's disease is associated with gastrointestinal (GI) dysfunction, including constipation symptoms and abnormal intestinal permeability and inflammation. A Mediterranean diet (MediDiet) may aid in disease management. This parallel, randomized, controlled trial in people with Parkinson's (PwP) and constipation symptoms compared a MediDiet against standard of care on change in constipation symptoms, dietary intake, and fecal zonulin and calprotectin concentrations as markers of intestinal permeability and inflammation, respectively. Participants were randomized to either standard of care for constipation (control; n = 17, 65.1 ± 2.2 years) or a MediDiet plus standard of care (n = 19, 68.8 ± 1.4 years) for 8 weeks. Constipation scores decreased with both interventions (p < 0.01), but changes from baseline were not different between groups (MediDiet, -0.5 [-1.0, 0]; control, -0.8 [-1.0, 0.2]; median [25th, 75th]; p = 0.60). The MediDiet group had a higher intake of dietary fiber at week 4 than the control group (13.1 ± 0.7 g/1000 kcal vs. 9.8 ± 0.7 g/1000 kcal; p < 0.001). No differences in fecal zonulin were observed between groups (p = 0.33); however, fecal calprotectin tended to be lower in the MediDiet group at week 8 (45.8 ± 15.1 µg/g vs. 93.9 ± 26.8 µg/g; p = 0.05). The MediDiet and standard interventions reduced constipation symptoms; however, the MediDiet provided additional benefit of increased dietary fiber intake and less intestinal inflammation.

Multiple system atrophy (MSA) is a rare, rapidly-progressive neurodegenerative disorder, neuropathologically characterized by oligodendroglial α-synuclein aggregates.1 While in Parkinson's disease (PD), a neuronal α-synucleinopathy, both monogenic forms and a polygenic risk profile are known,2 MSA is generally considered a sporadic disorder.1 A family history (FH) for parkinsonism or other neurodegenerative disorders may in fact occur in people with MSA, but the contribution of genetic factors to MSA pathogenesis is not fully understood to date.3, 4 Here we retrospectively assessed the frequency rates of FH for parkinsonism, dementia, tremor, ataxia, or motor neuron disease within first-to-third-degree relatives of people included in the Innsbruck MSA Registry (n = 144), and compared them with historical MSA cohorts (cumulative n = 1173), Innsbruck-based PD cases (n = 226), and published population-based controls (cumulative n = 20,784). A detailed methodological description is provided in Supplementary Document 1. Forty-five MSA cases (40%) had a positive FH for neurodegenerative disorders, with parkinsonism being most prevalent (n = 26, 18%). FH rates mostly matched or exceeded those of historical MSA cohorts (Fig. 1A). The cumulative first-to-third-degree FH rates for neurodegenerative disorders and familial clustering (ie, ≥2 affected relatives) remained comparable between the MSA and PD cohort (Fig. 1B). Compared to pooled population-based controls, first-degree FH rates for dementia were significantly lower in both the MSA and PD cohorts, whereas the rate of first-degree FH for parkinsonism in MSA cases (10%, 95% CI 6–17) was between that of PD (17%, 95% CI 13–23; P = 0.079) and population-based controls (6%, 95% CI 5–6; P = 0.012; Fig. 1C and Supplementary Document 2). The ultimate mechanisms underlying MSA pathogenesis remain largely unknown.1, 5 The high frequency of FH for parkinsonism in people with MSA, close to that of PD and exceeding the one observed in population-based elderly controls, supports the contention that multiple, yet unidentified genetic variants might contribute to MSA pathogenesis. It also suggests a shared genetic susceptibility to the development of MSA and PD. Our study has limitations. FH history was collected retrospectively, carrying the risk for a documentation bias, and with the FH method, which obtains information on FH exclusively from patients and may both under- and overestimate FH rates.6 In the age of genomic medicine, however, FH still represents a valuable tool to assess the heritability of a given disorder, especially if genetic methods fail to disclose a causal relation. Non-neurodegenerative causes of tremor, dementia, or parkinsonism were also not systematically excluded in the relatives of our patients; genetic testing was available in a small percentage of patients only; and neuropathological confirmation in none. We also did not include an age- and sex-matched control group, but compared our data with the cumulative results of historical MSA cohorts and large population-based studies in aging individuals. Similar to PD, genetic susceptibility variants — if discovered for MSA — may be exploited for identifying persons at risk of developing the disease or in very early stages thereof, when putative neuroprotective strategies should ideally be most effective.7 Understanding the genetic underpinnings of the MSA pathological cascade might ultimately point out new therapeutic targets for this currently untreatable condition. Academic study without external funding. Dr Leys was supported by the Stichting ParkinsonFonds, US MSA Coalition and Dr Johannes & Hertha Tuba Foundation. Due to its retrospective nature and initiation before July 2020, neither written informed consent nor ethic approval was required for the present study. This study was conducted in accordance with the Declaration of Helsinki and the current European Data Protection Regulation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The first and last named authors take full responsibility for the integrity of the data and the accuracy of the data analysis. The data supporting the findings of this study are available upon reasonable request from any qualified investigator. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. F.L.: 1B, 1C, 2B, 3A S.E.: 1C, 2C, 3B N.C.: 1C, 2C, 3B P.M.: 1A, 1C, 2C, 3B M.P.: 1C, 2C, 3B G.G.: 1A, 2A, 2C, 3B V.S.: 1A, 2C, 3B R.G.: 1A, 2C, 3B V.B.: 1A, 2C, 3B J.Z.: 1A, 2C, 3B S.K.: 1A, 2C, 3B W.P.: 1A, 2C, 3B K.S.: 1A, 2C, 3B G.K.W.: 1A, 2C, 3B A.F.: 1A, 1B, 1C, 2A, 2C, 3B F.L., S.E., N.C., P.M., M.P., G.G., V.S., R.G.: none. V.B.: receives research grants from the Stichting ParkinsonFonds and from Alzheimer Nederland (The Netherlands); honoraria from the International Parkinson and Movement Disorder Society, as Chair of the Congress Scientific Program Committee 2019–2021; and from Elsevier Ltd, as Co-Editor-in-Chief of Parkinsonism & Related Disorders, outside of the submitted work. J.Z.: none. S.K.: reports support from the Austrian Research Promotion Agency FFG, outside of the submitted work. W.P.: reports receiving personal fees from AbbVie, AFFiRiS, AstraZeneca, BIAL, Boston Scientific, Britannia, Intec, Ipsen, Lundbeck, NeuroDerm, Neurocrine, Denali Pharmaceuticals, Novartis, Orion Pharma, Prexton, Teva, UCB, and Zambon. He receives royalties from Thieme, Wiley Blackwell, Oxford University Press, and Cambridge University Press and grant support from The Michael J. Fox Foundation, EU FP7, and Horizon 2020, outside of the submitted work. K.S.: reports personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, Roche, Grünenthal, Stada, Licher Pharma, Biogen, BIAL, and Abbvie; honoraria from the International Parkinson and Movement Disorders Society; research grants from FWF Austrian Science Fund, The Michael J. Fox Foundation, and AOP Orphan Pharmaceuticals AG, outside the submitted work. G.K.W.: reports consultancy and lecture fees from AbbVie, AFFiRiS AG, AstraZeneca, Biogen, Biohaven, Inhibicase, Lundbeck, Merz, Ono, Teva, and Theravance, and research grants from the Austrian Science Fund (FWF), the Austrian National Bank, the US MSA Coalition, Parkinson Fonds Austria, the Dr Johannes und Hertha Tuba Foundation, and the International Parkinson and Movement Disorder Society, outside of the submitted work. A.F.: reports royalties from Springer Verlag, speaker fees and honoraria from Impact Medicom, Theravance Biopharma, AbbVie, the International Parkinson Disease and Movement Disorders Society, the Austrian Neurology Society, the Austrian Autonomic Society, and research grants from the Parkinson Fond, the US MSA Coalition, the Dr Johannes and Hertha Tuba Foundation, and the Austrian Exchange Program, outside of the submitted work. The data supporting the findings of this study are available upon reasonable request from any qualified investigator. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Objective To evaluate the apparant diffusion coefficient (ADC) values of cerebellar and the middle cerebellar peduncles in the differential diagnosis of multiple system atrophy (MSA) and Parkinson disease (PD). Methods Conventional MRI and DWI were performed in 18 clinically proved MSA patients with 7 cases of early cases (early-stage MSA group), 19 PD patients (PD group) and 18 agematched normal controls (the control group). DWI was performed using a single shot-spin echo-echo planar imaging sequences, and ADC values were measured in the ROIs (0. 16 cm2) of the bilateral cerebellum, the middle cerebellar peduncles and cerebral white matter. Then one way ANOVA test was used for statistical analysis. Results Of the 18 MSA patients, 11 had MR abnormalities, 8 had hot-cross bun sign in the pens on T2-weighted images, 11 patients had pontine, cerebellar and medulla oblongata atrophy, 10 patients had atrophy of the middle cerebellar peduncles, 2 patients had hyperintense rim of the putamen and putaminal atrophy on T2-weighted images. The ADC values in the middle cerebellar peduncles were significantly increased in the MSA group[ (0. 98 ±0. 07) × 103 mm2/s] and early-stnge MSA group [ (0. 95 ±0. 05) ×103 mm2/s] as compared to PD group [ (0. 77 ±0. 04) × 103 mm2/s] and control group[ (0. 78 ±0. 04) ×103 mm2/s]. There was statistical significant difference among them (F = 91.049,55. 301, P ＜ 0.01 ).There was no overlap in the distribution of ADC values of the middle cerebellar peduncles among the MSA group [ (0.86-1.13 ) × 103 mm2/s ], early-stage MSA group [ (0. 86-1.02 ) × 103 mm2/s ] and PD group [ (0. 68-0. 84) × 103 mm2/s] and the control group [ (0. 69-0. 82) × 103 mm2/s]. The ADC values in the cerebellum were significantly increased in the MSA group[ (0. 95 ±0. 09) × 103 mm2/s] and early-stage MSA group [ (0. 92 ±0. 07) × 103 mm2/s] as compared to PD group [ (0. 78 ±0. 05) × 103 mm2/s] and control group[ (0. 79 ± 0. 05 ) × 103 mm2/s ]. Statistically significant difference was found among them (F =39. 274,18. 623 ,P ＜0. 01 ). There was overlap in the distribution of ADC values of the cerebellum [ MSAgroup(0. 80-1.10) × 103 mm2/s,early stage MSA group (0. 80-0. 99) × 103 mm2/s,PD group(0. 72-0. 90) × 103 mm2/s,control group (0. 71-0. 87) × 103 mm2/s]. There was no significant difference among the ADC values of MSA group, MSA group(early stages) and PD group and the control group in the cerebral white matter( P ＞ 0. 05 ). Conclusions ADC values in the cerebellum and the middle cerebellar peduncles have very important significance in differential diagnosis between MSA and PD. Key words: Multiple system atrophy; Parkinson disease; Diffusion magnetic resonance imaging

OBJECTIVESUrinary dysfunction is a prominent autonomic feature in Parkinson's disease (PD) and multiple system atrophy (MSA), which is not only troublesome but also a cause of morbidity in these disorders....

Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA) are synucleinopathies whose primary pathogenic event is the deposition of inclusions composed of aberrantly fibrillized α-synuclein.1 In PD and LBD, Lewy bodies are the key aggregate, whereas in MSA, α-synuclein accumulates in the form of oligodendroglial and neuronal cytoplasmic inclusions (GCIs and NCIs).2,3 Parkinsonian manifestations have been noted in a subset of patients with Gaucher disease and there is evidence that parkinsonism is more frequent among carrier relatives of patients with Gaucher disease.4 In a remarkable study, the glucocerebrosidase (GBA) gene was sequenced in an American PD brain bank series where GBA mutations were detected at a much higher frequently than in controls (PD 21% vs control 4.5%).5 These findings have since been replicated, mainly in Ashkenazi patient groups who have a higher mutation frequency but also in patients with clinically and pathologically diagnosed PD and LBD in a number of studies in different populations.4 In a study of 75 neuropathologically confirmed synucleinopathies, GBA mutations were found in 23% of the cases with Lewy bodies.6 The frequency of GBA mutations around the world between 2.3 and 31% (depending on population) indicates that GBA mutations are one of the commonest genetic risk factors for PD. GBA mutation carriers have a wide spectrum of phenotypes, ranging from classic l-dopa-responsive PD to LBD. In neuropathologic studies of PD/LBD cases, GBA mutations, α-synuclein inclusions, and Lewy bodies have been seen. This spectrum of clinical and pathologic features would suggest that MSA should also be a candidate to have GBA mutation.3 Only 12 cases of MSA have been analyzed for GBA mutations and defects were seen in this handful of cases.6 We extracted DNA from the brain tissue of 108 neuropathologically confirmed British MSA cases that had been diagnosed according to brain bank criteria and 257 normal British controls. Mean age at onset was 58.2 ± 10.7 years (range 34–83), mean age at death 64.5 ± 10.2 years (39–87), mean disease duration 6.8 ± 2.9 years (2–16), and 48% were men. All exons and flanking intronic regions of the GBA gene were sequenced in MSA and control cases. To avoid amplifying and sequencing the GBA pseudogene we employed long range GBA PCR and then BigDye sequencing as previously described.7 In our MSA study group of 108 cases, we identified one heterozygous GBA mutation (c.904C>T; R262H), giving a mutation frequency of 0.92%. In the British controls, three heterozygous mutations (V497L, N409S, and R269Q) out of 257 cases were identified (1.17%). There was no significant difference between the two groups (p = 0.66). The single MSA case with the heterozygous R262H mutation was a woman with an age at onset of 44 years. She had parkinsonian, cerebellar, and autonomic features (MSA–mixed type) with no family history. She died at age 51 years and the neuropathology revealed widespread GCIs and NCIs with a predominance in striatonigral structures. There were no Lewy bodies. One limitation of our study is the small sample size. Our study has a power of 80% to detect variants with an OR >1.61 or <0.63 at a significance level of 0.05. The results of this study indicate that GBA mutations are not common etiologic players in Caucasian patients with MSA. We cannot exclude that GBA mutations confer modest or low risk to disease. Furthermore, we did not sequence risk variants in regulatory regions (such as the promotor region or untranslated regions). Mutations in these regions would therefore have been missed. The unexpected role of GBA mutations has been demonstrated in several populations and is undoubtedly a highly significant risk factor for PD and LBD. More importantly, GBA mutations reveal a direct link between the lysosomal protein pathway and the clearance or the development of α-synuclein aggregates into Lewy bodies. Our study indicates that GBA mutations are not associated with MSA in the population that we analyzed, and that this branch of the ceramide pathway is unlikely to be associated with all types of primary α-synuclein deposition.