Validation of the Body Scan®, a new device to detect small fiber neuropathy by assessment of the sudomotor function: agreement with the Sudoscan®

BackgroundSudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (μS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting.MethodsIn patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 μS and > 50 μS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 μS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland–Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices.ResultsA total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [−5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®.ConclusionThe ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice.Clinical trial registrationClinicalTrials.gov, identifier NCT05178459

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Diabètes, vascularisation pancréatique et pancréas exocrine

Blood glucose regulation in humans and animals depends on insulin secretion. Therefore, the different types of diabetes mellitus (DM) are linked to dysfunctions of the Beta cells, located within the islets of Langerhans. However, the exocrine pancreas is also involved in the pathophysiology of DM: patients with diseases of the exocrine pancreas such as chronic pancreatitis, pancreatic cancer or cystic fibrosis can develop DM, and abnormalities of the exocrine pancreas are frequent in patients with type 1 or type 2 diabetes. Since lesions of the pancreatic vessels appear earlier, are more common and more severe in the latter, we studied the relationship between DM, pancreatic vascularization and the exocrine pancreas. Our work consisted of several experimental studies: - We compared images of pancreatic computed tomography (CT) from patients with cystic fibrosis related diabetes (CFRD) to those from patients with cystic fibrosis without diabetes. Patients with CFRD presented more often with complete pancreatic lipomatosis and pancreatic calcifications than those without diabetes. - We compared images of pancreatic CT from patients with type 2 diabetes to those from controls. In patients, the splenic artery, which vascularizes the tail of the pancreas, was more frequently and severely calcified, and the pancreatic vascular tree was less dense than in controls. Furthermore, variations in volume and fatty infiltration were different between patients and controls. Namely, the pancreas volume correlated with the splenic artery diameter in patients but not in controls. - We developed a murine model of pancreatic ischemia by definitive ligation of the splenic artery. Ischemia of the pancreatic tail did not alter glycemia regulation or Beta-cell mass. In contrast, the ischemic area showed clear signs of pancreatitis such as acinar atrophy, inter- and intralobular fibrosis and leucocytic infiltration. There was also significant fatty degeneration of the pancreas. Six weeks after ligation, the exocrine pancreatic abnormalities largely resolved, showing that, in mice, the pancreas has important regenerative capacities. This work shows an interconnection between exocrine and endocrine pancreatic abnormalities. Pancreatic vascularization may be an important factor of this interconnection, with a particular effect on fatty degeneration of the pancreas.La régulation glycémique, chez l'humain comme chez l'animal, dépend de la sécrétion d'insuline. Les différents types de diabète sont ainsi liés à des dysfonctionnements spécifiques des cellules bêta situées au sein des îlots de Langerhans. Cependant, le pancréas exocrine est lui aussi impliqué dans la physiopathologie des diabètes : les maladies du pancréas exocrine (pancréatite chronique, cancer du pancréas, mucoviscidose) peuvent se compliquer de diabète, et les anomalies du pancréas exocrine sont fréquentes chez les patients présentant un diabète de type 1 ou un diabète de type 2. Les lésions vasculaires pancréatiques étant par ailleurs plus fréquentes, plus précoces et plus sévères chez ces derniers, nous avons étudié les liens entre diabètes, vascularisation pancréatique et pancréas exocrine. Notre travail a consisté en plusieurs séries d'expérimentation : - Une première étude comparant les scanners pancréatiques de patients présentant un diabète de la mucoviscidose à ceux de patients présentant une mucoviscidose sans diabète. Les patients présentant un diabète de la mucoviscidose présentaient plus de dégénérescence graisseuse du pancréas et de calcifications pancréatiques que ceux qui n'avaient pas de diabète. - Une deuxième étude comparant les scanners pancréatiques de patients présentant un diabète de type 2 avec celui de témoins. Chez les patients, l'artère splénique vascularisant la queue du pancréas était plus fréquemment calcifiée, et de façon plus sévère, et l'arbre vasculaire pancréatique était moins dense que chez les témoins. Par ailleurs, les variations de volume et d'infiltration graisseuse étaient différentes entres les patients et les témoins, le volume pancréatique étant notamment corrélé au diamètre de l'artère splénique uniquement chez les patients. - L'élaboration d'un modèle murin d'ischémie pancréatique par ligature définitive de l'artère splénique : l'ischémie de la queue du pancréas n'a pas montré d'effet sur la régulation glycémique ni sur la masse Bêta pancréatique. En revanche, la zone ischémiée présentait des signes clairs de pancréatite tels qu'une atrophie acinaire, une fibrose inter- et intralobulaire et une infiltration leucocytaire. On observait également une dégénérescence graisseuse importante du pancréas. Ces anomalies avaient régressé en grande partie 6 semaines après la ligature, montrant des capacités importantes de régénération du pancréas chez la souris. Ainsi, ce travail montre qu'il existe une interconnexion entre les anomalies du pancréas exocrine et du pancréas endocrine dans ces différentes pathologies, et que la vascularisation pancréatique joue un rôle dans cette interconnexion avec un effet notamment sur la dégénérescence graisseuse pancréatique

Diabètes, vascularisation pancréatique et pancréas exocrine

Blood glucose regulation in humans and animals depends on insulin secretion. Therefore, the different types of diabetes mellitus (DM) are linked to dysfunctions of the Beta cells, located within the islets of Langerhans. However, the exocrine pancreas is also involved in the pathophysiology of DM: patients with diseases of the exocrine pancreas such as chronic pancreatitis, pancreatic cancer or cystic fibrosis can develop DM, and abnormalities of the exocrine pancreas are frequent in patients with type 1 or type 2 diabetes. Since lesions of the pancreatic vessels appear earlier, are more common and more severe in the latter, we studied the relationship between DM, pancreatic vascularization and the exocrine pancreas. Our work consisted of several experimental studies: - We compared images of pancreatic computed tomography (CT) from patients with cystic fibrosis related diabetes (CFRD) to those from patients with cystic fibrosis without diabetes. Patients with CFRD presented more often with complete pancreatic lipomatosis and pancreatic calcifications than those without diabetes. - We compared images of pancreatic CT from patients with type 2 diabetes to those from controls. In patients, the splenic artery, which vascularizes the tail of the pancreas, was more frequently and severely calcified, and the pancreatic vascular tree was less dense than in controls. Furthermore, variations in volume and fatty infiltration were different between patients and controls. Namely, the pancreas volume correlated with the splenic artery diameter in patients but not in controls. - We developed a murine model of pancreatic ischemia by definitive ligation of the splenic artery. Ischemia of the pancreatic tail did not alter glycemia regulation or Beta-cell mass. In contrast, the ischemic area showed clear signs of pancreatitis such as acinar atrophy, inter- and intralobular fibrosis and leucocytic infiltration. There was also significant fatty degeneration of the pancreas. Six weeks after ligation, the exocrine pancreatic abnormalities largely resolved, showing that, in mice, the pancreas has important regenerative capacities. This work shows an interconnection between exocrine and endocrine pancreatic abnormalities. Pancreatic vascularization may be an important factor of this interconnection, with a particular effect on fatty degeneration of the pancreas.La régulation glycémique, chez l'humain comme chez l'animal, dépend de la sécrétion d'insuline. Les différents types de diabète sont ainsi liés à des dysfonctionnements spécifiques des cellules bêta situées au sein des îlots de Langerhans. Cependant, le pancréas exocrine est lui aussi impliqué dans la physiopathologie des diabètes : les maladies du pancréas exocrine (pancréatite chronique, cancer du pancréas, mucoviscidose) peuvent se compliquer de diabète, et les anomalies du pancréas exocrine sont fréquentes chez les patients présentant un diabète de type 1 ou un diabète de type 2. Les lésions vasculaires pancréatiques étant par ailleurs plus fréquentes, plus précoces et plus sévères chez ces derniers, nous avons étudié les liens entre diabètes, vascularisation pancréatique et pancréas exocrine. Notre travail a consisté en plusieurs séries d'expérimentation : - Une première étude comparant les scanners pancréatiques de patients présentant un diabète de la mucoviscidose à ceux de patients présentant une mucoviscidose sans diabète. Les patients présentant un diabète de la mucoviscidose présentaient plus de dégénérescence graisseuse du pancréas et de calcifications pancréatiques que ceux qui n'avaient pas de diabète. - Une deuxième étude comparant les scanners pancréatiques de patients présentant un diabète de type 2 avec celui de témoins. Chez les patients, l'artère splénique vascularisant la queue du pancréas était plus fréquemment calcifiée, et de façon plus sévère, et l'arbre vasculaire pancréatique était moins dense que chez les témoins. Par ailleurs, les variations de volume et d'infiltration graisseuse étaient différentes entres les patients et les témoins, le volume pancréatique étant notamment corrélé au diamètre de l'artère splénique uniquement chez les patients. - L'élaboration d'un modèle murin d'ischémie pancréatique par ligature définitive de l'artère splénique : l'ischémie de la queue du pancréas n'a pas montré d'effet sur la régulation glycémique ni sur la masse Bêta pancréatique. En revanche, la zone ischémiée présentait des signes clairs de pancréatite tels qu'une atrophie acinaire, une fibrose inter- et intralobulaire et une infiltration leucocytaire. On observait également une dégénérescence graisseuse importante du pancréas. Ces anomalies avaient régressé en grande partie 6 semaines après la ligature, montrant des capacités importantes de régénération du pancréas chez la souris. Ainsi, ce travail montre qu'il existe une interconnexion entre les anomalies du pancréas exocrine et du pancréas endocrine dans ces différentes pathologies, et que la vascularisation pancréatique joue un rôle dans cette interconnexion avec un effet notamment sur la dégénérescence graisseuse pancréatique

Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case–control study

International audienceAbstract Background Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. Methods In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA 1c and body mass index (BMI). Results 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects ( p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA 1c and BMI evolution did not differ between the groups. Conclusions PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders. Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-0904

Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice

International audienceThe antigenic peptides processed by β-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes

Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome

peer reviewedBackground: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. Objectives: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. Design: Cross-sectional study. Setting: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). Participants: Control participants of the Luxembourg Parkinson’s Study. Measurements: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0–10, 11–16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. Results: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15–0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. Conclusions: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.MCI-BIOME_20193. Good health and well-bein