Partial endorsement of: "Video-polysomnography procedures for diagnosis of rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages: Guidelines from the International RBD Study Group" by the World Sleep Society.

Updated guidelines for the video-polysomnography (vPSG) procedures for diagnosing rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages have recently been proposed by the Neurophysiology Working Group of the International RBD Study Group (IRBDSG). These guidelines were selected for review by a World Sleep Society (WSS) Parasomnias Task Force and the WSS International Sleep Medicine Guidelines Committee. A survey was completed by sleep society leaders and prominent sleep clinicians and researchers in 31 WSS member countries across six continents, focused on sleep technologist training and certification; extent of public/private health insurance coverage for the vPSG evaluation of RBD; extent of hospital-based sleep-technologist-attended overnight vPSG studies; availability of video during PSG studies; and sufficient specification of PSG machines to record and analyze REM sleep without atonia. The findings from this survey indicated that most health systems and medical communities across WSS member countries would not be capable of implementing the proposed more stringent guidelines, which would then strongly interfere with the diagnosis of RBD in a large portion of patients who would not be able to receive the required (often repeated) vPSG evaluation. Therefore, the WSS can only partially endorse the updated guidelines and concludes that the current International Classification of Sleep Disorders-3rd edition diagnostic criteria for RBD should still be retained as the standard reference for the diagnosis of RBD, and that further discussion across all members of the IRBDSG should take place to ensure the feasibility of any future proposed changes.

Fatty acid overproduction by gut commensal microbiota exacerbates obesity.

Although recent studies have highlighted the impact of gut microbes on the progression of obesity and its comorbidities, it is not fully understood how these microbes promote these disorders, especially in terms of the role of microbial metabolites. Here, we report that Fusimonas intestini, a commensal species of the family Lachnospiraceae, is highly colonized in both humans and mice with obesity and hyperglycemia, produces long-chain fatty acids such as elaidate, and consequently facilitates diet-induced obesity. High fat intake altered the expression of microbial genes involved in lipid production, such as the fatty acid metabolism regulator fadR. Monocolonization with a FadR-overexpressing Escherichia coli exacerbated the metabolic phenotypes, suggesting that the change in bacterial lipid metabolism is causally involved in disease progression. Mechanistically, the microbe-derived fatty acids impaired intestinal epithelial integrity to promote metabolic endotoxemia. Our study thus provides a mechanistic linkage between gut commensals and obesity through the overproduction of microbe-derived lipids.

Striatal-Inoculation of α-Synuclein Preformed Fibrils Aggravated the Phenotypes of REM Sleep without Atonia in A53T BAC-SNCA Transgenic Mice.

Accumulation of α-synuclein (α-syn) is the pathological hallmark of α-synucleinopathy. Rapid eye movement (REM) sleep behavior disorder (RBD) is a pivotal manifestation of α-synucleinopathy including Parkinson's disease (PD). RBD is clinically confirmed by REM sleep without atonia (RWA) in polysomnography. To accurately characterize RWA preceding RBD and their underlying α-syn pathology, we inoculated α-syn preformed fibrils (PFFs) into the striatum of A53T human α-syn BAC transgenic (A53T BAC-SNCA Tg) mice which exhibit RBD-like phenotypes with RWA. RWA phenotypes were aggravated by PFFs-inoculation in A53T BAC-SNCA Tg mice at 1 month after inoculation, in which prominent α-syn pathology in the pedunculopontine nucleus (PPN) was observed. The intensity of RWA phenotype could be dependent on the severity of the underlying α-syn pathology.

What is the subtype of dementia in patients with fragility hip fracture?

INTRODUCTION: Cognitive function is an important factor that affects functional recovery after hip fracture (HipFx) surgery. The literature on the pathophysiology of dementia in HipFx patients is scarce. We performed a differential diagnosis of dementia in HipFx patients using clinical and brain MRI findings. METHODS: This is a prospective study in which brain MRI was evaluated for patients with HipFx for research purposes. One-hundred-and-five HipFx patients (85 females and 20 males) who underwent surgery and were subsequently able to undergo brain MRI at our hospital were evaluated. The mean age was 84 years. The presence of dementia was determined based on clinical findings and whether the patient meets its diagnostic criteria according to the International Classification of Diseases 10th Edition (ICD-10). The differential diagnosis of dementia was made based on brain MRI findings and the dementia diagnostic flow chart published in the Clinical Practice Guideline for Dementia 2017 (Japanese Society of Neurology). The Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) advance 2 diagnostic software was used to evaluate atrophy of the para-hippocampal gyrus. RESULTS: Fifty-six (53%) patients were clinically diagnosed with dementia according to the ICD-10 criteria. The MRI findings were diverse: Alzheimer's disease (AD)-type, asymptomatic multiple ischemic cerebral lesions, past symptomatic cerebral infarction or cerebral hemorrhage, Binswanger's disease (BW)-type, chronic subdural hematoma, disproportionately enlarged subarachnoidal hydrocephalus (DESH), and their combinations thereof. A combination of MRI and clinical findings of dementia patients demonstrated the following distribution of dementia subtypes: AD (n = 20), vascular dementia (n = 33), AD and BW vascular dementia (n = 3). CONCLUSION: This study revealed that the brain MRI findings of HipFx patients were diverse. Although vascular dementia is found to be common in this particular population, this could be an incidental finding. Further study is warranted to clarify the specificity of our findings by increasing the number of patients, setting the control, and investigating whether dementia subtypes affect postoperative gait acquisition and fall risk.

Polygenic burden of Parkinson's disease risk stratifies the prognosis of isolated rapid-eye-movement disorder: A preliminary observational study.

BACKGROUND: Polygenic burden of Parkinson's disease (PD) risk single nucleotide polymorphisms (SNPs), is associated not only with PD development and age at onset, but also with higher PD penetrance in GBA and LRRK2 carriers. OBJECTIVES: To assess the impact of polygenic burden of PD risk SNPs in isolated rapid-eye-movement disorder (iRBD). METHODS: In this observational study using the data of the Parkinson's progression marker initiative, we retrospectively reviewed the records of iRBD patients of European-ancestry with genotype data for 90 PD risk SNPs available. We calculated the genetic risk score for PD (PD-GRS) as a weighted sum of those SNPs, and examined the association of PD-PRS with the subsequent course of iRBD patients. RESULTS: 37 IRBD patients (median age = 71.0 years, male = 65.4%) were included. Median follow-up years from the diagnosis was 6.8 years, and 14 patients (38.9%) developed overt α-synucleopathies during the follow-up period. PD-GRS was significantly associated with an increased phenoconversion risk [hazard ratio per +1 standard deviation (adjusted for age, sex, and baseline cognitive, motor, autonomic, and olfactory dysfunction as well as principal components 1 to 5 to account for the population stratification) = 7.4 (95% confidence interval, 1.6-34.6)]. Furthermore, iRBD patients with PD-GRS higher than the median showed an accelerated decline in motor function [standardized fixed-effects ß coefficients of the interaction term = 0.08 (95% confidence interval, 0.02-0.14)]. CONCLUSION: Our study showed the intriguing possibility that the disease course of iRBD patients differed according to the degree of polygenic burden of PD risk SNPs, although future validation is warranted.

Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome.

STUDY OBJECTIVES: To carry out an analysis of leg movement activity during sleep in a polysomnography dataset of patients with multiple sclerosis (MS) in comparison to idiopathic restless legs syndrome (iRLS) and healthy controls. METHODS: In this cross-sectional, observational, instrumental study, 57 patients (males/females: 11/46; mean age 46.2 ± 10.2 years) with a diagnosis of MS underwent a telephone interview assessing the 5 standard diagnostic criteria for RLS and polysomnography. Sleep architecture and leg movement activity during sleep were subsequently compared: 1) 40 patients with MS without RLS (MS-RLS) vs 28 healthy controls; 2) 17 patients with MS with RLS (MS+RLS) vs 35 patients with iRLS; 3) MS+RLS vs MS-RLS. RESULTS: MS-RLS and MS+RLS presented increased sleep latency, percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and iRLS, respectively. The periodic limb movements during sleep (PLMS) index was higher in MS-RLS than in healthy controls (P = .035) and lower in MS+RLS compared to iRLS (P = .024). PLMS in MS+RLS were less periodic, less often bilateral, and with shorter single movements compared to the typical PLMS in iRLS. CONCLUSIONS: MS is a risk factor for RLS, PLMS, and for a lower sleep quality in comparison to healthy patients. PLMS in MS+RLS are fewer and shorter if compared to iRLS. Our results suggest a dissociation between motor (PLMS) and sensory symptoms (RLS sensory component) in RLS secondary to MS, with possible treatment implications. CITATION: Ferri R, Sparasci D, Castelnovo A, et al. Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome. J Clin Sleep Med. 2022;18(1):11-20.

The new procedure for manual CPAP titration†:†the afternoon CPAP titration (aPT).

Study Objectives : Although the full-night continuous positive airway pressure (CPAP) titration (fnPT) has been recognized as the gold standard for determining an optimal therapeutic pressure for obstructive sleep apnea (OSA) treatment, it is labor-intensive, time-consuming because it requires overnight polysomnography attended by well-experienced sleep technologists. The aim of this study is to develop a practical and feasible alternative titration method. Methods : We assessed demographic data and diagnostic polysomnographic parameters, time spent in CPAP titration, CPAP efficacy and long-term adherence of the two groups of our OSA patients who had received CPAP titration either by fnPT (n = 46) or by afternoon CPAP titration (aPT, n = 22). Main results : Mean total recording time of aPT was significantly shorter than that by fnPT (p < 0.0001). There was no significant difference in mean residual apnea hypopnea index (AHI) on treatment, percent days with device usage, cumulative device usage hours during the 360 days, average device usage hours per day (360 days, days used), and percent of days with device usage ≥ 4 hours during the 360 days after starting CPAP treatment between the two groups. Conclusions : Our study demonstrated that aPT was feasible procedure as an alternative to fnPT. J. Med. Invest. 68 : 170-174, February, 2021.

Restless legs syndrome and periodic limb movements in 86 patients with multiple sclerosis.

STUDY OBJECTIVES: To assess the frequency of restless legs syndrome (RLS), periodic limb movements during sleep (PLMS), and their overlap in a large sample of patients with multiple sclerosis (MS). To compare clinical and paraclinical findings among four subgroups of patients: RLS-/PLMS- (patients without RLS and PLMS), RLS+/PLMS- (patients with RLS and without PLMS), RLS-/PLMS (patients without RLS and with PLMS), and RLS+/PLMS+ (patients with both RLS and PLMS). METHODS: In this cross-sectional, observational, instrumental study, 86 patients (M/F: 27/59; mean age 48.0 ± 10.8 years) with a diagnosis of MS underwent a telephone interview assessing the five standard diagnostic criteria for RLS. Seventy-six participants underwent polysomnography (PSG) and maintenance of wakefulness test (MWT). Instrumental and clinical findings were subsequently statistically compared to investigate their association with RLS and PLMS index (PLMSI). RESULTS: RLS and PLMS (PLMSI ≥15/h) frequency in patients with MS were of 31.4% and 31.6%, respectively. Among patients with RLS, 37.5% had a PLMSI of at least 15/h. RLS-/PLMS+ group showed higher wake after sleep onset (p = 0.01), stage shifts per hour (p = 0.03), increased stage N1 (p = 0.03), and reduction in stage N3 (p = 0.01) compared to RLS-/PLMS-. RLS had no influence on clinical and PSG parameters (p = 0.45). CONCLUSIONS: RLS is highly frequent in patients with MS. The frequency of PLMS is comparable to the general population. The low percentage of patients with RLS having a high PLMSI, together with the absence of correlation between RLS and female gender and older age, supports the existence of a distinct symptomatic form of RLS in MS.

Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder.

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Appropriate assessment method of 123I-MIBG myocardial scintigraphy for the diagnosis of Lewy body diseases and idiopathic REM sleep behavior disorder.

BACKGROUND: In 123I-metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy, the early heart-to-mediastinum (H/M) ratio is considered to reflect the density of the cardiac sympathetic nerve endings, washout rate (WR) is an indicator of the cardiac sympathetic tone, and the delayed H/M ratio reflects both. The Delayed H/M ratio is usually used to support the diagnosis of Lewy body diseases (LBDs) and idiopathic REM sleep behavior disorder (iRBD); however, which values should be used have not been specified. Here, we hypothesized that the combination of these values is appropriate for the diagnostic purpose. METHODS: In this single-center retrospective cohort study, we recruited 106 patients with LBDs or iRBD and 33 patients without those diseases, of whom we reviewed the 123I-MIBG myocardial scintigraphy results. RESULTS: Sensitivity/specificity to diagnose LBDs and iRBD were 0.77/0.94 for the early H/M ratio (≤ 2.0), 0.82/0.94 for the delayed H/M ratio (≤ 2.0), and 0.89/0.91 for WR (≥ 23.0). When patients were considered positive if at least either the early H/M ratio or WR was abnormal, the sensitivity significantly increased to 0.97, whereas the specificity remained similar at 0.91. Furthermore, our subgroup analyses revealed that WR enhancement preceded H/M ratio reduction, but, in patients with a severely reduced early H/M ratio, paradoxically normal WR could be observed. CONCLUSION: We propose the highly sensitive, combined early H/M ratio and WR assessments for 123I-MIBG myocardial scintigraphy. The temporal precedence of cardiac sympathetic dysfunction over denervation and the floor effect in 123I-MIBG uptake may underlie the sensitivity improvement.

[A rare case of inclusion body myositis associated with anti-PM/Scl-75 antibodies].

A 71-year-old man presented with progressive muscle weakness of the four limbs in November 2014. His symptoms had started from the left leg in 2008, resulting in frequent falls. In 2011, he became unable to stand up without a handrail due to weakness of the both legs. Physical examination showed almost symmetric muscle weakness of the arms and legs; MMT4. The CK level was slightly elevated of 304 IU/l. The patient was diagnosed as having inclusion body myositis based on the muscle biopsy findings showing many fibers with rimmed vacuoles in addition to mononuclear cell infiltrating into the endomysium, surrounding and sometimes invading into non-necrotic muscle fibers. Anti-PM/Scl-75 antibodies were positive. Muscle strength improved after intravenous immunoglobulin therapy, although the effect was only temporary. This rare case suggests the autoimmunological etiology in inclusion body myositis.

Framing multiple sclerosis under a polysomnographic perspective.

Multiple sclerosis (MS) is a mainly demyelinating, autoimmune, and disabling neurological disease. In addition to well-known clinically evident symptoms such as coordination or motor problems, increasing attention has been posed to a constellation of less evident symptoms significantly contributing to the clinical impact of MS. Among others, sleep symptoms have been only recently explored. This systematic review summarizes objective sleep findings detected by using polysomnography and their relationship with clinical variables in MS patients. While it is well known that sleep disorders are frequent in MS, objective clinical data are still scarce. Literature based on subjective reports indicate sleep disorders as highly frequent in MS patients; however, objective data are still scarce. New large case-control instrumental investigations are warranted to establish the real objective entity and impact of sleep comorbidities.

Dietary Antigens Induce Germinal Center Responses in Peyer's Patches and Antigen-Specific IgA Production.

The primary induction sites for intestinal IgA are the gut-associated lymphoid tissues (GALT), such as Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). The commensal microbiota is known to contribute to IgA production in the gut; however, the role of dietary antigens in IgA production is poorly understood. To understand the effect of dietary antigens on IgA production, post-weaning mice were maintained on an elemental diet without any large immunogenic molecules. We found that dietary antigens contribute to IgA production in PPs through induction of follicular helper T cells and germinal center B cells. The role of dietary antigens in the PP responses was further confirmed by adding bovine serum albumin (BSA) into the elemental diet. Although dietary antigens are important for PP responses, they have fewer effects than the microbiota on the development and maturation of ILFs. Furthermore, we demonstrated that dietary antigens are essential for a normal antigen-specific IgA response to Salmonella typhi serovar Typhimurium infection. These results provide new insights into the role of dietary antigens in the regulation of mucosal immune responses.

Potential Clinical Applications and Future Prospect of Wireless and Mobile Electroencephalography on the Assessment of Cognitive Impairment.

Electroencephalography (EEG) systems have been used for assessing cognitive function in dementia for several decades. Studies have demonstrated that EEG in Alzheimer's disease (AD) patients is generally characterized by significant and specific increases in delta and theta power, a decrease in alpha power, and a decrease in the coherence of the fast bands between different brain areas linked by long corticocortical fibers. Posterior EEG characteristics in dementia with Lewy bodies (DLB) allowed discrimination of DLB from AD and controls with high accuracy. Traditional EEG systems require a long application time and discomfort, which limited its use in dementia patients. Alternative tools for assessing cognition may be simple, low-cost, and mobile medical devices such as wireless and mobile EEG (wmEEG) sensor platforms with flexible electronics and stretchable electrode sheets that could be compatible with long-term EEG monitoring even in dementia patients. In this study, we review the utility of EEG in reflecting cognitive function and the prospects for clinical application of wmEEG monitoring for detecting early dementia and discriminating subtypes of dementia effectively and objectively assessing longitudinal cognitive changes. Repeated and longitudinal documentation of EEG using wmEEG will contribute to detection of specific sleep/wake EEG patterns for patients with sleep and wake-related problems related to dementia.

Rate of augmentation and risk factors with long-term follow-up in Japanese patients with restless legs syndrome.

OBJECTIVES: Preventing augmentation is the critical clinical issue for RLS treatment. As for augmentation in Asian RLS patients, there have been only four studies and the follow-up durations of these studies were not long. We investigated Japanese RLS patients with longer duration of treatment in a clinical setting. METHODS: This study is a retrospective assessment of 42 RLS patients with follow-up durations of longer than 18 months (78.4 ± 29.2, range 19-139) at two urban sleep centers in Osaka, Japan from May 2004 to April 2014. RESULTS: The mean age of first visit was 63.5 ± 14.1 years old and the estimated age of RLS onset was 47.9 ± 16.5 years old. Twenty-eight out of 42 patients were female. At initial evaluation, the mean International Restless Legs Scale score (IRLS score) was 22.0 ± 5.9. Thirty-one of 42 had already visited other clinics before coming to our sleep centers, and the number of clinics visited was 1.3 ± 0.6. Augmentation developed in two patients (4.8%), and the dosage of dopamine equivalent in patients with and without augmentation was 12.5 and 18.8 mg vs. 15.8 ± 17.7 mg. In the two RLS patients with augmentation, ferritin was 113.1 and 114.1 ng/mL, respectively, and the number of clinics before coming to our sleep centers was both three. CONCLUSIONS: The augmentation rate of Japanese RLS patients from our study is low compared with previous Western and Asian studies. It might be attributable to racial difference, lower dosage of dopaminergic treatment, and the level of ferritin.

[Improvement of human T-lymphotropic virus type 1 associated demyelinating neuropathy with corticosteroid therapy].

The patient was a 58-year-old man, who was hospitalized with progressive bilateral leg weakness, and sensory impairment in all four extremities. Chronic inflammatory demyelinating polyneuropathy (CIDP) was suspected based on an electrophysiological examination, and intravenous immunoglobulin therapy (IVIg) was initiated. However, his symptoms progressed. The serum and cerebrospinal fluid were positive for human T-lymphotropic virus type 1 (HTLV-1) antibodies; hence the patient was diagnosed as having HTLV-1 associated neuropathy. After administration of corticosteroid, muscle strength markedly improved. Thus, our findings suggest that rather than IVIg, corticosteroid therapy is recommended for the treatment of CIDP like neuropathy in HTLV-1 infected patients.

Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling.

M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor-associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.