Cross-sectional association of continuous glucose monitoring-derived metrics with cerebral small vessel disease in older adults with type 2 diabetes.

AIM: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes. MATERIALS AND METHODS: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score. RESULTS: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores. CONCLUSIONS: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes.

High performance plasma amyloid-ß biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-ß deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-ß positron-emission tomography (PET) imaging or measurement of amyloid-ß in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-ß markers. Here we demonstrate the measurement of high-performance plasma amyloid-ß biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-ß precursor protein (APP)669-711/amyloid-ß (Aß)1-42 and Aß1-40/Aß1-42 ratios, and their composites, to predict individual brain amyloid-ß-positive or -negative status was determined by amyloid-ß-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-ß burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-ß-PET burden and levels of Aß1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-ß burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Associations of dietary patterns and longitudinal brain-volume change in Japanese community-dwelling adults: results from the national institute for longevity sciences-longitudinal study of aging.

BACKGROUND: The association of dietary patterns and longitudinal changes in brain volume has rarely been investigated in Japanese individuals. We prospectively investigated this association in middle-aged and older Japanese community-dwelling adults. METHODS: Data with a 2-year follow-up from the sixth wave (July 2008 to July 2010; baseline) to the seventh (July 2010 to July 2012; follow-up) of the National Institute for Longevity Sciences-Longitudinal Study of Aging project were analyzed. Dietary intake was assessed using a 3-day dietary record, and longitudinal volume changes (%) in the total gray matter (TGM), total white matter, and frontal, parietal, occipital, temporal, and insular lobes were assessed using 3-dimensional T1 magnetic resonance imaging scans. Multiple factor analysis and hierarchical clustering revealed sex-specific dietary patterns. Associations between dietary patterns and annual brain-volume changes (%) were evaluated using general linear models adjusted for age, apoprotein E genotype, body mass index, medical history, lifestyle behaviors, socioeconomic factors, and energy intake. RESULTS: Among the 1636 participants (age: 40.3-89.2 years), three dietary patterns were determined for men (n = 815; Western; Vegetable-Fruit-Dairy; and Traditional Japanese diets) and women (n = 821; Western; Grain-Vegetable-Fruit; and Traditional Japanese diets). Compared to women following the Western diet, those on the Traditional Japanese diet had less TGM atrophy. Multivariable-adjusted ß (95% confidence interval) of the annual change (%) of TGM was - 0.145 (-0.287 to -0.002; P = 0.047), which correlated with reduced parietal lobe atrophy. No association between dietary pattern and brain atrophy was observed in men. CONCLUSIONS: Adherence to healthy dietary patterns, with higher consumption of whole grains, seafood, vegetables, fruits, mushrooms, soybean products, and green tea, potentially confers a protective effect against brain atrophy in middle-aged and older Japanese women but not in men. Further research to confirm these results and ascertain the underlying mechanisms is required. This study highlights the importance of sex-specific effects on the relationship between dietary patterns and brain health in diverse populations.

Japan-Multimodal Intervention Trial for the Prevention of Dementia: A randomized controlled trial.

INTRODUCTION: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. HIGHLIGHTS: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions.

Safety and immunogenicity of mRNA COVID-19 vaccine in inpatients with muscular dystrophy.

INTRODUCTION/AIMS: Due to muscular weakness and cardiopulmonary dysfunction, patients with muscular dystrophy (MD) have an increased risk of serious complications from coronavirus disease-2019 (COVID-19). Although vaccination is recommended, COVID-19 vaccination safety and immunogenicity in these patients are unknown. We investigated reaction frequency, post-vaccine antibody titers after two mRNA COVID-19 vaccine doses, and clinical predictors of antibody response among patients with MD. METHODS: We recruited 171 inpatients with MD receiving two BNT162b2 mRNA COVID-19 vaccine doses from seven hospitals. Blood samples were obtained from 53 inpatients before the first dose and 28 to 30 days after the second dose, and antibody titers were measured. RESULTS: Overall, 104 (60.8%) and 115 (67.6%) patients had side effects after the first and second doses, respectively. These were generally mild and self-limited. Multiple logistic regression analysis showed that a bedridden state was associated with reduced side effects (odds ratio [OR] = 0.29; 95% confidence interval [CI], 0.12 to 0.71). The antibody titers of all participants changed from negative to positive after two vaccine doses. The geometric mean titer (GMT) of the inpatients was 239 (95% CI, 159.3 to 358.7). Older age (relative risk [RR] = 0.97; 95% CI, 0.95 to 0.99) and bedridden state (RR = 0.27; 95% CI, 0.14 to 0.51) were associated with a lower antibody titer. Patients with myotonic dystrophy type 1 (DM1) had a lower GMT than patients with other MDs (RR = 0.42; 95% CI, 0.21 to 0.85). DISCUSSION: COVID-19 vaccination is safe and immunogenic in inpatients with MD. Patients with DM1 appear to have a poorer COVID-19 antibody response than those with other MDs.

Early-onset Alzheimer Disease Associated With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. Although recent reports have noted that cognitive impairment is common in NMOSD, little longitudinal information is available on the trajectories of cognitive function in the disease. Here, we report a case of a 55-year-old woman with an 11-year history of NMOSD who visited our memory clinic for progressive memory loss. She was diagnosed with early-onset Alzheimer disease based on amyloid and tau positron emission tomography imaging biomarkers. This is the first report of early-onset Alzheimer disease in a patient with NMOSD. Complications of Alzheimer disease should be considered when patients with NMOSD exhibit rapid cognitive decline. More longitudinal studies of NMOSD with cognitive impairment are needed.

Variables for differential diagnosis of familial Mediterranean fever: multiple correspondence analysis of a large Japanese cohort.

OBJECTIVES: We investigated differential diagnoses that should be noted with familial Mediterranean fever (FMF) and useful variables for differentiation in a large Japanese cohort. METHODS: Patients aged ≥13 years who were clinically suspected of having FMF by Livneh criteria were studied 1 year after MEFV genetic testing. Patients ultimately diagnosed with other diseases were studied, and the association among each disease, patient characteristics, and clinical variables were analyzed using multiple correspondence analysis. RESULTS: In total, 504 patients were included in this study; 34 (6.7%) were diagnosed with a disease other than FMF. The most common diagnosis was Behçet's disease, followed by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, inflammatory bowel disease, myelodysplastic syndromes (MDS), and infectious diseases. Although none of the non-FMF patients had exon 10 variants, some responded to colchicine treatment. Multiple correspondence analysis suggested that atypical symptoms such as stomatitis were associated with Behçet's disease and PFAPA syndrome, whereas characteristic situations such as disease onset ≥40 years were associated with MDS and infectious diseases. CONCLUSION: Careful follow-ups and reanalysis of the diagnosis should be performed for patients with atypical findings and no exon 10 variants, even if their symptoms meet the clinical criteria for FMF.

The effects of visual cues from optical stimulation devices on gait disturbance in patients with Parkinson's disease.

[Purpose] The purpose of this study was to identify the optimal visual cues for gait disturbance in patients with Parkinson's disease based on the luminous duration and the individual patient preferences for a wearable visual cue device. [Participants and Methods] Twenty-four patients with Parkinson's disease walked while wearing only a visual cue device in the control condition. They then walked while the device was set to two stimulus conditions: the luminous duration at 10% and 50% of the individual gait cycle. After walking under the two stimulus conditions, the patients were asked for their preferred visual cue condition. The walking results were compared between the two stimulus conditions and the control condition. Gait parameters were compared among the three conditions. The comparisons with preference, non-preference, and control conditions were also made for the same gait parameter. [Results] When compared to the control condition, walking with visual cues in the stimulus conditions reduced stride duration and increased cadence. The preference and non-preference conditions had shorter stride durations than the control condition. Furthermore, the preference condition also resulted in a faster gait speed than the non-preference condition. [Conclusion] This study suggests that a wearable visual cue device with the patient's preferred luminous duration may help manage gait disturbance in patients with Parkinson's disease.

Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy.

AIMS: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy. METHODS: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2). RESULTS: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy. CONCLUSION: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

Basic lifestyle habits and volume change in total gray matter among community dwelling middle-aged and older Japanese adults.

The brain controls human behavior, and the gray matter is the main resource of neuronal cells. We examined the longitudinal relationship between six basic lifestyle habits (diet, exercise, sleep, alcohol consumption, smoking, and social activity including employment) and total gray matter volume in community-dwelling adults in Japan. This two-year follow-up study with data derived from the National Institute for Longevity Sciences, Longitudinal Study of Aging, Aichi, Japan, included adults aged 40-87 years (n = 1665, men: 51%). Lifestyle habits were assessed at baseline (2008-2010) using self-reported questionnaires and three-day dietary records. Total gray matter volume at baseline and after two years was estimated using T1-weighted brain magnetic resonance imaging and FreeSurfer software. The association between each lifestyle factor, the total number of healthy lifestyle habits, and gray matter volume change was determined via a multiple linear regression analysis adjusting for baseline age, total gray matter volume, and other confounders. The mean ± standard deviation decrease in total gray matter volume during the two-year follow-up period was 0.94 ± 1.86% in men and 0.61 ± 2.27% in women. In the multiple regression analysis, volume loss in total gray matter positively correlated with male smoking, while it was negatively correlated with male social activity and employment, female dietary diversity, and the total number of healthy lifestyle habits (standardized beta coefficient; -0.061 in men [p = 0.07], -0.113 in women [p < 0.05]). Therefore, engaging in social activities, non-smoking, a diverse diet, or adopting one healthy lifestyle habit may help prevent gray matter volume loss.

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.

Changes in motor function in Duchenne muscular dystrophy patients after travel restrictions due to COVID-19.

INTRODUCTION/AIM: This retrospective study aimed to quantify the changes in motor function in patients with Duchenne muscular dystrophy (DMD) due to the government-imposed travel restrictions associated with the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Twelve DMD patients were enrolled in this investigation (mean ± SD age: 9.8 ± 3.6 y). Their physical characteristics and motor function were evaluated approximately 3 mo before, immediately before, and approximately 3 mo after the travel restrictions were decreed. Statistical comparisons were performed of the changes in motor function before and after the travel restrictions. RESULTS: The change in range of motion (ROM) of ankle dorsiflexion was significantly decreased after the travel restrictions. Changes in body mass index and other motor function parameters were not significant. DISCUSSION: An apparent decrease in the amount of physical activity due to travel restrictions in response to COVID-19 negatively affected ankle dorsiflexion ROM but not other motor functions. A more sedentary lifestyle and lack of regular physical therapy services most likely contributed to this reduction. The use of remote rehabilitation tools with the involvement of physiotherapists may help mitigate such changes and prevent more severe physical decline.

Reversible cerebral vasoconstriction syndrome with cardiac involvement during treatment for iron deficiency anemia: caser report.

BACKGROUND: The diagnosis and therapy of reversible cerebral vasoconstriction syndrome (RCVS) tends to focus on neurological symptoms, but less attention has been paid the occurrence of extracerebral lesion such as the myocardium. CASE PRESENTATION: A 40-year-old woman taking iron supplements for iron deficiency anemia due to menorrhagia had suffered from a thunderclap headache and seizure. Brain magnetic resonance imaging revealed high-intensity lesions bilaterally in the cerebellar and cerebral hemispheres. Her symptoms once subsided with steroids and anticonvulsant therapy; however, she experienced a severe headache again while bathing and was transferred to our hospital. Based on the clinical course and imaging data, she was diagnosed as having RCVS triggered by a rapid improvement of anemia. At the same time, she had cardiac involvement revealed by electro and echocardiographs despite without chest symptoms. After the administration of a calcium channel blocker and nitrite, her cerebral and cardiac involvements were rapidly improved. CONCLUSIONS: The case presented RCVS with transient myocardial damage. With RCVS, we should always pay attention to the complication of extracerebral lesions.

An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging.

AIM: The amyloid cascade hypothesis posits that the accumulation of amyloid ß (Aß) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging. METHODS: Path analysis was used to estimate the relationships among Aß accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aß-positive subjects. We also performed additional regression analyses to evaluate the effect of Aß on the toxicity of tau aggregation/neuroinflammation. RESULTS: Path analysis supported our hypothesized model: Aß accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant. CONCLUSION: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aß not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease.

Convergent validity of a simplified device and relationship between blood lactate and salivary lactate after a vertical squat jump in healthy non-athletes.

[Purpose] The aims of this study were 1) to examine the convergent validity between Lactate pro 2 and a standard JCA-BM 8000 automatic analyzer using salivary lactate and 2) to investigate the relationship between blood and salivary lactate levels after a vertical squat jump. [Participants and Methods] Healthy non-athletes participated in this observational study. The participants performed a vertical squat jump for 1 min 30 s. Blood and salivary lactate levels were measured before and after exercise using Lactate Pro 2. [Results] The intraclass correlation coefficient between Lactate Pro 2 and the JCA-BM 8000 automatic analyzer was 0.773, which can be considered as substantial convergent validity. However, in some samples, the salivary lactate level was out of the measurable range, and numerical values could not be obtained. The cross-correlation function between the blood and salivary lactate levels was 0.535 at lag 0 and 0.750 at lag 1, which indicated a 5-min lag between the salivary and blood lactate values. [Conclusion] Salivary lactate levels can be easily measured using Lactate Pro 2, although its sensitivity needs to be resolved. Further research is required for salivary lactate level, which can be collected non-invasively, to be used as an alternative parameter to blood lactate level.

Triggering factors for febrile attacks in Japanese patients with familial Mediterranean fever.

OBJECTIVES: We occasionally encounter patients with familial Mediterranean fever (FMF) whose attacks are triggered by specific factors; however, information regarding these factors is limited. Our purpose was to identify the factors that trigger febrile attacks in Japanese patients with FMF. METHODS: Our retrospective study included 372 patients (229 women, 143 men) with FMF, who were diagnosed between April 2007 and June 2018. We retrospectively investigated clinical features, genetic variants, and the factors that the patients perceived to have triggered their attacks. Patients completed a questionnaire that included the following triggering factors, anxiety, psychological stress, tiredness, excitement, environmental change, and menstruation. RESULTS: Of 372 patients, 180 (49.4%) reported some triggering factors. Psychological stress and tiredness were commonly reported factors regardless of sex; however, menstruation (39.7%, n=91) was the most commonly reported triggering factor in female patients with FMF. Menstrual-related patients had a younger age of onset and diagnosis, a higher frequency of peritonitis, and a higher rate of patients with endometriosis compared with the non-menstrual-related patients. CONCLUSIONS: Gaining an understanding of these triggering factors could help to reduce attacks and educate the patients. Clinicians may need to consider FMF for patients who have fever and serositis that occurs with every menstrual period.

Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by an absence of the dystrophin protein in bodywide muscles, including the heart. Cardiomyopathy is a leading cause of death in DMD. Exon skipping via synthetic phosphorodiamidate morpholino oligomers (PMOs) represents one of the most promising therapeutic options, yet PMOs have shown very little efficacy in cardiac muscle. To increase therapeutic potency in cardiac muscle, we tested a next-generation morpholino: arginine-rich, cell-penetrating peptide-conjugated PMOs (PPMOs) in the canine X-linked muscular dystrophy in Japan (CXMDJ) dog model of DMD. A PPMO cocktail designed to skip dystrophin exons 6 and 8 was injected intramuscularly, intracoronarily, or intravenously into CXMDJ dogs. Intravenous injections with PPMOs restored dystrophin expression in the myocardium and cardiac Purkinje fibers, as well as skeletal muscles. Vacuole degeneration of cardiac Purkinje fibers, as seen in DMD patients, was ameliorated in PPMO-treated dogs. Although symptoms and functions in skeletal muscle were not ameliorated by i.v. treatment, electrocardiogram abnormalities (increased Q-amplitude and Q/R ratio) were improved in CXMDJ dogs after intracoronary or i.v. administration. No obvious evidence of toxicity was found in blood tests throughout the monitoring period of one or four systemic treatments with the PPMO cocktail (12 mg/kg/injection). The present study reports the rescue of dystrophin expression and recovery of the conduction system in the heart of dystrophic dogs by PPMO-mediated multiexon skipping. We demonstrate that rescued dystrophin expression in the Purkinje fibers leads to the improvement/prevention of cardiac conduction abnormalities in the dystrophic heart.

Late-onset familial Mediterranean fever in Japan.

Objectives: Most patients with familial Mediterranean fever (FMF) have their first attack at age < 20 years. Information about late-onset (age ≥40 years) FMF is limited. We aimed to evaluate the demographic, clinical, and genetic characteristics of late-onset FMF patients in the Japanese population.Methods: We retrospectively analyzed 292 patients with FMF. Patients were divided into three groups according to age of disease onset: Group I, ≤19 years; Group II, 20-39 years; and Group III, ≥40 years.Results: Of 292 patients, 44 (15.1%) experienced their first attack at age ≥40 years. While high fever (97.7%) and arthritis (45.5%) were common symptoms in Group III patients, peritonitis (40.9%) and pleuritis (25.0%) were significantly lower than in other groups. The frequency of patients carrying p.M694I (18.2%), which is the most representative mutation in Japan, was significantly lower in Group III than in Group I. The response to colchicine therapy was good (95.1%) and similar in all groups.Conclusions: In Japan, more patients than expected had late-onset FMF. They had a milder form of disease, with less frequent peritonitis and pleuritis. The response to colchicine treatment was good. Clinicians should consider FMF for patients with unexplained recurrent febrile episodes, regardless of age.

Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes.

Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by frameshift mutations in the DMD gene. DMD involves cardiac muscle, and the presence of ventricular arrhythmias or congestive failure is critical for prognosis. Several novel therapeutic approaches are being evaluated in ongoing clinical trials. Among them, exon-skipping therapy to correct frameshift mutations with antisense oligonucleotides is promising; however, their therapeutic efficacies on cardiac muscle in vivo remain unknown. In this study, we established induced-pluripotent stem cells (iPSCs) from T cells from a DMD patient carrying a DMD-exon 46-55 deletion, differentiated the iPSCs into cardiomyocytes, and treated them with phosphorodiamidate morpholino oligomers. The efficiency of exon-45 skipping increased in a dose-dependent manner and enabled restoration of the DMD gene product, dystrophin. Further, Ca2+-imaging analysis showed a decreased number of arrhythmic cells and improved transient Ca2+ signaling after exon skipping. Thus, exon-45 skipping may be effective for cardiac involvement in DMD patients harboring the DMD-exon 46-55 deletion.

Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease.

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-ß deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-ß-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-ß-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-ß-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-ß-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-ß deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-ß deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.