One-leg standing time is a simple measure for loss of skeletal muscle mass and fat deposition in muscle: the J-SHIPP study.

BACKGROUNDS: One-leg standing time (OLST) has been frequently used physical performance measure; however, what muscular characteristics OLST represents remains uncertain. AIM: This cross-sectional study aimed to investigate the association between OLST and muscle characteristics to clarify the possibility of using OLST as a physical performance measure. METHODS: Study participants comprised 1144 older adults aged 65 years or older. Computed tomography images provided mid-thigh skeletal muscle cross-sectional area and mean attenuation value. OLST was measured for a maximum of 60 s. Static postural instability was assessed using a posturography. RESULTS: A frequency of OLST < 20 s was increased by quartiles of muscle cross-sectional area (Q1: 33.6, Q2: 12.8, Q3: 13.6, Q4: 11.9%, P < 0.001) and mean attenuation value (Q1: 32.3, Q2: 21.7, Q3: 14.3, Q4: 7.7%, P < 0.001). Results of the multinomial regression analysis indicated that muscle cross-sectional area and mean attenuation value were independently associated with an OLST of less than 20 s. The crude odds ratio of OLST less than 20 s for the lowest quartiles of both cross-sectional area and mean attenuation value was 4.19 (95% CI: 3.01 - 5.84). The cross-sectional area of muscles with greater fat deposition was inversely associated with OLST, while that with smaller fat deposition showed a positive association with OLST, indicating why mean attenuation value and cross-sectional area were independently associated with OLST. No clear relationship was observed with static postural instability. CONCLUSION: OLST was a simply measurable quantifiable physical measure representing the loss of muscle mass and quality in older adults.

Ingestion of a collagen peptide containing high concentrations of prolyl-hydroxyproline and hydroxyprolyl-glycine reduces advanced glycation end products levels in the skin and subcutaneous blood vessel walls: a randomized, double-blind, placebo-controlled study.

In this randomized, double-blind, placebo-controlled study, we investigated the effects of collagen peptides (CP) containing high concentrations of prolyl-hydroxyproline and hydroxyprolyl-glycine on advanced glycation end products (AGEs) levels in the skin and subcutaneous blood vessel walls. A total of 31 individuals aged 47-87 years were randomly assigned to receive either 5 g/day of fish-derived CP or a placebo for 12 weeks. Body and blood compositions and AGEs levels were measured at the beginning and end of the study. No adverse events were observed, and both groups' blood and body compositions did not change significantly. However, the CP group had significantly lower AGEs levels and a slightly lower insulin resistance index (homeostasis model assessment ratio [HOMA-R]) than the placebo group. In addition, the percentage changes in AGEs and HOMA-R levels were positively and strongly correlated in both groups. These findings suggest that fish-derived CP may be effective in reducing AGEs levels and improving insulin resistance.

Insulin deficiency promotes formation of toxic amyloid-ß42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model.

The toxic conformer of amyloid ß-protein (Aß) ending at 42 (Aß42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aß42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aß42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aß42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aß42 levels and the ratio of toxic Aß42 conformer/total Aß42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aß42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aß42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aß42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = -0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aß42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3ß measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aß42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aß. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aß burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Therapeutic Strategies for Alzheimer's Disease in the View of Diabetes Mellitus.

Recently, Alzheimer's disease (AD) is understood as "diabetes of the brain" or "type 3 diabetes." Recent clinical trials of anti-amyloid ß-protein (Aß) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aß degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aß-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.

A double-blind, placebo-controlled, randomised clinical study of the effect of pork collagen peptide supplementation on atherosclerosis in healthy older individuals.

We examined whether baPWV could be affected by pork collagen peptide (CP) ingestion. Seventy subjects were randomized into two groups (2.5 g/day CP and 2.5 g/day placebo). A significant reduction in baPWV was observed in the CP group compared to the placebo group. This study demonstrated that pork CP may contribute to the prevention of atherosclerosis in elderly.

A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy.

The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.

ABCA7 Deficiency Accelerates Amyloid-ß Generation and Alzheimer's Neuronal Pathology.

In Alzheimer's disease (AD), the accumulation and deposition of amyloid-ß (Aß) peptides in the brain is a central event. Aß is cleaved from amyloid precursor protein (APP) by ß-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aß was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aß by increasing the levels of ß-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. SIGNIFICANCE STATEMENT: Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-ß (Aß) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aß deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aß production by increasing the levels of ß-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aß clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2.

OBJECTIVE: The objective of this study was to identify new causes of Charcot-Marie-Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT. METHODS: To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. RESULTS: We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aß)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aß in Pittsburgh compound-B positron emission tomography imaging. INTERPRETATION: Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT.

Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population.

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T (P = 5.39×10-47, 1.81×10-22, 2.09×10-16, and 9.25×10-15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber's hereditary optic neuropathy.

We report the first case of definite neuromyelitis optica (NMO) with a pathogenic mitochondrial DNA (mtDNA) mutation for Leber's hereditary optic neuropathy (LHON) (G11778A point mutation). A 36-year-old Japanese woman had experienced recurrent neurological symptoms originating from involvements of the optic nerves and spinal cord. She finally lost her bilateral vision, and spastic paraparesis and sensory disturbances below the T6 level remained despite intensive immunotherapies. Brain and spinal magnetic resonance imaging (MRI) revealed T2-high-intensity lesions in the optic nerves and thoracic spinal cord, but no lesions in the brain. A blood examination revealed positivity for both anti-aquaproin-4 antibodies and an LHON mtDNA mutation.

Episodic ataxia type 2 with a novel missense variant (Leu602Arg) in CACNA1A.

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis.

We report a sporadic case of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) confirmed by biopsy and colony-stimulating factor 1 receptor (CSF1R) sequencing. A 28-year-old woman developed progressive spastic gait and dysarthria. Brain T2/FLAIR-weighted magnetic resonance imaging showed bilateral high signal intensity lesions in the parietal deep white matter, which subsequently extended anteriorly. Biopsied brain specimens demonstrated demyelinated white matter tissue with axonal spheroids infiltrated with foamy macrophages, and CD8(+) and CD4(+) T cells. She had a heterozygous mutation, c.2381T>C (p.782 Ile>Thr), in CSF1R. This is the first genetically proven case of HDLS mimicking primary progressive multiple sclerosis.

Associations between adiponectin and leptin levels and skeletal muscle mass and myosteatosis in older adults: The Shimanami Health Promoting Program study.

AIM: Identifying plasma molecules associated with skeletal muscle properties can elucidate the pathophysiology of sarcopenia. Because adipocytokines are a promising candidate marker, the current study aimed to clarify the possible associations between adiponectin and leptin levels and mid-thigh muscle cross-sectional area and mean attenuation value, which are indices of muscle mass and fat deposition in muscle, respectively. METHODS: The current study included 1440 older Japanese adults (mean age 69.3 years). Mid-thigh skeletal muscle cross-sectional area and mean attenuation value were evaluated through computed tomography scan. A low attenuation value showed a greater fat deposition in muscle. Circulating adiponectin and leptin levels were assessed using blood specimens collected during the baseline investigation. RESULTS: Plasma leptin level was inversely correlated with muscle cross-sectional area, but not with attenuation value. The association with cross-sectional area was independent of possible confounding factors including body size (Q1: reference; Q2: ß = -0.032, P = 0.033; Q3: ß = -0.064, P < 0.001; Q4: ß = -0.111, P < 0.001). In contrast, adiponectin level was independently and inversely associated with attenuation value (Q1: reference; Q2: ß = -0.044, P = 0.122; Q3: ß = -0.080, P = 0.006; Q4: ß = -0.159, P < 0.001), but not with cross-sectional area. These associations between adipocytokine levels and muscle properties were independent of abdominal fat area and insulin resistance. CONCLUSIONS: There were adiposity- and insulin resistance-independent associations between adipocytokines levels and skeletal muscle mass and fat deposition in muscle, suggesting an involvement of adipocytokines in muscle properties. Geriatr Gerontol Int 2023; 23: 444-449.

Bioimpedance phase angle is independently associated with myosteatosis: The Shizuoka study.

BACKGROUND & AIMS: Phase angle (PhA) calculated from the resistance and reactance measured using a bioimpedance device was suggested to represent the degree of fat deposition in muscle (myosteatosis), though no direct evidence is available. We aimed to clarify the possible association between PhA and skeletal muscle myosteatosis in community-dwelling middle-aged to older adults. METHODS: Participants consisted of 424 Japanese (aged ≥50 years). Leg PhA and skeletal muscle mass index (SMI) were obtained by bioelectrical impedance analysis. The mean attenuation values and cross-sectional area of the mid-thigh skeletal muscle were calculated from computed tomography images and considered as indexes of myosteatosis and skeletal muscle mass, respectively. RESULTS: Leg PhA was positively associated with SMI, and cross-sectional area and mean attenuation value at mid-thigh. Multiple regression analysis adjusted for possible covariates identified leg PhA (ß = 0.214) and SMI (ß = 0.260) as independent factors of mid-thigh muscle cross-sectional area (P < 0.001), while leg PhA (ß = 0.349, P < 0.001) but not SMI (P = 0.645) was associated with mean attenuation value. Similar results were observed in the analysis in the older (≥65 years) subpopulation. The combination of low SMI and low leg PhA showed stepwise association with cross-sectional area, while only individuals with low leg PhA had lower mean attenuated value. CONCLUSIONS: Leg PhA was independently associated with mean attenuated value of the mid-thigh skeletal muscle, suggesting that the assessment of PhA in combination with SMI could provide additional information for the evaluation of muscle properties.

Case report: Frontotemporal dementia and amyotrophic lateral sclerosis caused by a missense variant (p.Arg89Trp) in the valosin-containing protein gene.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Apomorphine treatment in Alzheimer mice promoting amyloid-ß degradation.

OBJECTIVE: Intracellular amyloid ß-protein (Aß) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. METHODS: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aß degradation, activity of Aß-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. RESULTS: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aß, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aß, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells. INTERPRETATION: 3xTg-AD mice show intraneuronal Aß accumulation and memory disturbances before extracellular Aß deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aß and p-tau levels by APO treatment strongly suggest that intraneuronal Aß is an important therapeutic target and APO will be a novel drug for AD.

Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

INTRODUCTION: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. METHODS: A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. RESULTS: A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. CONCLUSIONS: Progressive myopathy involvement could be a hitherto unknown manifestation of APECED.

Alzheimer's disease: diagnosis by different methods of voxel-based morphometry.

PURPOSE: The purpose of this study was to determine the optimal computational options in voxel-based morphometry (VBM) for discrimination between Alzheimer's disease (AD) patients and healthy control (HC) subjects. MATERIALS AND METHODS: Structural magnetic resonance images of 24 AD patients and 26 HC subjects were analyzed using VBM to determine brain regions with significant gray matter (GM) loss due to AD. The VBM analyses were performed with 4 different computational options: gray matter concentration (GMC) analysis with and without global normalization, and gray matter volume (GMV) analysis, with and without global normalization. Statistical maps calculated with the 4 computational options were obtained at 3 different P-value thresholds (P < 0.001, P < 0.0005, and P < 0.0001, uncorrected for multiple comparisons), yielding a total of 12 sets of maps, from which regions-of-interest (ROI) were generated for subsequent analyses of performance in terms of discrimination between AD patients and HC subjects as based on the mean value of either the GMC or GMV within the ROI for each of the 12 maps. Discrimination performance was evaluated by means of comparing the area-under-the-curve derived from the receiver-operating characteristic analysis as well as on the accuracy of the discrimination. RESULTS: Discrimination based on GMC analysis resulted in better performance than that based on GMV analysis. The best discrimination performance was achieved with GMC analysis either with or without proportional global normalization. CONCLUSION: The findings suggested that GMC-based VBM is better suited than GMV-based VBM for discrimination between AD patients and HC subjects.