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IMPORTANCE: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. OBJECTIVE: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD. DESIGN, SETTING, AND PARTICIPANTS: This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS–based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS–based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. MAIN OUTCOMES AND MEASURES: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status. RESULTS: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. CONCLUSIONS AND RELEVANCE: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.

BackgroundAlthough research indicates that a physically active lifestyle has the potential to prevent cognitive decline and dementia, the optimal type of physical activity/exercise remains unclear. The present study aimed to determine the cognitive benefits of a golf-training programme in community-dwelling older adults.MethodsWe conducted a randomised controlled trial between August 2016 and June 2017 at a general golf course. Participants included 106 Japanese adults aged 65 and older. Participants were randomly assigned to either a 24-week (90–120 min sessions/week) golf-training group or a health education control group. Postintervention changes in Mini-mental State Examination (MMSE) and National Centre for Geriatrics and Gerontology-Functional Assessment Tool scores were regarded as primary outcome measures. Secondary outcome measures included changes in physical performance and Geriatric Depression Scale (GDS) scores.ResultsA total of 100 participants (golf training, n=53; control, n=47) completed the assessments after the 24-week intervention period. The adherence to the golf programme was 96.2% (51/53 participants). Analysis using linear mixed models revealed that the golf training group exhibited significantly greater improvements in immediate logical memory (p=0.033), delayed logical memory (p=0.009) and composite logical memory (p=0.013) scores than the control group. However, no significant changes in MMSE, word memory, Trail Making Test or Symbol Digital Substitution Test scores were observed. In addition, no significant changes in grip strength, walking speed or GDS were observed.ConclusionsGolf-based exercise interventions may improve logical memory in older adults, but no significant changes in other cognitive tests. Further follow-up investigations are required to determine whether the observed effects are associated with delayed onset of mild cognitive impairment or Alzheimer’s disease in older adults.Trial registration numberUMIN-CTR UMIN000024797; Pre-results.

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient’s sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A (FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.

Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O2uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation–CO2production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE-5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg·min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline (P= 0.047); VP was greater after three months than at baseline (P= 0.019) and further improved at six months compared with three months (P= 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal-oriented treatment for PAH.

Background: To date, very little is known about the nature of sarcopenia in subjects with cognitive impairment. The aims of this study were firstly to clarify the prevalence of sarcopenia at various stages of cognitive impairment, and secondly to examine factors related to sarcopenia in men and women with cognitive impairment. Method: The subjects were 418 outpatients (normal cognition; NC: 35, amnestic mild cognitive impairment; aMCI: 40, Alzheimer disease; AD: 343) who attended the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan during the period from October 2010 to July 2014. Cognitive status, vitality, depressive mood, body mass index, hand grip strength, timed up and go test, skeletal muscle mass and serum levels of 25-hydroxyvitamin D, albumin and creatinine were assessed. Sarcopenia was defined as the presence of both poor muscle function (low physical performance or low muscle strength) and low muscle mass. We performed the univariate and multivariate logistic regression analyses to explore factors associated with sarcopenia. Results: The overall prevalence of sarcopenia was 21.1% (NC = 8.6%, aMCI = 12.5%, AD = 23.3%). In both sexes, factors associated with sarcopenia were age (P < .01), body mass index (P < .001) and vitality (P < .05). In women, serum level of 25-hydroxyvitamin D was associated with sarcopenia (P < .05). Conclusion: Low vitality could be a dementia-specific risk factor for sarcopenia. Prevention of sarcopenia in patients with cognitive impairment should be approached from physical and psychologic points of view.

Background: It has been reported that periodontitis is associated with Alzheimer’s disease. However, the association between paranasal sinusitis and Alzheimer’s disease has not been studied, although olfactory dysfunction frequently precedes the progress of dementia or Alzheimer’s disease. Methods: We studied 783 patients (283 men, 500 women; mean age 77.0 ± 7.9 years) who visited the Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, and 2139 control subjects who participated in a population-based study conducted by the National Institute for Longevity Sciences – Longitudinal Study of Aging (NILS–LSA) in Japan. Sinusitis was evaluated using magnetic resonance imaging (MRI) according to the Lund–Mackay scoring system. A sinusitis score of ≥ 4 was classified as positive and a score of ≤ 3 was classified as negative. Results: The prevalence of positive sinusitis was 6.3% in patients with a mini-mental state examination (MMSE) score of < 24 (n = 507), and 5.7% in patients with Alzheimer’s disease (n = 280). The rate of positive sinusitis was7.2% in the control group. The prevalence of sinusitis was not significantly different between normal controls and patients with dementia or Alzheimer’s disease after adjustments for age and sex. The rate of positive sinusitis was higher in male than in female subjects in both groups. Conclusion: The prevalence of sinusitis in patients with Alzheimer’s disease or dementia was not higher than in the general population.

Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function and carotid intima-media thickness. Further, we determined whether a reduced dosage of estrogen may maintain its beneficial effects.

Recent advances in molecular genetics made the mouse model important for studying the genetic basis of hypertension and vascular diseases such as the components of the renin–angiotensin system. This study was undertaken to investigate the role of angiotensin converting enzyme (ACE) in the mouse vascular injury model.

We investigated the expression of mRNA for arginine vasopressin in vascular smooth muscle cells and A10 cells using reverse transcription–polymerase chain reaction and Northern blot analysis. Arginine vasopressin mRNA was identified both in rat aortic smooth muscle cells and A10 cells, suggesting that arginine vasopressin is locally produced in vascular smooth muscle cells. Arginine vasopressin, a potent vasoconstrictor, may modulate vascular function in an autocrine or paracrine fashion.

The effect of dietary calcium (Ca) supplementation on blood pressure (BP) and the central nervous system (CNS) mechanism underlying this effect were studied in angiotensin II (Ang II)-induced hypertensive rats. The effects of dietary Ca (0.5, 2, 4%) on systolic blood pressure (SBP), ionized Ca concentration (Ca++) in cerebrospinal fluid (CSF) and central norepinephrine (NE) turnover were investigated in male Wistar rats receiving subcutaneous infusion of Ang II (100 ng/min). Central NE turnover was studied by measuring 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration in CSF with multiple electrode liquid chromatography. Ang II significantly increased SBP, and dietary Ca dose-dependently attenuated the increase. SBP inversely correlated with Ca++ and MHPG in CSF. Intracerebroventricular injection of CaCl2 more markedly reduced BP in Ang II-treated rats than that in control rats. These results suggest that modulation of central NE turnover possibly caused by the increase in CNS Ca++ is involved in the anti-hypertensive mechanism of dietary Ca supplementation in Ang II-induced hypertensive rats.

Parathyroid hormone-related peptide (PTHrP) is a potent vasodilatory peptide whose expression has been demonstrated in various tissues. The present study was undertaken to examine the regulation of PTHrP expression in cultured endothelial cells derived from human umbilical vein. Immunoradiometric assay revealed that the amount of PTHrP in the conditioned medium was increased by both tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) in both a time- and a dose-dependent manner. The induction of PTHrP mRNA was also observed, with a peak after 2 hours of incubation with both TNF-α and IL-1β. Angiotensin II, endothelin-1, and arginine vasopressin had no affect on PTHrP production. Our results suggest that PTHrP produced in vascular endothelial cells in response to cytokines may modulate vascular function as a local factor.

To investigate the mechanism underlying the antiatherogenic effect of estrogen, we examined the role of estrogen in the regulation of endothelin-1 (ET-1) production by cultured bovine carotid arterial endothelial cells. Treatment of the cells with 17β-estradiol dose dependently inhibited gene expression and peptide secretion of ET-1. This inhibitory effect of 17β-estradiol was more marked when ET-1 production was stimulated by transforming growth factor-β1. Simultaneous addition of ICI 182,780, a pure estrogen receptor antagonist, completely blocked the effect of 17β-estradiol, indicating that 17β-estradiol acted via estrogen receptor. These results suggest that reduced ET-1 production by endothelial cells may be involved in the vasoprotective effect of estrogen.

Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, is expressed at a high level in adipose tissue and plays an important role in adipocyte differentiation. In the present study, we identified the expression of PPARγ in rat aortic smooth muscle cells (RASMC) using reverse transcription-polymerase chain reaction and gel mobility shift assay. In addition, to investigate whether PPARγ in RASMC is functional or not, we examined the effect of two specific ligands for PPARγ, a thiazolidinedione anti-diabetic agent, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2, on the transcriptional activity of PPAR responsive element (PPRE). A significant increase in the activity of PPRE by addition of these ligands was found. These results suggest that in RASMC, target genes for PPARγ may be activated by specific ligands for PPARγ through PPRE in their promoters. In conclusion, PPARγ is expressed and functional in vascular smooth muscle cells.

The effects of intracerebroventricular (i.cv.) administration of calcitonin gene-related (CGRP) on blood pressure and heart rate (HR), and the underlying mechanisms were studied in conscious rats. CGRP (0.1–3.0 nmol i.cv.) increased mean arterial blood pressure (MABP) and HR. CGRP (3.0 nmol i.cv.) also significantly increased both plasma norepinephrine and epinephrine concentrations. Pretreatment with 16.5 nmol i.cv. CGRP(8–37), a specific CGRP receptor antagonist, significantly inhibited the i.cv. CGRP (1.0 nmol)-induced increases in MABP and HR. Phenoxybenzamine inhibited the i.c.v. CGRP-induced increase in MABP, while propranolol suppressed the tachycardiac response to i.cv. CGRP. Chemical sympathectomy by 6-hydroxydopamine inhibited the increases in MABP and HR produced by i.cv CGRP. These results suggest that the central pressor and tachycardiac effects of i.c.v. CGRP are mediated by catecholamine release due to stimulation of sympathetic nervous system activity, possibly via specific CGRP receptors in the central nervous system.

Age-related changes in the effect of parathyroid hormone-related protein (PTHrP) on the cytosolic free calcium level ([Ca+]i) and on the tension in rat aortic smooth muscle were investigated. The possible involvement of cAMP, a second messenger of PTHrP, in such changes was also investigated. Spiral aortic strip preparations without endothelium from 8-weeks, 6-months, and 24-months old rats were treated with fura 2/AM, and the fluorescence ratio R340/380, an index of [Ca+]i was measured. Simultaneously, the tension of the preparations was measured. PTHrP-(1–34) and dibutyryl cAMP produced concentration-dependent decreases in the tension and in R340/380 in aortas precontracted with phenylephrine (10-7 M). These effects were significantly lower in the aortas of 24-months old rats than in the vessels of 8-weeks and 6-months old rats. The effects were similar in the aortas of 8-weeks and 6-months old rats. PTHrP-(1–34) concentration-dependently increased cAMP production in vascular smooth muscle cells (VSMCs) from 8-weeks old rats. However, the increase in cAMP production was significantly lower in cultured VSMCs from 6-months and 24-months old rats than in cells from 8-weeks old rats.