To investigate the relationship between selenium (Se) based multi-element combined exposure and cognitive function in rural elderly individuals, a cross-sectional study was conducted. The study involved 416 older adults aged 60 and above, residing in four different areas of Enshi county, China, with varying soil Se levels. Inductively coupled plasma mass spectrometry (ICP-MS) was employed to measure the concentrations of Se, copper (Cu), iron (Fe), zinc (Zn), calcium (Ca), magnesium (Mg), cadmium (Cd), arsenic (As), and lead (Pb) in whole blood. Nine standard cognitive tests were applied to assess cognitive function. Analysis of the least absolute shrinkage and selection operator regression (LASSO), covariance (ANCOVA), and generalized linear model (GLM) were utilized to investigate the relationship between element exposure and cognitive function. The results of LASSO revealed that Se, Cu, Fe, Zn, Ca, and Pb were independently identified to be associated with cognition. Both ANCOVA and GLM demonstrated that Se and Ca were correlated with cognitive function. The multi-element model showed higher composite Z scores of 0.32 (95% CI: 0.09 to 0.55) for log-transformed Se ( P = 0.007), 0.75 (95% CI: 0.01 to 1.49) for log-transformed Cu ( P = 0.048), and a lower score of − 0.67 (95% CI: − 1.26 to − 0.08) for log-transformed Ca ( P = 0.025). Furthermore, there was evidence that Se could counteract the negative impact of Ca on cognitive function ( P for interaction = 0.031). Our findings suggested that higher levels of Se and Cu were associated with better cognitive function in the elderly and Se can counteract the cognitive damage caused by Ca.

Background and aims: Earlier studies have reported inconsistent association between selenium (Se) and homo-cysteine (Hcy) levels, while no evidence could be found from Chinese population. To fill this gap, we investigated the association between blood Se and hyperhomocysteinemia (HHcy) of rural elderly population in China.Methods: A cross-sectional study on 1823 participants aged 65 and older from four Chinese rural counties was carried out in this study. Whole blood Se and serum Hcy concentrations were measured in fasting blood samples. Analysis of covariance and restricted cubic spline models were used to examine the association between Se and Hcy levels. Logistic regression models were used to evaluate the risk of prevalent HHcy among four Se quartile groups after adjusting for covariates.Results: For this sample, the mean blood Se concentration was 156.34 (74.65) mu g/L and the mean serum Hcy concentration was 17.25 (8.42) mu mol/L. A significant non-linear relationship was found between blood Se and serum Hcy, the association was inverse when blood Se was less than 97.404 mu g/L and greater than 156.919 mu g/L. Participants in the top three blood Se quartile groups had significantly lower risk of prevalent HHcy compared with the lowest quartile group. When defined as Hcy> 10 mu mol/L, the odds ratios and 95% confidence interval of HHcy were 0.600 (0.390, 0.924), 0.616 (0.398, 0.951) and 0.479 (0.314, 0.732) for Q2, Q3, and Q4 Se quartile groups compared with the Q1 group, respectively. When defined as Hcy >= 15 mu mol/L, the odds ratios and 95% confidence interval of HHcy were 0.833 (0.633, 1.098) and 0.827 (0.626, 1.092), 0.647 (0.489, 0.857) for Q2, Q3, and Q4 Se quartile groups compared with Q1 group.Conclusions: Our findings suggest that higher blood Se level could be a protective factor for HHcy in the elderly.

Studies have established the association between blood β-amyloid (Aβ) levels and Alzheimer’s disease, but population-based studies concerning the association between selenium (Se) and Aβ levels in blood samples are very limited. Therefore, we explored the association in an elderly population with Se status and serum Aβ measures. A cross-sectional study on 469 elderly individuals from four rural counties with diverse soil Se levels was carried out. Fasting blood Se, serum selenoprotein P (SELENOP), and glutathione peroxidase (GPX), serum Aβ42, and Aβ40 were measured. Quantile regression models were used to determine the associations of blood Se, serum GPX, and SELENOP with Aβ levels. Significant negative associations were observed between blood Se and serum Aβ42 and Aβ40 levels at all percentiles (P < 0.05). The associations were generally stronger at higher Aβ42 and Aβ40 percentiles than lower Aβ42 and Aβ40 percentiles. Blood Se was positively associated with serum Aβ42/Aβ40 ratio at 25th, 50th, and 75th percentiles. Significant positive associations were observed between serum GPX and Aβ42 and Aβ40 levels at all percentiles (P < 0.05). The positive associations were generally stronger at higher Aβ42 and Aβ40 percentiles than at lower percentiles. Serum GPX was negatively associated with Aβ42/Aβ40 ratio at 25th, 50th, 75th, and 95th percentiles. No associations with serum SELENOP and Aβ levels were observed. Our results suggest that higher Se levels are associated with lower serum Aβ42 and Aβ40 levels and with higher Aβ42/Aβ40 ratio, and the results are specific for different selenoproteins.

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE). To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment. Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities. At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE. Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC. SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810

Cadmium (Cd) exposure has been reported to have neurotoxic effects in animal studies and associated with increased Alzheimer's Disease mortality and lower cognitive function in cross-sectional and case-control studies. However, no results from longitudinal studies on Cd and cognitive decline are available. In this prospective cohort study, we recruited 1867 participants aged 65 years or older from rural areas in China, blood Cd and cognitive function were measured at baseline (2010-2012), and 1554 participants completed cognitive function tests during a 3-year follow-up (2013-2015). Cognitive function was evaluated using nine standardized cognitive tests: The Community Screening Instrument for Dementia, the CERAD Word List Learning. Word list recall, IU Story Recall, Animal Fluency Test, Boston Naming Test, Stick Design, Delayed Stick Design and the IU Token Test. Analysis of covariance models and logistic regression models were used to determine the association between Cd and standardized cognitive decline adjusting for covariates. The median blood Cd concentration of this study population was 2.12 mu g/L and the interquartile range was 1.42-4.64 mu g/L Significant association of higher Cd levels with lower cognitive scores were observed in five individual cognitive tests ( Delayed Stick Design Test, Boston Naming Test, CERAD Word List Learning Test, Word List Recall Test and IU Story Recall Test) and the composite cognitive score adjusting for multi-covariates at baseline. Higher Cd levels were significantly associated with greater 3-year cognitive decline in Delayed Stick Design Test, Boston Naming Test, Hi Token Test, Word List Recall Test and Composite cognitive score. For these cognitive tests, participants in the top two Cd quartile groups had significantly greater decline than those in the lowest Cd quartile group, while the two lowest Cd quartile groups were not significantly different Our findings suggest that higher Cd exposure is associated with greater cognitive decline in older Chinese adults. (C) 2020 Elsevier B.V. All rights reserved.

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT 1B/1D receptors. The discovery that the serotonin 1F (5-HT 1F ) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT 1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT 1B receptors, the activation of 5-HT 1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT 1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT 1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT 1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT 1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT 1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT 1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT 1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Migraine is a common and disabling disorder with substantial personal, social, and economic burden that affects 37 million people in the United States. Risk factors for migraine include age, sex, and genetics. The goal of acute treatment of migraine attacks is to stop the pain and associated symptoms of the migraine attack and return the patient to normal function. The acute treatment landscape for migraine has recently expanded beyond the standard nonsteroidal anti-inflammatory drugs, analgesics, triptans, ergotamines, and combination therapies, to include neuromodulation devices, and recently approved calcitonin gene-related peptide receptor antagonists and a serotonin (5-HT1F) receptor agonist. Unmet acute treatment needs still exist due to lack of efficacy, unwanted side effects, or contraindication to treatment. Effective treatment of migraine requires the clinician to assess the patient, make an accurate diagnosis, and then offer appropriate therapy based on the patient's medical history, comorbidities, and preferences, as well as published clinical evidence. The objective of this narrative review is to familiarize primary care clinicians with the variety of acute treatment options available in the United States today based on clinical trial findings, meta-analyses, evidence-based guidelines, and professional society consensus statements.

ABSTRACT Migraine is a common and disabling disorder with substantial personal, social, and economic burden that affects 37 million people in the United States. Risk factors for migraine include age, sex, and genetics. The goal of acute treatment of migraine attacks is to stop the pain and associated symptoms of the migraine attack and return the patient to normal function. The acute treatment landscape for migraine has recently expanded beyond the standard nonsteroidal anti-inflammatory drugs, analgesics, triptans, ergotamines, and combination therapies, to include neuromodulation devices, and recently approved calcitonin gene-related peptide receptor antagonists and a serotonin (5-HT1F) receptor agonist. Unmet acute treatment needs still exist due to lack of efficacy, unwanted side effects, or contraindication to treatment. Effective treatment of migraine requires the clinician to assess the patient, make an accurate diagnosis, and then offer appropriate therapy based on the patient’s medical history, comorbidities, and preferences, as well as published clinical evidence. The objective of this narrative review is to familiarize primary care clinicians with the variety of acute treatment options available in the United States today based on clinical trial findings, meta-analyses, evidence-based guidelines, and professional society consensus statements.

Migraine is associated with substantial functional impairment and affects many aspects of daily life. Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase 3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations. For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (p < 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN. All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose. SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).

Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer’s disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study.

BACKGROUND Alzheimer's disease is characterized by amyloid-beta (A beta) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble A beta, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or A beta 1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline.

INTRODUCTION:Informed consent forms that restrict the distribution of data and samples have been an impediment to advancing Alzheimer's disease (AD) understandings and treatments. The Coalition Against Major Disease public-private partnership developed concise addenda to responsibly broaden data access of informed consent forms.METHODS:Coalition Against Major Disease members identified key elements for ensuring data and biospecimen access, and patient privacy protection according to applicable US law. Collaboration with the Alzheimer's Association established the understandability and relevance of the addenda with AD patients and Care Partners.RESULTS:Two key findings are (1) patients with dementia and Care Partners were shocked that their data and samples are not broadly shared and (2) with diverse feedback, two concise addenda were created to enable data and sample sharing both within and outside future sponsored studies (see Boxes).DISCUSSION:Increasing the access of valuable anonymized patient-level clinical trial data has the potential to inform the foundational and regulatory science required to deliver innovative treatments for AD.

This cross-sectional study aimed to examine the association between selenium levels and diabetes in an older population with life-long natural exposure to selenium in rural China. A total of 1856 subjects aged 65 years or older from four Chinese rural counties with different environmental selenium levels were evaluated. Analysis of covariance models and logistic regression models were used to examine the relationship between nail selenium levels and serum glucose, serum insulin, insulin resistance [using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)], and the risk of diabetes. The mean nail selenium level was 0.461 μg/g and the prevalence rate of diabetes was 8.3% in this population. The mean nail selenium level was significantly higher in the group with diabetes than in the group without diabetes (P<0.0001). The adjusted odds ratios for diabetes were 2.65 (95% CI: 1.48 to 4.73), 2.47 (95% CI: 1.37 to 4.45), and 3.30 (95% CI: 1.85 to 5.88) from the second selenium quartile to the fourth quartile, respectively, compared with the first quartile group. The mean serum glucose and HOMA-IR in the higher selenium quartile groups were significantly higher than those of the lowest quartile group. However, no significant differences in insulin were observed among the four quartile groups. A long-term, higher level of exposure to selenium may be associated with a higher risk of diabetes. Future studies are needed to elucidate the association between selenium and insulin resistance.

INTRODUCTION:Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). METHODS:Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. RESULTS:Sixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during solanezumab treatment. DISCUSSION:Asymptomatic ARIA-E was detected in solanezumab-treated and placebo-treated AD patients. ARIA-E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients.

AbstractIntroductionSolanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD).MethodsPatients (n = 2042) with mild and moderate AD were randomized 1:1 to 400‐mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open‐label extension. Magnetic resonance imaging scans monitored for amyloid‐related imaging abnormalities‐edema/effusion (ARIA‐E) and amyloid‐related imaging abnormalities‐hemorrhage/hemosiderin deposition.ResultsSixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA‐E during the double‐blind phase, and 7 patients developed ARIA‐E during the open‐label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA‐E was present and a patient who developed ARIA‐E during placebo treatment and again during solanezumab treatment.DiscussionAsymptomatic ARIA‐E was detected in solanezumab‐treated and placebo‐treated AD patients. ARIA‐E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients.

OBJECTIVE:To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort.DESIGN:Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels.SETTING:Indianapolis, Indiana.PARTICIPANTS:From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included.MAIN OUTCOME MEASURES:Incident dementia and incident AD.RESULTS:After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD.CONCLUSIONS:Consistent use of statin medications during eight years of follow-up resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia.