Lasmiditan mechanism of action - review of a selective 5-HT1F agonist.

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-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F 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-HT1F 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-HT1F 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-HT1F 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-HT1F 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-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Nail Selenium Level and Diabetes in Older People in Rural China.

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.

Dementia incidence declined in African-Americans but not in Yoruba.

INTRODUCTION: To compare dementia incidence of African-American and Yoruba cohorts aged ≥70 years enrolled in 1992 and 2001. METHODS: African-Americans residing in Indianapolis and Yoruba in Ibadan, Nigeria without dementia were enrolled in 1992 and 2001 and evaluated every 2-3 years until 2009. The cohorts consist of 1440 African-Americans, 1774 Yoruba in 1992 and 1835 African-Americans and 1895 Yoruba in the 2001 cohorts aged ≥70 years. RESULTS: In African-Americans, dementia and Alzheimer's disease (AD) incidence rates were significantly lower in 2001 than 1992 for all age groups except the oldest group. The overall standardized annual dementia incidence rates were 3.6% (95% confidence interval [CI], 3.2%-4.1%) in the 1992 cohort and 1.4% (95% CI, 1.2%-1.7%) in the 2001 cohort. There was no significant difference in dementia or AD incidence between the Yoruba cohorts. DISCUSSION: Future research is needed to explore the reasons for the differential changes in incidence rates in these two populations.

Mild cognitive impairment, incidence, progression, and reversion: findings from a community-based cohort of elderly African Americans.

OBJECTIVE: To examine the long-term outcomes of community-based elderly African Americans by following their transitions from normal cognition to mild cognitive impairment (MCI) to dementia. METHODS: Participants were from the community-based Indianapolis Dementia Project. A total of 4,104 African Americans were enrolled in 1992 or 2001 and followed until 2009 with regularly scheduled evaluation of cognitive assessment. A two-stage sampling was used at each evaluation to select individuals for extensive clinical assessment following the results of Stage 1 cognitive testing. Age- and gender-specific incidence, progression, and reversion rates for MCI were derived using the person-year method in a dynamic cohort and predicted probabilities from weighted multinomial logistic models of transitional probabilities among normal cognition, MCI, and dementia. RESULTS: Annual overall incidence rate for MCI was 5.6% (95% confidence interval [CI]: 4.6%-6.6%). Annual progression rate from MCI to dementia was 5.9% (95% CI: 5.3%-6.5%), and annual reversion rate from MCI to normal was 18.6% (95% CI: 16.7%-20.4%). Both MCI incidence rates and MCI to dementia progression rates increased with age, whereas reversion rates from MCI to normal decreased with age. CONCLUSION: MCI progression to dementia was much more frequent in the older age groups than in younger participants where reversion to normal cognition is more common. Future research is needed to determine factors related to the heterogeneous outcomes in MCI individuals.

Multi-element Exposure and Cognitive Function in Rural Elderly Chinese.

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.

Blood Selenium and Serum Glutathione Peroxidase Levels Were Associated with Serum ß-Amyloid in Older Adults.

BACKGROUND: Studies have established the association between blood ß-amyloid (Aß) levels and Alzheimer's disease, but population-based studies concerning the association between selenium (Se) and Aß levels in blood samples are very limited. Therefore, we explored the association in an elderly population with Se status and serum Aß measures. METHODS: 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 Aß42, and Aß40 were measured. Quantile regression models were used to determine the associations of blood Se, serum GPX, and SELENOP with Aß levels. RESULTS: Significant negative associations were observed between blood Se and serum Aß42 and Aß40 levels at all percentiles (P < 0.05). The associations were generally stronger at higher Aß42 and Aß40 percentiles than lower Aß42 and Aß40 percentiles. Blood Se was positively associated with serum Aß42/Aß40 ratio at 25th, 50th, and 75th percentiles. Significant positive associations were observed between serum GPX and Aß42 and Aß40 levels at all percentiles (P < 0.05). The positive associations were generally stronger at higher Aß42 and Aß40 percentiles than at lower percentiles. Serum GPX was negatively associated with Aß42/Aß40 ratio at 25th, 50th, 75th, and 95th percentiles. No associations with serum SELENOP and Aß levels were observed. CONCLUSIONS: Our results suggest that higher Se levels are associated with lower serum Aß42 and Aß40 levels and with higher Aß42/Aß40 ratio, and the results are specific for different selenoproteins.

Higher blood selenium level is associated with lower risk of hyperhomocysteinemia in the elderly.

BACKGROUND AND AIMS: Earlier studies have reported inconsistent association between selenium (Se) and homocysteine (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) µg/L and the mean serum Hcy concentration was 17.25 (8.42) µmol/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 µg/L and greater than 156.919 µg/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 µmol/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 µmol/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.

The Association Between the Occurrence of Common Treatment-Emergent Adverse Events and Efficacy Outcomes After Lasmiditan Treatment of a Single Migraine Attack: Secondary Analyses from Four Pooled Randomized Clinical Trials.

BACKGROUND: 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). OBJECTIVE: To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. GOV REGISTRATION: SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810.

Weight loss and incident dementia in elderly Yoruba Nigerians: a 10-year follow-up study.

BACKGROUND: The relationship between weight and dementia risk has not been investigated in populations with relatively low body mass index (BMI) such as the Yoruba. This study set out to achieve this objective using a prospective observational design. METHODS: The setting was Idikan Ward in Ibadan City, Nigeria. The participants were all aged 65 years or older and were enrolled in the Indianapolis-Ibadan Dementia Project. Repeated cognitive assessments and clinical evaluations were conducted to identify participants with dementia or MCI during 10 years of follow-up (mean duration: 5.97 years). BMI measures, information on alcohol, smoking history, cancer, hypertension, diabetes, heart attack, stroke and depression were collected at each follow-up evaluation. Mixed effect models adjusted for covariates were used to examine the differences in BMI among participants who developed dementia or MCI and those who remained cognitively normal during the follow-up. RESULTS: This analysis included 1559 participants who had no dementia at their first BMI measurements. There were 136 subjects with incident dementia, 255 with MCI and 1168 with normal cognition by the end of the study. The mean BMI at baseline was higher for female participants (22.31; SD = 4.39) than for male (21.09; SD = 3.61, p < 0.001). A significantly greater decline in BMI was found in those with either incident dementia (p < 0.001) or incident MCI (p < 0.001) compared to normal subjects. CONCLUSION: Decline in BMI is associated with incident MCI and dementia in elderly Yoruba. This observation calls for close monitoring of weight loss in elderly individuals which may indicate future cognitive impairment for timely detection and tailored interventions.

Implementing innovative models of dementia care: The Healthy Aging Brain Center.

BACKGROUND: Recent randomized controlled trials have demonstrated the effectiveness of the collaborative dementia care model targeting both the patients suffering from dementia and their informal caregivers. OBJECTIVE: To implement a sustainable collaborative dementia care program in a public health care system in Indianapolis. METHODS: We used the framework of Complex Adaptive System and the tool of the Reflective Adaptive Process to translate the results of the dementia care trial into the Healthy Aging Brain Center (HABC). RESULTS: Within its first year of operation, the HABC delivered 528 visits to serve 208 patients and 176 informal caregivers. The mean age of HABC patients was 73.8 (standard deviation, SD 9.5), 40% were African-Americans, 42% had less than high school education, 14% had normal cognitive status, 39% received a diagnosis of mild cognitive impairment, and 46% were diagnosed with dementia. Within 12 months of the initial HABC visit, 28% of patients had at least one visit to an emergency room (ER) and 14% were hospitalized with a mean length of stay of five days. The rate of a one-week ER revisit was 14% and the 30-day rehospitalization rate was 11%. Only 5% of HABC patients received an order for neuroleptics and only 16% had simultaneous orders for both definite anticholinergic and anti-dementia drugs. CONCLUSION: The tools of 'implementation science' can be utilized to translate a health care delivery model developed in the research laboratory to a practical, operational, health care delivery program.