Lower extremity functioning in older adults provides a measure of poor physical performance and can predict negative health outcomes. The consequences of reduced lower extremity functioning on cognitive decline, measured as time-varying variables, have not been well documented in previous studies. We aimed to evaluate whether lower extremity functioning is associated with an increased incidence rate of probable dementia among older adults using data from the National Health and Aging Trends Study (NHATS). Participants (n = 6457) were followed for 8 years to examine the relationship between lower extremity functioning, as measured by the Short Physical Performance Battery (SPPB), and incident probable dementia. Using weighted data, a multivariable Poisson regression with generalized estimating equations (GEE) was used to calculate incidence rate ratios (IRR), adjusting for covariates and clustering. Participants with low SPPB scores (0–5) had a 5% increase in incident probable dementia when compared with those who had good SPPB scores (10–12) in the adjusted model (IRR = 1.05; 95% CI = 1.04–1.07). Lower extremity functioning is associated with a modest increase in incident probable dementia. The SPPB score may be helpful in identifying subjects at risk of dementia. Efforts aimed at improving physical functioning may lead to better cognitive outcomes.

Purpose Treatment of hyperprolactinemia and prolactinomas with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Ropinirole (ROP) is a low cost selective D2/D3 receptor non-ergot DA, approved for treatment of Parkinson’s disease and Restless Leg Syndrome, that has been shown to acutely lower prolactin levels (PRL). This study investigated the efficacy and tolerability of long-term ROP therapy in patients with hyperprolactinemia. Methods & Results Ten healthy women (21-45 yrs) with hyperprolactinemia were treated with ROP (0.25-6.0mg/d) for 6 months in an open-label dose escalation study. Clinical and biochemical status was assessed monthly and ROP doses were up-titrated to achieve normal PRL levels, restore menses, and eliminate galactorrhea. Two subjects had macroprolactinomas, 7 had microprolactinomas, and 1 had idiopathic hyperprolactinemia. 8/10 had previously been treated with cabergoline and/or bromocriptine. 5/10 were intolerant and 1/10 was resistant to ergot DAs. Pituitary MRIs were performed at baseline and 6 months.ROP was initiated at 0.25mg QHS in 9/10 subjects. One subject with severe DA intolerance was initiated on 0.125mg QHS. Subjects reaching a total daily dose (TDD) > 2.0mg/d were transitioned to ROP extended release. At study completion, TDDs ranged from 1-6mg/d, with a median TDD of 2mg/d. Baseline PRL levels were 136 ± 49ng/ml (1.9-25ng/ml). Stable PRL normalization was achieved in 50% of subjects. Of the subjects achieving normal PRL, 4 had microadenomas and 1 had idiopathic hyperprolactinemia, and the median effective TDD was 1mg/d (1-4mg/d, range). Among those not achieving PRL normalization, PRL decreased 46 ± 5.4% (Mean ± SEM) from baseline, at a median TDD of 4.0mg/d (2-6mg/d, range). In the subject with documented resistance to ergot DAs, PRL decreased from 529 to 320ng/ml, after 3 months of ROP on the maximum dose studied (6mg/d), but rose to 690ng/ml at 6 months. During ROP treatment, menses normalized in 57%, and galactorrhea resolved in 67% of affected subjects. At study completion, tumor size was unchanged in 7/8 prolactinomas. A 20% decrease in tumor size was observed in one macroadenoma, accompanied by a 30% reduction in PRL levels. There were no changes in BP, HR, weight, renal or kidney function. Mild adverse effects (AEs) were recorded in 80% of subjects. Fatigue (60%), nausea (40%), and headache (20%) were most common. Reported AEs declined after month 1 and ROP was not discontinued due to intolerance. Conclusion These data provide support for the efficacy of ROP in the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia. While further study is needed, ROP treatment for hyperprolactinemia could be considered in patients with ergot DA intolerance or significant cardiac valve disease.

ObjectiveCentral obesity has been associated with several adverse health events, but little research exists about the longitudinal effects of central obesity on multisite pain. The purpose of this study was to assess if central obesity, as measured by waist circumference measurement, was associated with an increased rate of having multisite pain among older adults aged 65 years and older.DesignThe National Health and Aging Trends Study is a longitudinal cohort study initiated in 2011 and intended to be representative of Medicare beneficiaries in the contiguous United States.MethodsThere were 7,145 community-dwelling participants included in this study. Data for this study were collected annually between 2011 and 2018. Researchers assessed if waist circumference risk level was associated with an increased rate ratio of multisite pain. Weighted data were used in a multivariable generalized estimating equation model that used a log link specified with a Poisson distribution.ResultsParticipants with high-risk waist circumferences (98 cm or greater for women and 109 cm or greater for men) had a 11% higher rate of multisite pain than those with low-risk waist circumferences [rate ratio (RR) 1.11, 95% CI: 1.07–1.15] adjusting for gender, age, race, education, probable major depression, arthritis, and multimorbidity count.ConclusionAs measured by waist circumference, central adiposity is associated with multisite pain in older adults. While more research is needed, reducing waist circumference may prove beneficial in reducing the burden of multisite pain.

Context Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive. Objective We investigated biomarkers associated with use of lorcaserin, a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, in order to identify predictors of clinical efficacy. Methods Thirty subjects with obesity were treated with 7-days of placebo and lorcaserin in a randomized crossover study. Nineteen subjects continued on lorcaserin for 6-months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin and food intake during a meal were also studied. Results Lorcaserin induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide β-endorphin after 7-days; β-endorphin/POMC increased by 30% (p < 0.001). This was accompanied by a substantial decrease in insulin, glucose and HOMA-IR prior to WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6-months that were distinct from prior reports after diet alone. Changes in POMC, food intake or other hormones did not predicted WL. However, baseline CSF POMC correlated negatively with WL (p = 0.07) and a cutoff level of CSF POMC was identified that predicted > 10% WL. Conclusions Our results provide evidence that lorcaserin impacts the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists.

The need for personalized medicine in obesity is pressing, but we are currently unable to predict individual responses to weight loss (WL) medications. The melanocortin (MC) system consisting of proopiomelanocortin (POMC) and agouti related protein (AgRP) neurons and brain MC-Rs plays a critical role in regulating energy homeostasis and is targeted by lorcaserin (LOR), a 5HT2cR agonist previously FDA approved for WL. We therefore investigated the short and long-term effects of LOR on the MC system as assessed by cerebrospinal fluid (CSF) neuropeptide measurements and other parameters in order to identify potential biomarkers to predict WL response. Methods In phase-1 of our two-phase study, thirty subjects with obesity were randomized to receive placebo or LOR for 7-days and were then crossed over to 7-days of LOR or placebo after a 3-week washout period. Subjects then continued to phase-2 and were treated with LOR for 6-months. The study was terminated early as LOR was withdrawn from the market and only 19 subjects completed 6M. Anthropometrics, plasma and CSF were collected and test meals were administered after both placebo and LOR during phase-1 and at the end of phase-2. POMC prohormone and the POMC-derived peptide, β-endorphin (β-EP), were measured in CSF by in house ELISA and RIA. The MC-R antagonist, AgRP, was measured by ELISA in CSF and plasma as both may reflect brain AgRP. Results During phase-1 there was a decline in CSF POMC (p=0.001) and an increase in CSF β-EP (p=0.0017) resulting in an increase in the ratio of β-EP /POMC (processed peptide/prohormone) (p<0.0001) after 7-days of LOR vs placebo. Serum insulin and HOMA-IR also decreased despite no WL during phase-1 (p<0.005). After 6M of LOR, average WL was 6.9%, with 11/19 subjects achieving >5% and 7/19 >10% WL. Leptin, insulin and HOMA-IR declined. CSF POMC remained lower and β-EP and β-EP/POMC remained higher after 6M vs 7-day placebo (baseline), whereas AgRP increased only at 6M. Anthropometrics and caloric intake during test meals were not significantly different between LOR and placebo in phase-1 and did not predict WL at 6M. Phase-1 changes in POMC or β-EP did not predict WL. However, baseline CSF POMC and POMC/AgRP ratio correlated negatively with WL and were significantly lower in subjects with >10% WL. A CSF POMC cutoff of < 220 fmol/ml at baseline was found to predict 10% WL at 6M (p=0.045 Fisher). Conclusion In this study we show that the melanocortin system is impacted after 1 week of LOR. Furthermore lower melanocortin activity at baseline predicted a better weight loss response to drug treatment. Assessment of melanocortin activity could thus provide a way to personalize the pharmacotherapy of obesity with possible future alternative selective 5HT2cR agonists. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m.