Trial of Solanezumab in Preclinical Alzheimer's Disease.

BACKGROUND: Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results. METHODS: We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. RESULTS: A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. CONCLUSIONS: Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Applying climate change refugia to forest management and old-growth restoration.

Recent studies highlight the potential of climate change refugia (CCR) to support the persistence of biodiversity in regions that may otherwise become unsuitable with climate change. However, a key challenge in using CCR for climate resilient management lies in how CCR may intersect with existing forest management strategies, and subsequently influence how landscapes buffer species from negative impacts of warming climate. We address this challenge in temperate coastal forests of the Pacific Northwestern United States, where declines in the extent of late-successional forests have prompted efforts to restore old-growth forest structure. One common approach for doing so involves selectively thinning forest stands to enhance structural complexity. However, dense canopy is a key forest feature moderating understory microclimate and potentially buffering organisms from climate change impacts, raising the possibility that approaches for managing forests for old-growth structure may reduce the extent and number of CCR. We used remotely sensed vegetation indices to identify CCR in an experimental forest with control and thinned (restoration) treatments, and explored the influence of biophysical variables on buffering capacity. We found that remotely sensed vegetation indices commonly used to identify CCR were associated with understory temperature and plant community composition, and thus captured aspects of landscape buffering that might instill climate resilience and be of interest to management. We then examined the interaction between current restoration strategies and CCR, and found that selective thinning for promoting old-growth structure had only very minor, if any, effects on climatic buffering. In all, our study demonstrates that forest management approaches aimed at restoring old-growth structure through targeted thinning do not greatly decrease buffering capacity, despite a known link between dense canopy and CCR. More broadly, this study illustrates the value of using remote sensing approaches to identify CCR, facilitating the integration of climate change adaptation with other forest management approaches.

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States.

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

Magnetic resonance imaging measures of brain volumes across the EXPEDITION trials in mild and moderate Alzheimer's disease dementia.

Introduction: Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low-dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods: Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor-based morphometry (EXPEDITION3). Results: The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) ε4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all P-values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change. Discussion: Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low-dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken.

Integrated Alzheimer's Disease Rating Scale: Clinically meaningful change estimates.

Introduction: The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods: Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor-based, distribution-based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results: All three anchors met criteria for "sufficiently associated" (|r| = 0.4-0.7). Cumulatively, results from anchor-based and distribution-based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion: These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression.

Leveraging the potential of nature to meet net zero greenhouse gas emissions in Washington State.

The State of Washington, USA, has set a goal to reach net zero greenhouse gas emissions by 2050, the year around which the Intergovernmental Panel on Climate Change (IPCC) recommended we must limit global warming to 1.5 °C above that of pre-industrial times or face catastrophic changes. We employed existing approaches to calculate the potential for a suite of Natural Climate Solution (NCS) pathways to reduce Washington's net emissions under three implementation scenarios: Limited, Moderate, and Ambitious. We found that NCS could reduce emissions between 4.3 and 8.8 MMT CO2eyr-1 in thirty-one years, accounting for 4% to 9% of the State's net zero goal. These potential reductions largely rely on changing forest management practices on portions of private and public timber lands. We also mapped the distribution of each pathway's Ambitious potential emissions reductions by county, revealing spatial clustering of high potential reductions in three regions closely tied to major business sectors: private industrial forestry in southwestern coastal forests, cropland agriculture in the Columbia Basin, and urban and rural development in the Puget Trough. Overall, potential emissions reductions are provided largely by a single pathway, Extended Timber Harvest Rotations, which mostly clusters in southwestern counties. However, mapping distribution of each of the other pathways reveals wider distribution of each pathway's unique geographic relevance to support fair, just, and efficient deployment. Although the relative potential for a single pathway to contribute to statewide emissions reductions may be small, they could provide co-benefits to people, communities, economies, and nature for adaptation and resiliency across the state.

Effects of Lasmiditan on Cardiovascular Parameters and Pharmacokinetics in Healthy Subjects Receiving Oral Doses of Propranolol.

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT1F receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with ß-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was -6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.

Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study).

OBJECTIVES: To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. METHODS: In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. RESULTS: As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. CONCLUSIONS: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186.

Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease.

INTRODUCTION: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid ß and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). METHODS: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. RESULTS: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. DISCUSSION: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: findings from the phase 3 trials (SAMURAI and SPARTAN).

BACKGROUND: We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. METHODS: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. RESULTS: The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. CONCLUSIONS: A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Physical Functioning Among Patients Aging With Human Immunodeficiency Virus (HIV) Versus HIV Uninfected: Feasibility of Using the Short Physical Performance Battery in Clinical Care of People Living With HIV Aged 50 or Older.

BACKGROUND: The Short Physical Performance Battery (SPPB) is a well regarded physical functioning assessment including balance, gait speed, and chair-stand tests. Its use has not been widely assessed in human immunodeficiency virus (HIV) care. We evaluated the feasibility of integrating the SPPB into care of aging people living with HIV (PLWH) and compared SPPB performance with aged HIV-uninfected individuals. METHODS: We enrolled PLWH aged ≥50 at 3 HIV clinics and compared their SPPB scores and subscores with older HIV-uninfected adults in the Health, Aging, and Body Composition (Health ABC) study. We conducted regression analyses on age stratified by sex and adjusting for site, and we calculated percentage variance explained by age among PLWH and HIV-uninfected adults. RESULTS: The SPPB was feasible to implement in clinical care and did not require licensed professionals; 176 PLWH completed it with a mean completion time of 7.0 minutes (standard deviation = 2.6). Overall mean SPPB score among PLWH was 10.3 (median 11.0, 25th percentile 9.0, 75th percentile 12.0). People living with HIV were younger than HIV-uninfected individuals (55 vs 74 years old). Mean SPPB scores and most subscores were similar among PLWH and older HIV-uninfected individuals despite the ~20-year age difference. Regression analyses of gait speed revealed similar slopes in PLWH and HIV-uninfected individuals; however, separate intercepts were needed for PLWH. Mean gait speeds were faster in older HIV-uninfected men and women (P < .01), yet relationships with age within PLWH and HIV uninfected were similar. CONCLUSIONS: The SPPB can be implemented into busy HIV clinics. Despite the ~20-year age difference, mean scores were similar among PLWH and older HIV-uninfected individuals, although gait speed was faster among HIV-uninfected individuals.

Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

INTRODUCTION: Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid ß (Aß)1-40 and Aß1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aß isoforms and their relationship with solanezumab exposure. METHODS: CSF Aß isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3. RESULTS: Solanezumab produced statistically significant increases in CSF total Aß isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aß isoforms were observed. Solanezumab penetration into the central nervous system was low. DISCUSSION: Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aß concentrations.

Climate change impacts on the distribution of the allergenic plant, common ragweed (Ambrosia artemisiifolia) in the eastern United States.

Climate change is affecting the growth, phenology, and distribution of species across northeastern United States. In response to these changes, some species have been adversely impacted while others have benefited. One species that has benefited from climate change, historically and in response to experimental treatments, is common ragweed (Ambrosia artemisiifolia), a widely distributed annual weed and a leading cause of hay fever in North America. To better understand how climate change may affect the distribution of common ragweed, we built a maximum entropy (Maxent) predictive model using climate and bioclimatic data and over 700 observations across the eastern U.S. Our model performed well with an AUC score of 0.765 using four uncorrelated variables, including precipitation seasonality, mean diurnal temperature range, August precipitation, and January maximum temperature. After building and testing our model, we then projected potential future common ragweed distribution using a suite of 13 global climate models (GCMs) under two future greenhouse gas scenarios for mid and late-century. In addition to providing georeferenced hot spots of potential future expansion, we also provide a metric of confidence by evaluating the number of GCMs that agree. We show a substantial contraction of common ragweed in central Florida, southern Appalachian Mountains, and northeastern Virginia and areas of potential expansion at the northern margins of its current distribution, notably in northeastern U.S. However, the vast majority of this increase is projected to occur by mid-century and may be moderated somewhat by the 2070s, implying that common ragweed may be sensitive to climatic variability. Although other factors and modeling approaches should be explored, we offer preliminary insight into where common ragweed might be a new concern in the future. Due to the health impacts of ragweed, local weed control boards may be well advised to monitor areas of expansion and potentially increase eradication efforts.

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, 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 Aß1-42 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. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

Statistical properties of continuous composite scales and implications for drug development.

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.

Integrating mechanistic and empirical model projections to assess climate impacts on tree species distributions in northwestern North America.

Empirical and mechanistic models have both been used to assess the potential impacts of climate change on species distributions, and each modeling approach has its strengths and weaknesses. Here, we demonstrate an approach to projecting climate-driven changes in species distributions that draws on both empirical and mechanistic models. We combined projections from a dynamic global vegetation model (DGVM) that simulates the distributions of biomes based on basic plant functional types with projections from empirical climatic niche models for six tree species in northwestern North America. These integrated model outputs incorporate important biological processes, such as competition, physiological responses of plants to changes in atmospheric CO2 concentrations, and fire, as well as what are likely to be species-specific climatic constraints. We compared the integrated projections to projections from the empirical climatic niche models alone. Overall, our integrated model outputs projected a greater climate-driven loss of potentially suitable environmental space than did the empirical climatic niche model outputs alone for the majority of modeled species. Our results also show that refining species distributions with DGVM outputs had large effects on the geographic locations of suitable habitat. We demonstrate one approach to integrating the outputs of mechanistic and empirical niche models to produce bioclimatic projections. But perhaps more importantly, our study reveals the potential for empirical climatic niche models to over-predict suitable environmental space under future climatic conditions.

Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease.

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.

Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia.

BACKGROUND: Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%-87.3% sensitivity and 44.3%-70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. METHODS: Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. RESULTS: A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. CONCLUSIONS: These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.