bluuebunny/crossref_metadata_2025_split huggingface dataset:
evoke and evoke+: design of two large‐scale, double‐blind, placebo‐controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease
Authors: Atri Alireza , Feldman Howard H. , Hansen Charlotte Thim , Honore Julie Broe , Johannsen Peter , Knop Filip Krag , Poulsen Pernille , Raket Lars Lau , Sano Mary , Soininen Hilkka , Cummings Jeffrey 
Published: December 2022

AbstractBackgroundPreclinical, clinical, and real‐world evidence suggest benefits in Alzheimer’s disease (AD)‐related symptoms and reduced risk of dementia in type 2 diabetes following treatment with glucagon‐like peptide 1 receptor agonists (GLP‐1RA; Figure 1). The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of the oral GLP‐1RA semaglutide versus placebo in participants with early AD. Here, we present the design of these trials.Methodevoke and evoke+ are two randomized, double‐blind, placebo‐controlled trials (Figure 2) recruiting across 38 countries, with 2 further countries pending (Figure 3). In each trial, a planned 1,840 amyloid‐positive participants (aged 55 to 85 years) with mild cognitive impairment (MCI) due to AD (Clinical Dementia Rating [CDR] global = 0.5) or mild AD dementia (CDR global = 1.0) will be randomized (1:1) to oral semaglutide 14 mg once‐daily (escalated via 3‐ and 7‐mg doses over 8 weeks) or placebo for 156 weeks. Participants may use approved AD treatments if on a stable dose ≥3 months before screening. Other key inclusion criteria are: Mini‐Mental State Examination score ≥22 and Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index score ≤85. The key difference between the trials is the inclusion of ≥20% of participants with significant small vessel co‐pathology in evoke+. The primary endpoint is change in the CDR – Sum of Boxes score from baseline to week 104. Confirmatory secondary endpoints are change in Alzheimer’s Disease Cooperative Study‐Activities of Daily Living‐MCI score, and time to progression to dementia among participants with MCI at baseline. Exploratory endpoints include effects on neurodegeneration and neuroinflammation assessed by changes in plasma and cerebrospinal fluid biomarkers. After week 104, participants will continue their original randomized, double‐blind, placebo‐controlled treatment for a 52‐week extension phase followed by a 5‐week follow‐up, allowing assessment of the long‐term effects of semaglutide. A full list of endpoints is provided in Figure 4.ResultThe evoke and evoke+ read‐outs are expected in 2025.Conclusionevoke and evoke+ will be the first large‐scale phase 3 trials (Ntotal = 3,680) to investigate the hypothesized neuroprotective disease‐modifying effect of semaglutide in early AD.
Early striatal amyloid signal in Down Syndrome: Comparison of PiB and Florbetapir PET
Authors: McLachlan Max , Price Julie C , Laymon Charles M , Garimella Arun , Keator David B. , Kreisl William Charles , Klunk William E , Fryer Tim D , McVea Andrew K , DiFilippo Alexandra H , Christian Bradley T ,   Alzheimer’s Biomarker Consortium – Down Syndrome Investigators
Published: December 2022

AbstractBackgroundPET amyloid [11C]PiB imaging has revealed early detection of Ab in the striatum in individuals with Down Syndrome (DS), a group carrying genetic risk for AD. The goal of this investigation is to examine striatal binding of [11C]PiB and [18F]florbetapir (FBP) to determine if similar striatal uptake profiles are observed in individuals with DS.MethodsPET scans were acquired as part of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS) study. DS participants were scanned with either PiB (n=204; ages 25‐56 yrs) or FBP (n=84; ages 40‐85 yrs) at seven academic sites. SUVR images were created with acquisition times of 50‐70min for both radiotracers, using a cerebellar reference region. ROIs were defined for the anterior ventral striatum (AVS) and the full cortex (CTX). SUVR was then converted to centiloids (CL) using published methods (Klunk 2015) with DS‐specific modifications, including AVS extraction and approximate CL_AVS. Aβ(+) was defined using a threshold of 18.1 CL in CTX ROI, categorizing Aβ(‐) and Aβ(+) groups. Comparisons across PiB and FBP examined 1) the proportion of CL_AVS values exceeding the threshold in the Aβ(‐) group and 2) the difference between SUVR_AVS and SUVR_CTX in the Aβ(+) group.Results58/204 subjects (PiB) and 72/84 subjects (FBP) were Aβ(+), with differences in Aβ(+) presumably due to greater age and advanced neurodegeneration in the FBP group. For the Aβ(‐) comparison, elevated CL_AVS was detected in 16/146 (PiB) and 0/12 (FBP). The average CL_AVS of those that exceeded the threshold was 37.0±12.7 CL (PiB) (mean±SD). For the Aβ(+) comparison, 52/58 (PiB) and 52/72 (FBP) had CL_AVS greater than their CL_CTX. The average difference between SUVR_AVS and SUVR_CTX for the Aβ(+) group was 0.50±0.39 SUVR (46.9±36.8 CL) (PiB) and 0.08±0.18 SUVR (14.2±31.0 CL) (FBP).ConclusionsPiB PET exhibited higher uptake in the striatum during early stages of amyloid deposition. PiB revealed a 6x greater difference than FBP between striatal to cortical SUVR in the Aβ(+) group. Neuropathological investigation is ongoing to characterize these differences in striatal binding in DS. Despite this difference in early‐stage binding, both PiB and FBP demonstrate sensitivity for determining the presence of Aβ in DS.
Drug repurpose screening identifies regorafenib as potential amyloid‐beta aggregation inhibitor
Authors: Eby Blake , Chaapel Skye , Kasper Evan , Mancini Gabriella , Miller Isaiah , Fisher Liam , McKell Carmen , Martino Paul A 
Published: December 2022

AbstractBackgroundRegorafenib is an FDA‐approved multikinase inhibitor used to treat cancer. Drug repurposing may allow for indications as an Alzheimer’s therapeutic targeting inhibition of amyloid‐beta aggregation.MethodRegorafenib was one of several FDA‐approved drug candidates uncovered in a literature search. Initial in‐silico tests implemented [AutoDock Vina] to model the peptide‐ligand interactions between regorafenib and amyloid‐beta. Thioflavin T assays were used to measure regorafenib’s impact on amyloid‐beta aggregation relative to other small molecule candidates. Circular dichroism spectroscopy was performed to determine the dose‐response impact of regorafenib.ResultComputational analysis revealed strong binding between regorafenib and amyloid‐beta 42. Aggregation assays and CD spectroscopy data provide evidence for the effectiveness of regorafenib as an amyloid‐beta aggregation inhibitor.ConclusionRegorafenib inhibits amyloid‐beta 42 aggregation and may be repurposed as an Alzheimer’s Disease therapeutic. The structural activity of regorafenib as a kinase inhibitor could be used as a model for future drug repurposing.
Increased Dementia Incidence among Black and Hispanic Veterans across Regions of the United States
Authors: Kornblith Erica S , Bahorik Amber L , Boscardin W John , Xia Feng , Barnes Deborah E , Yaffe Kristine 
Published: December 2022

AbstractBackgroundAlthough the US military is increasingly diverse, the association of race/ethnicity and geographical region with incidence of dementia diagnosis among older Veterans is unknown.MethodWe identified a random sample of 1,869,090 patients age ≥ 55 years [mean age: 69.4 (standard deviation 7.9), 2% female] who received care at the Veterans Health Administration (VHA), the largest integrated health care system in the United States, between October 1, 1999 and September 30, 2019. Participants self‐reported race/ethnicity: White: 88.6% (n = 1,655,376); Black, 9.5% (n = 176,795); Hispanic (1.0%, n = 20,663), Asian (0.5%, n = 9,391), or American Indian/Alaska Native [AIAN (0.4%, n = 6,895). US region was derived using residential ZIP codes and categorized based on 10 Center for Disease Control and Prevention Health Promotion regions. Incident dementia was defined using International Classification of Diseases, 9th (ICD‐9) and 10th (ICD‐10) edition codes; age‐adjusted dementia incidence was estimated using direct standardization to compare rates by race/ethnicity overall and by US region.ResultOver a mean follow‐up of 10.1 years, 243,272 (13%) participants received a diagnosis of dementia. Age‐adjusted incidence per 1,000 person‐years was 14.2 [95% confidence interval (CI), 13.3‐15.1] for AIAN participants, 12.4 (95% CI, 11.7‐13.1) for Asian participants, 19.4 (95% CI, 19.2‐19.6) for Black participants, 20.7 (95% CI, 20.1‐21.3) for Hispanic participants, and 11.5 (95% CI, 11.4‐11.6) for White participants. Across US regions, a similar pattern was observed; compared to White participants, rates were significantly higher for Black participants across all regions (15.5 to 20.7, p values <0.001), and for Hispanic participants in all regions except the Southeast (14.0 to 21.7, p values ≤ 0.03). Across most regions, AIAN (8.6 to 16.2,) and Asian participants (8.4 to 15.6,) showed a pattern of rates that was similar to or slightly higher than for White participants (9.8 to 12.0, p values >0.05).ConclusionAmong older Veterans receiving care at VHA, where access to care for enrollees is held relatively equal, differences in dementia incidence were observed based on race/ethnicity. Across US regions, rates varied, but incidence was consistently higher for Black and Hispanic Veterans. Further research is needed to elucidate drivers of these differences.
OPTICAL COHERENCE TOMOGRAPHY AND COGNITIVE IMPAIRMENT IN BUENOS AIRES, ARGENTINA
Authors: Fernandez Maria Cecilia , Berrios Waleska , Campora Nuria , Golimstok Angel , Basso Tomas Ortiz , Challiol Camila Fernanda , Cagnasso Juan Ignacio 
Published: December 2022

AbstractBackgroundThe search for biomarkers for the early detection of mild cognitive impairment (MCI) and dementia continues, including ocular markers.An association between neurodegenerative diseases with thinning of optic nerve fiber layers (NFL), macular thickness (MT) and choroidal vessels has been shown by means of optical coherence tomography (OCT), since these structures correspond embryologically to the same origin.In this research we present our data from a population with mild cognitive impairment and dementia and the OCT findings.MethodWe carried out an observational, analytical, cross‐sectional study, comparing the OCT parameters (macular thickness and choroidal thickness) between people with cognitive impairment and a control group of patients treated in the Neurology and Ophthalmology services of the Italian Hospital from Buenos Aires between the years 2009 and 2019. The results were analyzed using the Kruskal‐Wallis and Wilcoxon test using the STATA v14 softwareResultWe included 26 patients with MCI, 21 with dementia and a control group of 30 patients. Regarding the main objective, the measurement of macular thickness, we found statistically significant differences only in the quadrants according to ETDRS (Early Treatment Diabetic Retinopathy Study) greater than 3 mm and in the nasal one, 6 mm, both in the right eye (p < 0.02), finding very similar thickness values in the remaining quadrants. We were also unable to find differences in choroidal thickness between the groups under study (p0.27 in RE and p0.25 in LE)ConclusionIn our study, we were unable to determine the association of cognitive impairment with significant thinning of the retinal macular thickness and choroidal thickness, either in early stages or in dementia, not knowing if this result derives from the way in which patients were selected or if there is another factor. It seems relevant to us to present these negative data and to propose future studies to clarify these results
Cognitively Assistive Robots at Home: Translating Clinical Interventions to Robots
Authors: Kubota Alyssa , Cruz‐Sandoval Dagoberto , Kim Soyon , Twamley Elizabeth W. , Riek Laurel D 
Published: December 2022

AbstractBackgroundMuch research in healthcare robotics explores extending rehabilitative interventions to the home. However, for adults, little guidance exists on how to translate human‐delivered, clinic‐based interventions into robot‐delivered, home‐based ones to support longitudinal interaction. This is particularly problematic for neurorehabilitation, where adults with cognitive impairments require unique styles of interaction to avoid frustration or overstimulation.MethodFor the past several years, our team has worked with neuropsychologists to develop cognitively assistive robots (CARs) that administer compensatory cognitive training (CCT) autonomously and longitudinally to people with mild cognitive impairment (PwMCI) at home. Our system helps users practice cognitive strategies to strengthen skills such as attention, learning/memory, and executive functioning.We explore the design of robot‐delivered neurorehabilitation interventions for PwMCI. We used these prototypes as design probes to understand how neuropsychologists (n=6) envision translating CCT to a CAR, and features the robot intervention needs to be successful, such as supporting goal setting, content personalization, encouragement for real‐world transfer, and ways to longitudinally maintain engagement. We also conducted interviews with PwMCI (n=3), the end users of the robot‐administered intervention.ResultWe report our findings and specify design patterns and considerations for translating neurorehabilitation interventions to robots. First, we provide insights for translating neurorehabilitation interventions to CARs in order to contextualize them to the lives of PwMCI. Second, we present new interaction design patterns for robot‐delivered neurorehabilitation interventions to maintain longitudinal engagement and intervention efficacy. Finally, we propose design considerations for developing robots for PwMCI, a population with unique needs and abilities distinct from those of people with dementia and older adults [1].ConclusionThis work will serve as a basis for future endeavors to translate cognitive training and other clinical interventions onto a robot, support longitudinal engagement with home‐deployed robots, and ultimately extend the accessibility of longitudinal health interventions for people with cognitive impairments.[1] Kubota, A., Cruz‐Sandoval, D., Kim, S., Twamley, E., and Riek, L.D. “Cognitively Assistive Robots at Home: HRI Design Patterns for Translational Science.” In Proceedings of the 17th Annual ACM/IEEE Conference on Human Robot Interaction (HRI). 2022.
Alteration of Fatty Acid Metabolism is Associated with Alzheimer’s Disease in People with Down Syndrome
Authors: Mapstone Mark ,   The Alzheimer's Biomarker Consortium‐ Down Syndrome (ABC‐DS)
Published: December 2022

AbstractBackgroundPeople with Down syndrome (DS) are at high risk for Alzheimer’s disease (AD) in part because nearly all carry an extra copy of the APP gene which results in overexpression of amyloid. However, other factors are likely to interact with this genetic risk to produce individual pathobiological and clinical trajectories. We sought to examine the impact of diverse physiological pathways on AD risk in people with DS using plasma metabolomics.MethodWe studied the plasma metabolome of 744 people with DS (mean age =49) using mass spectrometry (MS). A total of 144 individuals from our cohort met criteria for MCI or AD (DS‐AD, mean age= 55.0) and 600 were cognitively stable (DS‐NAD, mean age = 47.4). We quantified the relative abundance of over 7000 putative metabolites. We performed differential expression (DE) analysis and constructed group classification models (DS‐AD vs DS‐NAD) using Regularized Logistic Regression with age included as a covariate. We evaluated the classification models using Receiver Operating Characteristic (ROC) analysis.ResultWe found 20 DE features between the DS‐AD and DS‐NAD groups (q < 0.05), of which we definitively identified 11 through tandem mass spectrometry. Of the 11 metabolites, 5 were naturally occurring unique human metabolites involved in fatty acid metabolism, including two diacylglycerides, one monoglyceride, one lysophosphatidycholine, and one acylcarnitine. When combined, this set of lipids classified the DS‐AD and DS‐NAD groups with ROC area under the curve of 0.796 [95% CI: 0.784‐ 0.808] across resamples (Sensitivity 29%, Specificity 97%). The addition of participant sex or APOE status did not significantly alter classification performance.ConclusionHere, we find depletion of lipids in the plasma of people with DS who also have AD compared to people with DS who are not demented. While the overall number of DE metabolites is small, it is remarkable that from over 7000 putative metabolites measured, all are lipids involved in fatty acid metabolism. These results are consistent with an emerging picture of dysregulated lipid metabolism in AD, both in the people with DS and in the neurotypical population.
How many is enough? Sample size estimation for imaging‐based outcomes in clinical trials of neurodegenerative disease
Authors: Cash David M , Frost Christopher , Fox Nick C ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

AbstractBackgroundEffective treatments for neurodegenerative diseases are a global health priority. Appropriately powered clinical trials are critical to showing evidence of efficacy ‐ these are expensive and take years to complete. Depending on the study aims, imaging biomarkers can provide high precision measurements that reflect underlying pathology or downstream effects and may help in reducing the number of participants and/or duration of the trial. Identifying how to design trials that make the most efficient use of imaging endpoints, while maintaining sufficient statistical power to detect the desired therapeutic effect, will be critical to reduce approval time for effective therapies.MethodSample size estimates were computed for a wide range of imaging biomarkers, trial designs, and target therapeutic effects. We examined how sample size estimates were affected by the target population (inclusion/exclusion criteria), visit schedule, and the rate of participant dropout. From the resulting trial designs, appropriate formulae for sample size estimation were derived. These formulae require estimates of a number of parameters including both the mean rate of change over time in the outcome measure and the related variances. These were obtained from natural history studies, including ADNI, DIAN, and TRACK‐HD. The precision of these estimates is calculated by bootstrap resampling.ResultAcross target populations, imaging biomarkers produced lower sample sizes to detect a clinically relevant slowing of change compared to conventional primary endpoints, particularly in shorter duration (i.e. 1‐2 years) trials. Imaging biomarkers that incorporated longitudinal information into the measurements were often the best performers. If the participant dropout rate is non‐negligible, this can result in noticeable increases in sample size, which can be partially mitigated by including interim visits into the analysis. The precision of sample sizes estimates can vary substantially between biomarkers and should be considered when making decisions on trial design.ConclusionImaging based outcomes can play an important role in providing evidence of disease modification in trials, particularly in primary and secondary prevention studies. Accurate sample size estimates for the desired treatment effect are critical for the success of these studies.
Net Carbohydrate Consumption is Associated with Cortical Thickness in Cognitively Impaired Older Adults with Confirmed Amyloid Burden
Authors: Bramen Jennifer E. , Popa Emily S. , Rapozo Molly K. , Siddarth Prabha , Hodes John F. , Ganapathi Aarthi S. , Slyapich Colby B. , Glatt Ryan M. , Porter Verna R. , Wong Claudia L. , Bookheimer Susan Y. , Roach Jared C. , Merrill David A. 
Published: December 2022

AbstractBackgroundA low carbohydrate diet has been suggested as a treatment for Alzheimer’s disease (AD)1,2. One of the features of AD is widespread cortical thinning3; however, no study has demonstrated that carbohydrate intake is linked to cortical thickness in patients with confirmed AD‐related neuropathology. The aim of this study is to test the hypothesis that higher carbohydrate intake is associated with thinner cortex.MethodCortical thickness was estimated from T1‐weighted MR images using FreeSurfer with an alpha of p<0.05 (vertex‐wise) and p<0.01 (cluster‐wise correction for multiple comparisons). We calculated net carbohydrate intake using a Food Frequency Questionnaire (FFQ) as input to the validated FFQ EPIC Tool for Analysis4 in 22 participants aged 57‐84 (mean = 70.1 years, SD = 6.2) with a diagnosis of mild cognitive impairment (MCI) or mild AD and confirmed amyloid burden.ResultsParticipants, on average, ate moderate to low levels of net carbohydrates (mean = 124 g, SD = 66). No participant exceeded the USDA guidelines for net average daily carbohydrate intake5. Most ate less than CDC guidelines for managing diabetes6 (N = 19). Participants were drawn from the Pacific Brain Health Center, a clinical practice centered around addressing lifestyle and located in Santa Monica, California. We found that higher net carbohydrate intake was significantly associated with thinner cortex, accounting for age, within the left middle frontal gyrus (size = 2900 mm2). Uncorrected results (cluster size>100 mm2) showed that throughout the cortex, we saw a widespread pattern of cortical thinning, including regions within the middle temporal, fusiform, lingual, supramarginal, cingulate, superior parietal, postcentral, paracentral, orbitofrontal, inferior parietal, superior frontal gyri and insula. Only one region, the postcentral gyrus, showed a positive correlation, strongly suggesting the validity of these findings.ConclusionsHigher carbohydrate intake was significantly associated with thinner cortex in this cross‐section of older adults with cognitive impairment and confirmed amyloid burden. Prior research in older adults eating a Mediterranean diet did not detect this association7. Our sample was unique in that they ate fewer carbohydrates and had a diagnosis of cognitive decline with confirmed amyloid burden. Future directions of this research will assess how longitudinal trajectories of cortical thinning are impacted by changes in net carbohydrate consumption.