bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of concomitant acetylcholinesterase inhibitor use on the pharmacokinetic profile of pimavanserin in patients with dementia‐related psychosis: Modeling data from the phase 3 HARMONY study
Authors: Darwish Mona , Jaworowicz David , Owen Joel , Brandt Teresa , DeKarske Daryl , Stankovic Srdjan 
Published: December 2021

AbstractBackgroundPimavanserin is a selective serotonin modulator with inverse agonist/antagonist activity at the 5HT2A receptor, and to a lesser extent at the 5HT2C receptor. Pimavanserin efficacy and safety were evaluated in patients with dementia‐related psychosis (DRP) in the phase 3 HARMONY study. Many patients with DRP receive acetylcholinesterase inhibitors (AChEIs) to treat their dementia. This analysis evaluated the pharmacokinetic (PK) profile of pimavanserin in patients receiving concomitant AChEIs using data from HARMONY.MethodsHARMONY was a randomized discontinuation study in patients with DRP. Patients received open‐label pimavanserin, 34 mg daily with flexible dosing (20 mg) based on tolerability, for 12 weeks, and those with sustained response were randomized into the 26‐week double‐blind period where they continued their pimavanserin or switched to placebo. PK samples were collected at baseline and weeks 12, 13, 22, and 38 (or end of treatment). Individual Bayesian estimates of pimavanserin apparent clearance (CL/F) and apparent volume of distribution (V/F) were obtained using a previously developed population PK model for patients with/without concomitant AChEIs. Steady‐state area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were computed for pimavanserin doses normalized to 34 mg daily.Results158/337 (46.9%) patients in HARMONY had concomitant AChEI use (donepezil, galantamine, rivastigmine). In patients with/without AChEI use, CL/F and V/F showed no apparent differences between groups. Covariate testing found no statistically significant effect (α = 0.05) of AChEI use on CL/F or V/F. Minimal differences in predicted steady‐state pimavanserin exposures were observed between patients with concomitant AChEI use and those without (Table 1); median Cmax was 8.4% higher (with AChEI: 57.9 ng/mL; without AChEI: 53.4 ng/mL) and median AUC was 9.2% higher (with AChEI: 1328.9 ng × h/mL; without AChEI: 1216.5 ng × h/mL).ConclusionsConcomitant AChEIs had no significant effect on the PK parameters of pimavanserin. Differences in exposure measures (Cmax and AUC) between groups were negligible (<10%). These results suggest that concomitant AChEI use does not have a clinically relevant impact on the PK profile of pimavanserin.
TRAILBLAZER‐ALZ Study: Dynamics of amyloid reduction after donanemab treatment
Authors: Shcherbinin Sergey , Andersen Scott W. , Evans Cynthia Duggan , Lo Albert C. , Lu Ming , Navitsky Michael , Collins Emily C , Sims John R. , Brooks Dawn A. , Mintun Mark A 
Published: December 2021

AbstractBackgroundAccumulation of amyloid‐β (Aβ) peptide in amyloid plaques is a pathological hallmark of Alzheimer’s disease (AD). Reduction of Aβ could slow the progression of AD. Donanemab is an antibody specific for the N‐terminal pyroglutamate Aβ epitope that is only present in mature brain amyloid plaques. In the TRAILBLAZER‐ALZ study, 67.8% (n=61) of donanemab‐treated participants became amyloid negative by 76 weeks. Here we further characterize amyloid reduction after donanemab treatment.MethodParticipants (placebo N=84, donanemab N=69) that completed 4 florbetapir scans in TRAILBLAZER‐ALZ were analyzed for amyloid reduction rate, measured in centiloids (CL). Donanemab dosing was 700mg every 4 weeks (Q4W) for the first 3 doses, then 1400mg Q4W, for up to 76 weeks. Planned blinded dose reduction evaluations occurred at 24 and 52 weeks creating three periods of time between florbetapir scans: baseline‐24wk, 24wk‐52wk, or 52wk‐76wk. ANOVA were performed to compare baseline parameters.ResultAt 24wk, 15 participants in the donanemab group were assigned to 700mg dose and 19 were assigned to placebo. At 52wk, 10 participants were assigned to 700mg dose and 8 were assigned to placebo. In the 17 participants that remained on 1400mg donanemab until the end of the trial, amyloid reduction rate decreased during baseline‐24wk, 24wk‐52wk, and 52wk‐76wk (mean (SD): ‐2.7(1.5), ‐1.0 (0.7), and ‐0.5 (0.5) CL/wk, respectively). At the end of the trial, 5 out of 17 participants that remained in the 1400mg group became amyloid negative. In the 15 participants that were assigned to 700mg at 24wk, plaque lowering rate decreased from an average of ‐3.0 (1.2) CL/wk over the first 24wk to an average of ‐0.4 (0.4) CL/wk over 24wk‐52wk. At the end of the trial, 13 participants assigned to 700mg donanemab Q4W at 24wk became amyloid negative. Patients that received placebo at 24wk‐76wk (n=19) or 52wk‐76wk (n=19), had no re‐accumulation (mean (SD): 0.0 (0.1) CL/wk and ‐0.1 (0.2) CL/wk, respectively). Participants that stayed on 1400mg until study end had higher baseline amyloid (p=0.0000) and tau (p=0.0488) and were younger (p=0.0472) than those assigned to 700mg or placebo at 24wk.ConclusionDonanemab treatment reduced amyloid plaques and resulted in no re‐accumulation of amyloid over 1 year.
Cross‐sectional associations between sleep quality reports and core Alzheimer’s disease biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)
Authors: Stankeviciute Laura , Grau‐Rivera Oriol , Blackman Jonathan , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Sánchez‐Benavides Gonzalo , Vilor‐Tejedor Natalia , Minguillón Carolina , Iranzo Álex , Molinuevo Jose , Gispert Juan Domingo , Coulthard Elizabeth ,   EPAD Consortium
Published: December 2021

AbstractBackgroundSleep disturbances are prevalent in Alzheimer’s disease (AD), with sleep quality having been reported to be already impaired at the preclinical stage of the disease. However, most results originate from studies with rather limited sample sizes. This research aimed to evaluate the association of subjective sleep measures with cerebrospinal fluid (CSF) AD biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD‐LCS).MethodThis cross‐sectional study included 1257 cognitively unimpaired adults [CDR(clinical dementia rating scale)=0] aged over 50 years who underwent CSF sampling and filled out the Pittsburgh sleep quality index (PSQI) questionnaire. The PSQI includes 7 components (scored 0‐3), which summed yield a total score ranging from 0 to 21. We used multivariate linear regressions to analyse associations between CSF biomarkers (i.e. Aβ42, p‐tau and t‐tau) and the following PSQI measures: total score, binarized score (poor sleep categorized as PSQI>5), sleep latency, duration, efficiency and disturbance. For sleep duration and disturbance, the two highest categories were collapsed into one due to an insufficient number of responses. We used separated models, with each biomarker as the dependent variable and each sleep measure as the predictor, and adjusted them by known potential confounders.ResultPoor sleep quality (PSQI total>5) was associated with higher CSF levels of p‐tau (std. β=0.060, p=0.040) and t‐tau (std. β=0.066, p=0.019). Shorter sleep duration (6‐7 hours vs >7 hours) was associated with higher CSF levels of p‐tau (std. β=0.063, p=0.017) and t‐tau (std. β=0.054, p=0.037). A higher degree of sleep disturbance (1‐9 vs 0 and >9 vs 0) was associated with lower CSF levels of Aβ42 (std. β=‐0.106, p=0.016; std. β=‐0.091, p=0.046).ConclusionOur results show that self‐reported sleep quality is associated with AD biomarkers in people without cognitive impairment. Specifically, overall poor sleep quality and shorter sleep duration are related to higher p‐tau and t‐tau levels, whilst more profound sleep disturbances are associated with lower Aβ42 levels. These results potentially support sleep impairment before cognitive symptom onset in AD. Future longitudinal studies using objective sleep quantification will more precisely illuminate the role of sleep in the early stages of the AD continuum.
Considerations for the real‐world management of ARIA from the aducanumab phase 3 studies EMERGE and ENGAGE
Authors: Burkett Patrick , Chalkias Spyros , Umans Kimberly , Castrillo‐Viguera Carmen , Purcell Derk D , Barakos Jerome , Fam Sami , Smirnakis Karen , Haeberlein Samantha Budd 
Published: December 2021

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), a spectrum of imaging findings detected on brain magnetic resonance imaging (MRI), are associated with the investigational use of amyloid‐targeting monoclonal antibodies, including aducanumab, in patients with Alzheimer’s disease (AD). EMERGE (NCT02484547) and ENGAGE (NCT02477800) were Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early AD.MethodsARIA risk minimization included dose titration, routine brain MRI monitoring, ad hoc MRI testing as clinically indicated, and among patients who developed ARIA, possible dose suspension or permanent discontinuation. The criteria for dose suspension or discontinuation were based on the radiographic severity of ARIA and presentation of clinical symptoms. On detection of an ARIA episode, follow‐up MRIs were conducted approximately every 4 weeks to document radiographic resolution of ARIA‐edema (ARIA‐E) or stabilization of ARIA‐hemorrhage (ARIA‐H), which refers to brain microhemorrhages and localized superficial siderosis.ResultsThe integrated data set from EMERGE and ENGAGE consisted of 3285 participants (aducanumab treated, n=2198; placebo treated, n=1087). In the 10‐mg/kg group (n=1029 with ≥1 postbaseline MRI), ARIA‐E was the most common adverse event (35.2%), with a higher incidence in apolipoprotein ε4 carriers compared with noncarriers (43.0% versus 20.3%, respectively). Radiographic severity of ARIA‐E was characterized as mild (30.1%), moderate (57.7%), or severe (12.2%). ARIA‐E typically occurred within the first 32 weeks of treatment with aducanumab and were mostly asymptomatic (74.0%). Among participants who reported symptoms in the setting of ARIA, the majority of symptoms during ARIA were characterized as mild (67.7%) or moderate (28.3); the most common symptoms were headache (46.6%), confusion (14.6%), dizziness (10.7%), and nausea (7.8%). ARIA‐E were transient but recurred in 10.6% of participants in the 10‐mg/kg group. ARIA‐H microhemorrhage and superficial siderosis were typically asymptomatic and more common in participants who had ARIA‐E (40.3% and 38.7%, respectively), compared with participants without ARIA‐E (7.6% and 1.6%, respectively). In participants with ARIA‐E and ARIA‐H, these events frequently overlapped temporally. There were no fatal events due to ARIA.ConclusionsARIA are mostly asymptomatic; evidence supports the use of routine brain MRI to monitor for events in clinical practice.
Machine learning for the prediction of amyloid positivity in amnestic mild cognitive impairment
Authors: Kang Sung Hoon , Jang Hyemin , Kim Hee Jin , Park Kyung Won , Noh Young , Lee Jin San , Ye Byoung Seok , Na Duk L. , Lee Hyejoo , Seo Sang Won 
Published: December 2021

AbstractBackgroundAmnestic mild cognitive impairment (aMCI) patients with amyloid (Aβ) deposition have worse prognosis than those without Aβ deposition and are candidates for clinical trials of anti‐Aβ drugs. In this regard, Aβ evaluation in aMCI patients is important for predicting conversion to Alzheimer’s disease. However, Aβ evaluation through amyloid positron emission tomography (PET) is limited due to high cost and safety issues. We therefore aimed to develop and validate two different prediction models of Aβ positivity for aMCI using optimal interpretable machine learning (ML) approaches utilizing multimodal markers.MethodWe recruited 529 aMCI patients from multiple centres who underwent Aβ PET. We trained ML algorithms using a training cohort (324 aMCI from Samsung medical center) with two‐phase modelling: model 1 included age, gender, education, diabetes, hypertension, apolipoprotein E genotype, and neuropsychological test scores; model 2 included the same variables as model 1 with additional MRI features. We used four‐fold cross‐validation during the modelling and evaluated the model on an external validation cohort (187 aMCI from the other centres).ResultModel 1 showed good accuracy (area under the receiver operating characteristic curve [AUROC] 0·837) in cross‐validation, and fair accuracy (AUROC 0·765) in external validation. The addition of MRI features to the model 1 to create model 2 led to improvements in the prediction performance. Consequently, model 2 showed good accuracy (AUROC 0·892) in cross validation. Apolipoprotein E genotype, delayed recall task scores, and interaction between cortical thickness in the temporal region and hippocampal volume were the most important predictors of Aβ positivity.ConclusionOur results suggest that ML models are effective in predicting Aβ positivity at the individual level and could help the biomarker‐guided diagnosis of prodromal AD.
Recent regulatory and scientific developments suggest a novel oral formulation (CoM pat. pend.) of HP‐alpha‐cyclodextrin as a safe (not ototoxic) and convenient (oral) drug against Alzheimer's disease
Authors: Wittkowski Knut M. 
Published: December 2021

AbstractBackgroundThere are no disease‐modifying treatments (DMTs) for Alzheimer's disease (AD). HP‐beta‐cyclodextrin (HPβCD) was effective in AD models and, in Feb 2021, clinical results were presented at a conference: a phase 1/2 trial of IV HPβCD qow for >8 h had shown reduction of CSF tau protein after 12 wk. HPβCD is known for its risk of cholesterol‐related ototoxicity, but hearing loss was only transient (Fig. 1) and the FDA accepted INDs for overnight IV HPβCD as a drug against NPC1 (phase 3) and AD (phase 2).MethodTo test whether one could avoid ototoxicity and chaining patients to the bed overnight, we conducted a human PK/PD study of a novel (non‐covalent) clathrate of HPαCD and a milk/coconut oil medium‐chain fatty acid. HPαCD alone, co‐administered with, and as a clathrate with decanoate (both 2:1 molar) were administered orally before bedtime. HPαCD and phospholipids (PLs) were measured by FPLC in morning urine. We also conducted animal studies in breast cancer and movement disorders, where high levels of endocytosis are known to “derail” the endocytosis‐lysosome‐autophagy (ELA) axis.ResultIn the absence of dietary milkfat, no HPαCD was excreted into urine. With C10 added, some HPαCD and small increases in PLs were seen, but twice as much with the clathrate (Fig. 2). Animal studies showed IP HPαCD as more effective than HPβCD in breast cancer (reducing endocytosis and inflammation, Fig. 3) and also effective in movement disorders (not shown).ConclusionIntermittent fasting (IF) and the IF mimetic HPαCD (too small to fit cholesterol) were previously shown to be more effective than HPβCD in lysosomal storage diseases and in cancer, where endocytosis is also involved, albeit with manifestations in destinations different from AD (Fig. 4). With the new results showing that (a) the HPαCD clathrate ASD‐005 is intestinally absorbed, safe, and has systemic effects in other ELA axis diseases, including cancer (Ancidoni 2021, Alzheimers Res Ther 13:96), and (b) HP‐CDs are active across the blood‐brain barrier, two barriers against a more convenient, safer, and potentially more effective DMT for AD, as well as regulatory hurdles against cyclodextrins accepted as drugs were overcome in Feb 2021.
Characterizing brain age in the Alzheimer's disease connectome project using a deep neural network pre‐trained on the UK Biobank
Authors: Adluru Nagesh , Nair Veena A. , Prabhakaran Vivek , Bashyam Vishnu , Li Shi‐Jiang , Okonkwo Ozioma C. , Davidson Richard J. , Alexander Andrew L. , Bendlin Barbara B. 
Published: December 2021

AbstractBackgroundOverall age of an individual is commonly measured in chronological time. With the advent of in vivo imaging and reliable predictive modeling, a finer gradation of the age into many internal biological scales such as cellular, tissue, organ and cognitive aging etc. can be estimated. Accurate estimation of the age of the in vivo brain can offer insights into its differential aging patterns and accelerated excess aging due to the burden of disease processes eventually leading to dementia. Modern machine learning algorithms have allowed for accurate estimation of “brain age” using MRI data. The purpose of this study was to evaluate the applicability of a 3D fully‐convolutional neural network (FCNN), pre‐trained on a large dataset of over ten thousand T1‐weighted (T1‐w) MR images from the UK Biobank to data from the Alzheimer’s disease connectome project.MethodT1‐w data acquired from 152 participants were minimally pre‐processed (brain masking, B1 bias reduction, and linear registration to MNI) and input to the pre‐trained FCNN to predict their brain age. A linear regression between calendar age and brain age gap was used to correct the bias in each of the predicted brain age.ResultThe brain age predictions before and after bias correction, mean and spread of the calendar ages, mean absolute error of prediction for each group and sex are shown in Fig. 1. The quantiles of the excess brain aging are shown in Fig. 2.ConclusionWith a minimal pre‐processing of T1w‐MRI, the UK Biobank pre‐trained deep neural network (DNN), along with a linear bias correction, provided an estimate of the age of the brain in ADCP with excellent approximation. The analysis revealed that the median gap between the brain age and calendar age is about a year in the AD group, and about half‐a‐year in the MCI group and none in the CU group, when averaged over the sexes. This provides preliminary evidence of accelerated aging of the brain in the cognitively impaired groups (MCI/AD). Future analysis involves examining excess brain and cognitive aging due to amyloid and tau burden. Future work entails developing DNNs to improve generalization, standardization, and individualized precision of such predictive models.
Amyloid aggregation in temporal regions is associated with longitudinal memory decline in cognitively unimpaired Apoe‐ε4 carriers
Authors: Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Cacciaglia Raffaele , Salvadó Gemma , Collij Lyduine E. , Buckley Christopher , Van Berckel Bary N.M. , Perissinotti Andrés , Niñerola‐Baizán Aida , Milà‐Alomà Marta , Operto Grégory , Falcon Carles , Kollmorgen Gwendlyn , Suridjan Ivonne , Minguillón Carolina , Fauria Karine , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   for the ALFA Study
Published: December 2021

AbstractBackgroundEvidence shows that APOE‐ε4 is associated with amyloid‐beta (Aβ) aggregation in the medial temporal lobe (MTL), a crucial region supporting episodic memory (EM), early in the AD continuum. However, the impact of Aβ aggregation in the MTL of cognitively unimpaired (CU) APOE‐ε4 carriers has not been explored. We determine whether abnormal Aβ in the MTL of CU individuals APOE‐ε4 carriers has an impact on EM change.MethodThe study included 352 CU ALFA+ study individuals (age 45‐70) who completed a baseline cognitive assessment with valid T1w MRI, [18F]‐flutemetamol Aβ PET, CSF, and APOE genotyping, and also had a second cognitive assessment after 3 years. [18F]‐flutemetamol scans were visually assessed globally to rate the scan as positive or negative and regionally. CSF p‐tau, Aβ‐40 and Aβ‐42 concentrations were determined using the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays, and Elecsys® immunoassays (both Roche Diagnostics International Ltd). Hippocampal volumes (HV) were obtained from the T1w MRIs with Freesurfer 6.0. EM was assessed by the Memory and Binding Tests subscore Total Paired Recall (TPR). Annualized memory change was the dependent variable in linear models using regional or global visual read (VR), CSF biomarkers and HV as predictors, and age, sex, education and APOE‐ε4 as covariates. Interaction terms with APOE‐ε4 *VR were also modeled.Result57 (16.2%) participants were global VR amyloid‐positive and 41 (71.9%) were APOE‐ε4 carriers. For annualized change in memory, we found that APOE‐ε4 carriership modified the association between temporal VR and annualized change (p=0.02) (Figure 1). 29 (5.4%) were amyloid‐positive in temporal VR, of them 19 (65.5%) APOE‐ε4 carriers. This interaction remained significant after adjusting by CSF Aβ42/Aβ40 and ptau/Aβ42 ratios, and HV (Table 1). No significant interaction was found with global VR.ConclusionAPOE‐ε4 carriers with a positive temporal VR exhibited a decline in EM. This result shows the effects on cognition of previous findings showing the association between APOE‐ε4 and Aβ aggregation in the MTL for any given level of soluble Aβ alterations. Moreover, this work supports that regional VRs can detect early Aβ pathology with relevant effects on cognition.
Mayo Test Drive: Reliability and construct validity of the Stricker Learning Span and Symbols Test on a self‐administered web‐based testing platform optimized for smartphone
Authors: Karstens Aimee J , Stricker John L , Geske Jennifer , Hassenstab Jason , Fields Julie A. , Mielke Michelle M. , Stricker Nikki H. 
Published: December 2021

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment for novel (Stricker Learning Span; SLS) and open access (Symbols Test) cognitive measures. The SLS is a computer adaptive word‐list memory test that matches test difficulty to user performance. The SLS visually presents words for learning exposures and 4‐choice recognition to test encoding across 5 trials. Symbols is a measure of processing speed being used in many remote assessment studies and typically employs a burst design; in MTD participants complete 4 trials (12‐items each). We examine validity and reliability of the SLS and Symbols via MTD.MethodForty‐five women enrolled in an ongoing study of the Sex‐Specific Effects of Endocrine Disruption on Aging and Alzheimer’s Disease were recruited via email or phone. The Auditory Verbal Learning Test (AVLT) and Digit Symbol Coding (Coding), administered in person within the past 2 years (Mean=11 months), were used to establish construct validity. Participants (91.3% White, Mean age=66.2 years, Mean education=15.3 years) were emailed a link to complete the SLS and Symbols remotely at their convenience on their own device and emailed to repeat testing after approximately 1 week. Pearson correlations (n=45) and 2‐way mixed intraclass correlation coefficients (ICC; n=42) determined construct validity and test‐retest reliability, respectively. Significance was set at p<.05.ResultAcross all test sessions initiated, 97% were successfully completed. Most were completed at home (92.6%; vs. at work or in a public space), and device type varied (48% smartphone, 2% tablet, 50% PC). Median session completion time was 15 minutes. SLS learning scores (max span, total correct trials 1‐5) significantly correlated with AVLT 1‐5 total (r’s .37‐.39) and AVLT Trial 5 (r’s .51‐.52). SLS delay significantly correlated with AVLT delay (r=0.45) and recognition (r=0.61). Symbols time‐based scores averaged across trials were significantly correlated with Coding (r’s=‐.48‐(‐).50). Test‐retest reliabilities across 2 sessions were high for SLS (ICC’s=.80‐.88) and Symbols (ICC’s=.81‐.82).ConclusionSLS and Symbols are valid and reliable self‐administered remote tests in older females. Future work will examine effects of Alzheimer’s disease neuroimaging biomarkers and risk factors on these tests.