bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pimavanserin and concomitant anti‐dementia medication use in patients with neurodegenerative and/or neurovascular disorders: Safety outcomes from pooled clinical data and the HARMONY study
Authors: Foff Erin P. , McEvoy Bradley , Skoog Benjamin , Demos George 
Published: December 2021

AbstractBackgroundPimavanserin, a selective serotonin receptor modulating agent, is approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis and is being investigated for the treatment of hallucinations and delusions associated with dementia‐related psychosis (DRP). Many DRP patients also receive concomitant antidementia medication (cADM), such as acetylcholinesterase inhibitors or memantine. We evaluated the tolerability of cADM use in pimavanserin‐treated patients with neurologic disease.MethodsTreatment‐emergent adverse events (TEAEs) were examined using pooled data from 8 double‐blind, placebo‐controlled, parallel‐group studies of patients with neurodegenerative and/or neurovascular disease (collectively, NDD) who received pimavanserin 34 mg (N=580) or placebo (N=649) once daily and data from HARMONY, the phase 3 randomized discontinuation study of pimavanserin for DRP. HARMONY included a 12‐week open‐label (OL) period (N=392) followed by a 26‐week double‐blind (DB) period where subjects were randomized to continue pimavanserin treatment (N=105) or switch to placebo (N=112).ResultsIn the pooled NDD population, 291 (50.2%) pimavanserin‐treated and 305 (47.0%) placebo‐treated patients had cADM use. Those with cADM use had lower rates of TEAEs (pimavanserin: 51.2%, placebo: 52.1%) vs those without (pimavanserin: 56.7%, placebo: 59.6%). Rates of serious TEAEs were also similar in patients treated with cADM (pimavanserin: 6.9%, placebo: 4.6%) vs those without cADM (pimavanserin: 7.3%, placebo: 4.1%). In the OL period of HARMONY, 273 (69.6%) patients had cADM use; their rates of TEAEs (with cADM: 32.2%, without cADM: 45.4%) and serious TEAEs (with cADM: 3.3%; without cADM: 9.2%) were similar to patients without. In the DB period, 81 (77.1%) pimavanserin‐treated and 72 (64.3%) placebo‐treated patients used cADM. DB patients with cADM use exhibited rates of TEAEs (pimavanserin: 37.0%, placebo: 31.9%) and serious TEAEs (pimavanserin: 3.7%, placebo: 4.2%) similar to patients without (TEAEs, pimavanserin: 54.2%, placebo: 45.0%; serious TEAEs, pimavanserin: 8.3%, placebo: 2.5%).ConclusionsPatients with NDD receiving pimavanserin in clinical trials commonly took cADMs. There was no evidence that concomitant pimavanserin use resulted in a differential TEAE or serious TEAE profile in patients taking antidementia medications.
Depressive symptoms in patients referred for clinical amyloid PET imaging
Authors: Loreto Flavia , Fitzgerald Anna , Golemme Mara , Win Zarni , Patel Neva , Gunning Stephen , Gontsarova Anastasia , Kennedy Angus , Edison Paul , Carswell Christopher J , Perry Richard J , Malhotra Paresh A 
Published: December 2021

AbstractBackgroundThe clinical use of amyloid‐PET imaging (API) is guided by a set of published appropriate use criteria (Johnson et al., 2013). Patients meeting these criteria have suspected Alzheimer’s Disease (AD) accompanied by an atypical clinical presentation leading to substantial diagnostic uncertainty. Previous large‐cohort studies have investigated this clinical population from a diagnostic standpoint, looking at the impact of using amyloid‐PET to elucidate the aetiology of impairment. However, data concerning their clinical phenotypes is lacking. In this study, we investigated the prevalence of depression and its association with Alzheimer’s pathology in Memory Clinic patients who received clinical API.MethodWe reviewed the clinical records of 185 older adults (mean age 67.09±9.35, 49% females) who were assessed in our Clinic between January 2017 and June 2019 and received API. Referral to amyloid‐PET followed a multidisciplinary meeting and was in line with appropriate use criteria. Patients were categorised as ‘D+’, with history of depression, if they had received a previous depression diagnosis and/or if they had a history of depressive symptoms. Overall depression prevalence was compared with published cohort data. Amyloid‐PET results (positive versus negative) were compared between the D+ and the D‐ (without history of depression) groups. In D+ patients, we determined the onset and status of depressive symptoms.ResultOf 185 patients, 98 (53%) had a history of depression. Of these, 89 individuals had ongoing symptoms at the time of referral to our Clinic and 59 of them were on antidepressants. The mean age of depression onset was 58.25(±12.25) years. Depression prevalence in this cohort was considerably higher than that generally seen in memory clinics (20%; Knapskog et al., 2014) and in healthy older adults (19%; McDougall et al.,2017). Depression history was not associated with amyloid‐PET results (%positive: D+ 39.8%, D‐ 50.6%, χ2(1)=2.16 p=.14), age (mean±SD: D+ 66.47±9.03 years, D‐ 67.79±9.71 years, t(183)=‐.95 p=.342), or sex (%female: D+ 44.9%, D‐ 52.9%, χ2(1)=.1.17 p=.304).ConclusionDepression prevalence is high in patients referred for clinical amyloid‐PET imaging and is independent of the presence or absence of Alzheimer’s pathology. Depression may be one of the key contributors to diagnostic uncertainty in this group.
Associations between REM‐sleep EEG spectral power, the cholinergic basal forebrain volume and episodic memory in ageing
Authors: André Claire , Martineau‐Dussault Marie‐Ève , Daneault Véronique , Blais Hélène , Lorrain Dominique , Hudon Carol , Bastien Célyne , Petit Dominique , Lafrenière Alexandre , Legault Julie , Martinez Guillermo E. , Thompson Cynthia , Montplaisir Jacques , Gosselin Nadia , Carrier Julie 
Published: December 2021

AbstractBackgroundOur research team has demonstrated that quantitative electroencephalography (qEEG) slowing during rapid‐eye movement (REM) sleep is a more powerful tool to discriminate patients with mild cognitive impairment (MCI) or Alzheimer Disease (AD) from healthy controls than waking EEG. Cortical activation during REM sleep highly depends on the cholinergic basal forebrain system (BFCS) neurons, while other neuronal systems are less active compared to wakefulness. However, the BFCS degenerates early in AD. Here, we tested the hypothesis that REM sleep EEG activity could be strongly associated with neurodegeneration of the BFCS, before the onset of dementia.Method134 participants (mean age 68.45 ± 7.8 years; 52 women; 61 with MCI) underwent a polysomnography, structural magnetic resonance imaging, and a neuropsychological evaluation. T1‐weighted images were preprocessed using CAT12 and the DARTEL algorithm, and the JuBrain Anatomy Toolbox was used to extract bilateral BFCS volumes (i.e., Ch1‐2‐3, Ch4 and total volume). Based on prior evidence, theta (4‐8Hz) and alpha (8‐13Hz) absolute EEG power during REM sleep were computed on temporal electrodes (T3‐T4‐T5‐T6). A composite episodic memory score was calculated as the mean of Z‐scores obtained on the Rey Auditory Verbal Learning Test immediate and delayed free recalls. Multiple regressions were performed between (i) spectral power values or (ii) episodic memory performance, and basal forebrain volumes controlling for age, sex, the apnea‐hypopnea index, and the total intracranial volume. Complementary analyses were performed by stratifying the cohort by sex.ResultBoth Ch4 (r=0.24, p=0.006) and total BFCS (r=0.25, p=0.005) volumes were positively associated with episodic memory performance. Ch4 (r=‐0.21; p=0.025) and total BFCS (r=‐0.22; p=0.02) volumes were negatively associated with temporal theta power. Moreover, total BFCS (r=‐0.22; p=0.023) volumes were negatively associated with temporal alpha power. Sex‐stratified analyses revealed that the associations between BFCS volumes, REM‐sleep spectral power and episodic memory were significant in women, but not in men.ConclusionThese results confirmed that cortical activation during REM sleep is sensitive to volume loss in the BFCS, a cholinergic region known to degenerate early in AD. Why this association was only observed in women is intriguing and will need further investigation.
Subjective social status, objective socioeconomic status, and memory aging
Authors: Chen Xi , Varghese Leah , Jagust William J. 
Published: December 2021

AbstractBackgroundMemory aging is a heterogeneous process. Many research efforts have been made to explore what might “slow down” memory aging. The present study examined how subjective social status and objective socioeconomic status may be protective for memory aging in normal adults.MethodWe recruited 272 participants (aged 20‐70 yrs old) online using MTurk, and measured their memory performance using a newly developed task that examines multiple domains of visual memory. During this task (Fig. 1), participants viewed and made judgements of pictures depicting an object in a scene and later completed a surprise recognition test where they indicated if they remember seeing the identical picture earlier. In the recognition test, some pictures were the exact pictures presented earlier; some were lures that had a different object, a different scene, or a different spatial relation of the object to the scene; and some were completely new pictures. We measured memory performance based on participant’s response accuracy. We additionally collected information on participants’ subjective social status (using the MacArthur Scale of Subjective Social Status), education, occupation class, and individual and household income.ResultAs expected, increasing age was related to worse memory performance. Importantly, subjective social status moderated the aging effect on memory: people who rated their social status to be higher (top 40%) did not show the typical age‐related decrease in memory (Fig. 2a). Higher household income was also associated with slower memory aging: people who reported having higher household income (>$75,000) did not show an age‐related memory decrease (Fig. 2b). Education and occupation, however, did not moderate memory aging. Finally, we found the moderating effects of subjective social status and income were interactive: higher income was associated with less memory aging in people with low subjective social status, while higher subjective social status was associated with less memory aging for people with low income (Fig. 2c).ConclusionSubjective beliefs of having a high social position and objectively having a high income are two factors that may “slow down” memory aging. They work together in a way where one protects when the other fails to do so.
Reproducibility of applying multiple statistical analyses to data from the TRAILBLAZER‐ALZ clinical trial of donanemab in early symptomatic Alzheimer's disease
Authors: Sparks JonDavid , Lo Albert C. , Evans Cynthia Duggan , Chatterjee Saptarshi , Andersen Scott W. , Sims John R. , Brys Mirek , Mintun Mark A 
Published: December 2021

AbstractBackgroundThe Mixed Model for Repeated Measures (MMRM) is the most frequently used statistical analysis for clinical trial endpoints in Alzheimer’s disease (AD) but has the limitation of not efficiently leveraging data from intermediate time points due to the flexibility in the mean structure. In the TRAILBLAZER‐ALZ trial, donanemab, a humanized IgG1 antibody specifically targeting brain amyloid plaque, slowed disease progression in individuals with early symptomatic AD. The aim of this presentation is to apply different statistical models to clinical scale data gathered from this trial, as consistent conclusions following multiple methods would strengthen confidence in the results.MethodTRAILBLAZER‐ALZ (NCT03367403) was a randomized, placebo‐controlled, double‐blind, multi‐center Phase 2 study assessing the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. The change from baseline to 76 weeks was assessed using the Integrated AD Rating Scale (iADRS), a composite tool measuring cognition and daily function (primary endpoint), and the Clinical Dementia Rating Scale‐Sum of Boxes (CDR‐SB; secondary endpoint). In addition to MMRM, three statistical models were fit: Bayesian Disease Progression Model (DPM), Natural Cubic Spline (NCS) model, and Quadratic Mixed Model (QMM). Each model has unique assumptions and data handling, for example, in treating time categorically or continuously, which can lead to differences in power while still controlling the false‐positive rate to an allowable margin.ResultThe percent slowing estimates and treatment differences at 18 months from the models are consistent in supporting a positive treatment effect across the clinical scales. The DPM, NCS, and QMM provide a reduction in the standard error, which leads to tighter intervals due to the model assumptions generally being met.ConclusionThe consistency of the results between the statistical models and across the clinical scales suggests the general robustness and strength of the data, regardless of the statistical model used. DPM, NCS, and QMM may provide a more detailed estimate of the longitudinal trajectory of each treatment group when there are small sample sizes and noisy data, and an MMRM model may not be an ideal choice in trial designs that may have sparse data at later time points.
Association of neighborhood‐level socioeconomic advantage with cognition and dementia risk factors in an Australian cohort
Authors: Cavuoto Marina G , Rowsthorn Ella , Lavale Alexandra , Yassi Nawaf , Maruff Paul T , Buckley Rachel F , Lim Yen Ying , Pase Matthew P 
Published: December 2021

AbstractBackgroundResiding in areas of low socioeconomic advantage is associated with increased risk of dementia1 and associated brain pathology2,3. Given the long and insidious course of dementia pathologies, it is critical to establish the effect of ‘exposomic’ risk factors in midlife and to understand which groups of people are particularly vulnerable. Therefore, the objective of this study was to examine whether cognitive performance or dementia risk factors differed according to neighborhood‐level socioeconomic advantage in cognitively normal middle‐aged people.MethodsOur sample comprised 4798 participants from the Healthy Brain Project, an online cohort of community‐dwelling Australians aged 40‐70 years. Socioeconomic advantage was computed by matching participants’ residential address to the Australian Bureau of Statistics’ Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), assigning each participant a decile score (10 being the most advantaged). Scores were related to dementia risk estimated using the CAIDE dementia risk score and cognitive performance measured with the Cogstate Brief Battery (CBB) in linear regression models.ResultsOf the 4798 participants (mean age±SD 56±7 years, 26% male), 2762 (58%) were classified as living within an area of high neighbourhood socioeconomic advantage (IRSAD scores ≥ 8th decile), 1296 resided in rural or regional areas (27%), and 984 identified as “non‐European” (21%). Each decile unit increase in neighborhood socioeconomic advantage was associated with a lower CAIDE dementia risk score (β±SE= ‐0.088±0.024, p <0.001), following adjustments for race and rurality, and with better memory performance (β±SE= 0.084±0.024, p <0.001), following adjustments for age, sex, race, education, and rurality. An interaction was observed with differences in memory performance between levels of neighborhood advantage (comparing scores above and below the 8th decile) being larger at older ages and in people with higher dementia risk scores (Figure 1). There was no association between neighborhood‐level advantage and attention.ConclusionsIn a middle‐aged Australian cohort, higher neighborhood‐level socioeconomic advantage was associated with superior memory and lower dementia risk scores. Efforts to lower dementia risk factors, particularly in relation to reducing the negative impacts of disadvantage, are needed to curtail the growing burden of dementia.
Clinical performance of the beta‐amyloid 1‐42/1‐40 ratio determined from automated Lumipulse G1200 cerebrospinal fluid Abeta1‐42 and Abeta1‐40 assays, assessed by concordance with PET imaging status
Authors: Winslow John W. , Martone Robert L. , Badal Youssouf W. , Chenna Ahmed W. , Cai Suqin W , Sperinde Jeff W. , Ayonke Jeric W. , Vergara Jamie , Yee Brandon W. , Spiro Lisa W. , Ozegovich Terri , Nisenbaum Laura , Petropoulos Christos W. 
Published: December 2021

AbstractBackgroundβ‐amyloid measured in cerebrospinal fluid (CSF) has been widely used to assess Alzheimer’s disease (AD) patients. Reduced concentrations of Aβ1‐42 (Aβ42) in CSF are inversely correlated with increased retention of Aβ tracers in brain amyloid plaques observed with positron emission tomography (PET). Multiple studies, including those applying automated immunoassay platforms, have reported increased diagnostic accuracy of the CSF Aβ1‐42/Aβ1‐40 ratio (Aβ42/Aβ40 ratio) over Aβ42 levels alone. In the present study, the concordance between calculated CSF Aβ42/Aβ40 ratios derived from individual Lumipulse G1200 CSF Aβ42 and Aβ40 assays and PET imagining status was determined utilizing a well characterized patient cohort.MethodA subset of n=171 patient CSF samples from the Australian Imaging, Biomarkers and Lifestyle study (AIBL), and n=24 samples from an independent study cohort were included for a total of n=195 patients having amyloid PET status. Amyloid PET‐positivity was 51%. Clinical diagnosis groups included AD (n=43; 95% PET+), mild cognitive impairment (MCI; n=46; 67% PET+); subjective memory complainers (SMC; n=59; 39% PET+), non‐memory complainers (NMC; n=45; 9% PET+), and non‐AD dementia (frontotemporal dementia; n=2; 0% PET+). CSF Aβ42 and Aβ40 were measured with analytically validated Lumipulse G1200 immunoassays (Fujirebio Diagnostics), performed by state‐certified laboratory scientists under CLIA conditions, and the ratio calculated. An optimal cutoff for the Aβ42/Aβ40 ratio was determined from the maximal Youden J index.ResultThe median Aβ42/Aβ40 ratios for PET+ (0.088) and PET‐ (0.042) patient groups were significantly different (Wilcoxon p<0.001). An optimal Aβ42/Aβ40 ratio cutoff of 0.058 was determined, resulting in a sensitivity, specificity, PPV and NPV of 96.0% (CI 90.0%‐98.4%); 96.9% (CI 91.2%‐98.9%), 96.9% (CI 91.3%‐98.9%), and 95.9% (CI 89.9%‐98.4%), respectively. Receiver operating characteristics area under the curve (ROC‐AUC) was 0.968.ConclusionExcellent concordance was observed between amyloid PET status and Aβ42/Aβ40 ratio determined from Lumipulse G1200 assays, including results from patients diagnosed with earlier stage disease. The sensitivity and specificity of the CSF Aβ42/Aβ40 ratio determined with the Lumipulse system, together with high analytical performance, support its clinical utility as a biomarker of amyloid status and clinical assessment.
Inflammatory biomarkers in patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Ortiz Ana Maria , Minguet Carla , Gonzalo Ricardo , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Costa Montserrat 
Published: December 2021

AbstractBackgroundIncreasing evidence suggests that Alzheimer’s disease (AD) pathogenesis is not restricted to the neuronal compartment but would involve peripheral inflammatory mechanisms that contribute to cognitive impairment. The AMBAR phase 2b/3 trial is a therapeutic approach for mild‐moderate AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma exchange with albumin replacement (PE‐Alb) to remove neurotoxic Aβ and other pathological substances from plasma, thus slowing AD progression. The aim of this study was to assess PE‐Alb effects on inflammatory biomarkers across the AMBAR study.MethodTwenty‐three inflammatory biomarker levels (IFN‐γ, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TNF‐α, Eotaxin, MIP‐1β, Eotaxin‐3, TARC, IP‐10, MIP‐1α, MCP‐1, MDC, MCP‐4, SAA, CRP, VCAM‐1, ICAM‐1) were measured through three electrochemiluminescence V‐plex panels (Meso Scale Discovery). Up to 105 PE‐treated and 37 placebo [sham‐PE] patients’ samples serum (8 time points) and cerebrospinal fluid (CSF) (3 time points), collected from 2016 onwards, were assessed. Evaluable biomarkers (those that were detectable in more than 30% of the samples at baseline and final visit), were analyzed over time as the change from baseline with a mixed model for repeated measures (MMRM) approach. Fixed effects factors for month, treatment group, and month*treatment interaction, with adjustment for age, baseline MMSE, and baseline biomarker levels were used. Patient was included as a repeated factor and differences from placebo were estimated using least squares means (LSM) (± standard error of the mean [SEM]).ResultNineteen inflammatory biomarkers in serum and 11 out of 23 in CSF resulted evaluable. In serum, the LSM difference from baseline showed statistical significance (p<0.05) of PE‐treated patients compared to placebo in six biomarkers. Two presented a significant reduction before the last procedure of the first 6‐week intensive PE‐Alb period (1.5‐month), intermediate (2‐month) and at final visit (14‐month). Other four biomarkers showed a significant decrease at 1.5‐month, 2‐month, and/or 14‐month. CSF analysis indicated a significant decrease at 2‐month for two entries out of the biomarker panel.ConclusionPE‐Alb procedures used in AMBAR induced changes in tested patients’ CSF and serum inflammatory profiles. This supports the multimechanism basis of AMBAR therapeutic approach that may contribute to slowing AD progression.
Alcohol consumption and risk of dementia: 11‐year follow‐up of UK Biobank cohort study
Authors: Wei Chang , Zhao Ziyi , Li Bingyu , Sha Feng 
Published: December 2021

AbstractBackgroundThe negative effect of alcohol consumption on cognitive function is found to be J‐shaped. We analyzed the association between alcohol consumption and the risk of dementia and examined the effect modification by APOE genotypes.Method157,172 Participants with nearly equal alcohol consumption compared with ten years previously were included from UK Biobank cohort study. Levels of alcohol consumption were evaluated on both categorical scales such as abstainers, occasional drinkers, monthly drinkers, light‐to‐moderate drinkers (0‐ 14 units per week), and heavily drinkers (over 14 units per week) and continuous scales (total average weekly units of alcohol consumption), with Cox regression models and restricted cubic splines (RCS). Models over all participants and stratified on APOE genotypes were conducted to assess the risk of dementia, adjusted for sociodemographic, health behaviors, and health‐related variables.Result709 (0.45%) out of the 157,172 participants developed dementia over a mean follow‐up of 11.4 years. Among all participants, abstainers (HR = 1.75, 95% CI 1.25 to 2.45) and occasional drinkers (1.45, 1.03 to 2.02) have an increased risk compared with light‐to‐moderate drinkers, whereas monthly drinkers (0.77, p = 0.25) and heavy drinkers (1.02, p = 0.86) do not show a significant difference. In the stratified analysis, among APOE ɛ4 allele carriers, there’s no significant difference between any category of drinkers and mildly weekly drinkers. In RCS with Cox models, 589 (0.44%) out of the 132,417 participants developed dementia over a mean follow‐up of 11.4 years. A J‐shape association between total average weekly alcohol consumption and dementia incidence was found only among APOE ɛ4 allele non‐carriers.ConclusionThe effect of alcohol consumption on the risk of dementia differs between APOE ɛ4 carriers and non‐carriers. The association between light‐to‐moderate alcohol consumption and dementia will be further examined.