bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of Lomecel‐B in patients with mild Alzheimer’s disease: Results of a double‐blinded, randomized, placebo‐controlled phase 1 clinical trial
Authors: Oliva Anthony A. , Brody Mark , Agronin Marc , Herskowitz Brad , Bookheimer Susan Y , Hitchinson Ben , Ramdas Kevin , Wishard Tyler , McClain‐Moss Lisa , Diaz Liliana A. , Yousefi Keyvan , Perez Carmen , Fuquay Ana , Rodriguez Savannah , Hare Joshua M. , Baumel Bernard 
Published: December 2021

AbstractBackgroundLomecel‐B is a formulation of allogeneic medicinal signaling cells (MSCs), which exert pleiotropic mechanisms of action (MOAs) with potential to simultaneously target multiple pathophysiological features of Alzheimer’s disease (AD).MethodWe conducted a double‐blinded, randomized, placebo‐controlled trial (ClinicalTrials.gov: NCT02600130). Mild AD patients (Table) were infused with Lomecel‐B at 20 (20M, N=15) or 100 million cells (100M, N=10), or placebo (N=8). Eligibility screening included clinical evaluation, MRI to exclude other etiologies, and beta‐amyloid tracer PET to confirm AD. Scheduled follow‐ups were conducted through 1‐year post‐treatment. The primary endpoint was safety. Pre‐specified secondary endpoints evaluated efficacy in neurocognitive/neuropsychological, quality‐of‐life (QOL)/activities of daily living (ADL), and biomarker domains.ResultLomecel‐B was well‐tolerated and did not trigger safety stopping rules, meeting the primary endpoint. Efficacy endpoints were improved in the Lomecel‐B groups. Whereas the Mini Mental State Exam (MMSE) declined in placebo by 2.99±1.12 points at Week 13 (p=0.0337; 95%CI ‐5.84 – ‐0.31), the 20M Lomecel‐B group showed minimal decline (difference from placebo: 2.69±1.39 points; p=0.0182; 95%CI 0.51 – 4.97). This difference persisted over one year (Figure). On the QOL‐AD patient version, the 20M Lomecel‐B group significantly improved versus placebo at Week 26 by 3.85±1.94 points (p=0.0444; 95%CI 0.13 – 9.12). On the ADCS‐ADL, the placebo group significantly declined at Week 26 by 9.27±2.78 points (p=0.0211; 95%CI ‐17.83 – ‐2.10), and was significantly worse versus 20M Lomecel‐B by 6.95±3.46 points (p=0.0118; 95%CI 1.99 – 13.94). In contrast, these assessments did not significantly differ in the 100M Lomecel‐B group versus placebo. Anti‐inflammatory (IL‐10, IL‐12, sIL‐2Rα) and pro‐vascular (VEGF, IL‐4, IL‐6) serum biomarkers were significantly higher in both Lomecel‐B groups versus placebo, with 100M Lomecel‐B generally showing the greatest rises. Left hippocampal volume increased in the 100M Lomecel‐B group versus placebo at Week 13 (p=0.0311).ConclusionThese results support the safety and clinical potential of Lomecel‐B for AD. These hypothesis‐generating results also revealed potentially important biomarkers which are consistent with multiple MOAs of Lomecel‐B. Ongoing investigation of Lomecel‐B for AD in larger clinical trials powered for clinical efficacy is warranted. This study was supported through Alzheimer’s Association Part the Cloud Challenge on Neuroinflammation grants #PTC C‐16‐422443 and PTC‐CS‐19‐623225.
Design of a patient‐ and investigator‐blind, randomized, placebo‐controlled study to evaluate efficacy, safety, and tolerability of bepranemab, UCB0107, in prodromal to mild Alzheimer’s disease: The TOGETHER Study, AH0003
Authors: Barton Matthew E , Byrnes William , Mesa Irene Rebollo , Bloemers Jos , Maguire Ralph Paul , Bouw Rene , Tesseur Ina , Ewen Colin , Scheltens Philip 
Published: December 2021

AbstractBackgroundBepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Bepranemab is being developed to block or reduce the spread of tau pathology in people living with tau‐mediated diseases, like Alzheimer’s disease (AD).MethodTOGETHER (AH0003; NCT04867616) is a global, multicenter, patient‐blind, investigator‐blind, placebo‐controlled, parallel‐group study, investigating the efficacy, safety, and tolerability of bepranemab (intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80‐week treatment period, followed by an optional 48‐week open‐label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14‐item Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog14), Amsterdam‐Instrumental Activities of Daily Living, and Mini‐Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long‐term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (low‐dose and high‐dose bepranemab, and placebo; randomized 1:1:1). Eligible patients will meet the National Institute of Aging‐Alzheimer’s Association (NIA‐AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR‐Memory Box score ≥0.5 at screening and baseline. Patients will have a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau181/Aβ1‐42 ratio.ResultPatient enrollment and assessment will begin in Quarter 2 2021.ConclusionTOGETHER is a proof‐of‐concept study that will employ clinical outcome measures, imaging, PK, biomarkers, and safety to assess the ability of bepranemab to slow the progression of AD when administered in the prodromal/mild stages of disease.
A simple Mini‐Mental State Exam subscale formula to help differentiate Alzheimer's disease from dementia with Lewy bodies
Authors: Bakir Danah , Goel Srishti , Ala Tom 
Published: December 2021

AbstractBackgroundAlthough there are clinical criteria for the diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), the two conditions may sometimes be difficult to differentiate. Prior research has documented that the two conditions often have striking neuropsychological differences, and there have been a number of reports promoting the ability of simple screening tests to help the diagnostic accuracy of the clinician. These screening tests, however, have been limited in their specificity. Building upon previous research from our group and others, we now report a simple manipulation of the Mini‐Mental State Exam (MMSE) subscale scores that greatly improves the specificity of the screening test.MethodWe studied all AD and DLB patients who visited our dementia clinic during an 18‐month period, including both new and follow‐up visit patients. All who had an MMSE administered to them were included. All MMSE scores were included. The first MMSE recorded for each patient was studied.ResultWe studied the MMSEs from 136 AD and 24 DLB patients. The mean patient age was 77.8 ± 11.1 for AD, 78.3 ± 8.7 for DLB. Mean MMSE score was 20.0 ± 6.0 for AD, 21.8 ± 5.1 for DLB; MMSE range 1‐30 for AD, 10‐28 for DLB. Many different formulae were studied using the MMSE subscales of Memory (3 points max), Attention (5 points max), and Pentagon‐copying (1 point max) to determine which was the best to differentiate AD from DLB. The simple formula of the Pentagon score minus the Memory score (P‐M, range 1 to ‐3) provided the best discrimination between the AD and DLB patient groups. For P‐M scores = 1, the specificity of the equation to identify AD was 0.92. For P‐M scores < 0, the specificity to identify DLB was 0.85. The sensitivities for the P‐M equation were 0.43 for AD (scores = 1) and 0.46 for DLB (scores < 0).ConclusionThe simple MMSE subscale formula of Pentagon score minus Memory score (P‐M) provided good specificities to identify AD patients (0.92) and LBD patients (0.85) within our cohort of AD and DLB patients. A weakness of the P‐M equation was relatively weak sensitivity.
Machine learning on combined neuroimaging and plasma biomarkers for triaging participants of secondary prevention trials in Alzheimer’s disease
Authors: Cumplido‐Mayoral Irene , Salvadó Gemma , Shekari Mahnaz , Operto Grégory , Falcon Carles , Milà‐Alomà Marta , Niñerola‐Baizán Aida , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo 
Published: December 2021

AbstractBackgroundPlasma biomarkers have demonstrated excellent agreement with established markers of amyloid‐β (Aβ) positivity (PET and CSF) to identify patients with symptomatic AD. However, their predictive capacity in cognitively unimpaired (CU) individuals is lower. In this work, we aimed at assessing whether structural MRI features could improve the capacity of machine learning algorithms applied to plasma biomarkers to identify Aβ positive CU individuals.MethodWe included 344 CU individuals from the ALFA+ study, with available T1w MRI, Aβ PET and plasma measurements for p‐tau181, p‐tau231, and GFAP. We determined the capacity to predict Aβ+ according to PET visual read of plasma biomarkers in combination with clinical data (age, sex, education, MMSE, and APOE genotype) and MRI‐derived measurements. We trained Random Forest classifiers with clinical, clinical and plasma, clinical and MRI; and clinical, plasma and MRI data. The MRI‐selected measurements consisted of Jack’s AD‐signature and the two features best predictive of Aβ+: left‐lat‐inf‐ventricle and left caudal‐anterior‐cingulate as determined with Freesurfer 6.0. We conducted ROC and Precision‐Recall analyses and calculated savings as the percentage difference of costs between standard trial recruitment and a triaging step with the different classifiers. The threshold for positivity prediction was chosen to maximize savings and the precision‐recall ratio. We computed ROC‐AUC, PPV, sensitivity and savings as metrics for the comparison.ResultsThe mean centiloid values of Aβ+ subjects (13.66%) and Aβ‐ were 33.73 and ‐1.82, respectively (Table 1). ROC‐AUCs for the classifiers to detect Aβ+ was 0.723 for clinical information; 0.861 for clinical and plasma measurements; 0.711 for clinical and MRI; and 0.871 for clinical, plasma and MRI. Savings associated with the best classifier (clinical + plasma + MRI) would translate in savings (95%CI) of 52.8% (49.0, 56.3) in recruitment costs. See Figure 1 for all the metrics’ results.ConclusionMachine learning algorithms on plasma biomarkers achieved a high accuracy on predicting a positive visual read on amyloid PET scans in cognitively unimpaired individuals. MRI biomarkers marginally improved the predictive capacity. Used as a triaging method, such an algorithm would result in a reduction of over 50% in the cost to identify participants for secondary prevention trials.
Drivers and barriers to participation of Black and Hispanic groups in Alzheimer's disease clinical trials: A qualitative study
Authors: Montenigro Philip H , Tse Bob , Wilson Kate , Butts Cherie 
Published: December 2021

AbstractBackgroundFor years, studies have reported that Black and Hispanic groups distrust physicians and are less likely to enroll in clinical trials (CT). For example, despite having nearly twice the risk for Alzheimer’s disease (AD) vs Whites, Black and Hispanic groups represent less than 5% of participants in AD CTs. The purpose of this study was to engage major stakeholders across the healthcare ecosystem in the United States to assess drivers and barriers to Black and Hispanic group participation in AD CTs.MethodsIn this study, we performed interviews of major stakeholders, including patients, care partners, physicians, investigators, trial‐coordinators, and payers. Semi‐structured questionnaires were developed to identify rational, emotional, and subconscious drivers and barriers to Black and Hispanic group participation in CTs. We surveyed individuals of different geographies, genders, ages (20‐65), locations (rural‐urban), education (some high school‐graduate school), and employment (unemployed‐full‐time). Responses from physicians and patients both with and without CT experience were also collected.ResultsWe found a major barrier to CT participation reported by Black and Hispanic persons was mistrust. Additionally, patients reported confusion about their AD diagnosis and feared psychiatric side‐effects of study treatments. Additional barriers included misconceptions about trials and limited awareness of the potential benefits (e.g., slowing disease progression) of treatments. While there is limited research on drivers for CT participation, respondents in this study were motivated by the potential benefit to their communities. Among physicians, barriers to participation included lack of familiarity with AD screening methods and lack of awareness of CTs in general. Another barrier among physicians was a belief that Black and Hispanic patients would not understand a diagnosis of AD, instead opting to use less specific language such as “memory decline” with these patients.ConclusionInclusion of Black and Hispanic participants in AD CTs is necessary to determine the safety and efficacy of potential treatments for AD in these groups. This research identified a critical area of focus for health equity efforts: intentional engagement with physicians for optimal education, access, and inclusion in AD CTs.
Cortical neuroanatomical changes related to specific neuropsychological deficits in subcortical vascular cognitive impairment
Authors: Kang Sung Hoon , Park Yu Hyun , Chin Juhee , Seo Sang Won 
Published: December 2021

AbstractBackgroundNeuropsychological test‐specific neural substrates in subcortical vascular cognitive impairment (SVCI) are expected to differ from those in Alzheimer’s disease‐related cognitive impairment (ADCI) but the details are unclear. To determine neural substrates related to cerebral small vessel disease, we investigated the correlations between cognitive dysfunctions measured by standardized neuropsychological tests and cortical thickness in a large sample of participants with amyloid negative (Aβ (‐)) SVCI.MethodOne hundred ninety‐eight participants with Aβ (‐) SVCI were recruited from the memory clinic between November 2007 to August 2018. To acquire neural substrates, we performed linear regression using the scores of each neuropsychological test as a predictor, cortical thickness as an outcome, and age, sex, education years, intracranial volume and white matter hyperintensity (WMH) as confounders.ResultPoor performances in each neuropsychological test were associated with cortical atrophy in certain brain regions regardless of WMH. Especially, not the medial temporal but the frontal and posterior cingulate regions with cortical atrophy were mainly associated with memory impairment. Poor performance in animal fluency was more likely to be associated with cortical atrophy in the left hemisphere, while poor performance in the visuospatial memory test was more likely to be associated with cortical atrophy in the right hemisphere.ConclusionOur findings suggested that cortical atrophy was an important factor of cognitive impairment in Aβ (‐) SVCI regardless of WMH. Furthermore, our findings might give clinicians a better understanding of specific neural substrates of neuropsychological deficits in patients with SVCI.
Differences in temporal AD biomarker trajectories according to sex and APOE genotype: Implication of importance of striatal amyloid
Authors: Chun Min Young , Kim Jun Pyo , Kim Soo‐Jong , Jang Hyemin , Kim Hee Jin , Na Duk L. , Seo Sang Won 
Published: December 2021

AbstractBackgroundAccumulation of β‐amyloid (Aβ) plaques and neurofibrillary tangles are core components of Alzheimer's disease (AD) pathogenesis. Longitudinal in vivo observations of AD pathologic changes using amyloid and tau positron emission tomography (PET) enable us to obtain AD biomarkers' hypothetical trajectory curves. However, the difference in disease progression by striatal Aβ deposition, sex, and apolipoprotein E (APOE) genotype has not been explained with trajectory curves. The aim of this study is to develop the trajectory in accumulation of cortical and striatal Aβ and tau deposits. We also tried to investigate the differences in sex and APOE genotype on trajectory curves.MethodWe obtained 817 subjects from the Alzheimer’s Disease Neuroimaging Initiative database, who showed either 18F‐florbetapir (AV45) PET positivity at least once or AV45 PET negativity with normal cognition. We Z‐transformed each value based on Aβ‐negative, cognitively normal subjects. Instead of obtaining a single rate value (∆Z/∆t) per subject, we calculated the slope for every interval of PET scans. For each biomarker, we fitted a penalized spline to model the slope of Z value as a nonlinear function of baseline Z value. Using the fitted splines, we obtained the predicted Z curves as a function of time and developed trajectory curves.ResultAmong the subjects, 534 subjects were available for AV45 PET analysis and 163 subjects underwent 18F‐flortaucipir PET. While cortical Aβ accumulation rate increased until Z value reached 4.33 and decreased subsequently, ∆Z/∆t for the striatal Aβ and tau stayed more constant. Time from Z=0 to Z=2 was the longest for tau PET (22.6 years) and shortest for cortical Aβ (14.9 years). For cortical Aβ, Z values of males reached 1.7 years earlier than females. However, for striatal Aβ, males took 2.8 more years than females to reach Z=2. Also, APOE ɛ4 carriers showed faster progression for all biomarkers.ConclusionThis study shows that Aβ accumulates in the striatum after cortex and then tau protein, which is consistent with the amyloid cascade hypothesis. The trajectory curves differ according to sex and APOE genotype. Therefore, prognosis and treatment should be approached differently in clinical practice with respect to striatal involvement, sex, and APOE genotype.
Impact of Covid‐19 pandemic on lifestyle in a middle‐aged and elderly population
Authors: Wong Zi Xuen , Phua April , Chew Kimberly Ann , Mohamed Jameelah Sheik , Pérez Kristal Morales , Mangialasche Francesca , Kivipelto Miia , Chen Christopher 
Published: December 2021

AbstractBackgroundMandated lockdowns and restricted activity in response to the COVID‐19 pandemic has affected our everyday life1. Seniors, in particular, have been affected due to higher morbidity and mortality2. The World‐Wide‐FINGERS‐SARS‐CoV‐2 survey is part of an international project, consisting of members of the World‐Wide FINGERS (WW‐FINGERS) Network for dementia risk reduction and prevention3. The study aims to measure the direct and indirect effects of the outbreak in midlife and older age. Preliminary results of this ongoing study is focused on lifestyle changes.MethodThe survey commenced in September 2020.Participants aged 45 and above were recruited from existing research cohorts, memory clinic patients and community subjects. Sociodemographic factors, health related information, impact on lifestyle and behavior as well as personality factors were collected through three modalities: self‐administered online survey, telephone survey and in person with research staff.ResultAt present, 167 non‐demented participants were included in the current preliminary analysis. Majority of the participants were Chinese (83.2%), aged 65 and above (59.3%), male (58.1%), with at least secondary education (80.8%). The survey found that 61.6% of the participants reported decreased contact with friends and relatives, with 22.2% reporting an increase in loneliness. Approximately one‐third of the participants reported a decrease in physical activity (35.9%) and an increase in food intake (30.5% in snacking habits; 25.1% in fruits consumption). Approximately half of the participants reported increase in usage of internet and digital services to keep in contact with family and friends.ConclusionThe COVID‐19 pandemic has produced measurable impacts on lifestyle‐related behavior of individuals. The decrease in social interaction and increase in loneliness during the pandemic due to government directive, along with concerns of contracting the virus highlight the importance of digital services for and digital literacy in older adults to keep them connected and supported remotely.
Healthcare services for people with dementia in Vietnam: A situational analysis
Authors: Dang Thu Ha , Tran Kham , Esterman Adrian , Roughead Elizabeth E , Brodaty Henry , Hinton Ladson , Kim Giang Bao , Kurrle Susan , Crotty Maria , Pham Thang , Le Pham Tuan , Hoang Phuong , Nguyen Tuan Anh 
Published: December 2021

AbstractBackgroundVietnam is facing rapid population ageing, with one in four Vietnamese citizens being over 60 years old by 2050. This has contributed to a boom of chronic and non‐communicable diseases, such as dementia. In order to develop a national dementia plan as recommended by the World Health Organization (WHO) and increase the preparedness of the healthcare system to tackle dementia, a situational analysis of the current healthcare services related to dementia is needed.MethodIn late 2019, we conducted a situational analysis desk review of the healthcare system in Vietnam, focusing on health service delivery for the elderly, using the guidance developed by the Strengthening Responses to Dementia In Developing Countries (STRiDE) project. The WHO’s six‐building‐block framework was used to analyse the healthcare system in Vietnam, followed by the thematic and SWOT (Strengths, Weaknesses, Opportunities and Threats) analyses of dementia‐related healthcare services.ResultAlthough Vietnam has achieved significant improvement in healthcare in general, there are still inefficiencies in health service delivery. There are also discrepancies in health service readiness and quality across areas of healthcare. Despite of extensive primary healthcare system, grassroots‐level facilities have inadequate infrastructure required for basic care delivery and none for dementia. There are few healthcare facilities at central and provincial levels, mainly located in the three biggest cities of Hanoi, Ho Chi Minh and Danang, providing services for people with dementia. There is limited training in dementia diagnosis and management for health professionals.ConclusionDeveloping a national dementia plan, including transforming the current healthcare services to better cope with rapid population ageing and dementia disease is urgently needed in Vietnam. Integrating dementia services into existing health and social services for the elderly and the disabled, making use of the extensive primary healthcare system in detection, early interventions, management and support for people with dementia at community level are strategic solutions to deal with dementia in a sustainable way. To this end, a whole‐system approach in transformation and operation with implementing a patient centred care model is necessary.