bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global Alzheimer’s Platform Foundation® (GAP) development of a transatlantic Alzheimer’s disease clinical trial network
Authors: Dwyer John , Bork Jason , Zisko Leigh , Goldfeder Gabe , Trotter Jennifer , Ritchie Craig W. , Neild Julie , Syson Judi , Draper Kristy 
Published: December 2021

AbstractBackgroundThe Global Alzheimer’s Platform Foundation® (GAP) was launched in 2015 in response to the critical need to improve the delivery of Alzheimer’s disease (AD) clinical trials. Over 80 AD sites have joined GAP’s growing network (GAP‐Net). While initial efforts were focused on North America, a top priority of the platform was to develop an international trial network.MethodDevelopment of a transatlantic site network in Europe: (1) Site identification: European sites that participated in the European Prevention of Alzheimer’s Dementia (EPAD) network were approached as well as other leading sites. (2) Program identification: Sites were surveyed to understand what services were needed to improve AD trial delivery. Existing GAP programs that could be optimized in Europe with limited changes were identified along with new programs. (3) Infrastructure development: Europe‐specific agreements, regulatory strategies, and communication plans were developed to ensure alignment with the global mission. Evaluation and onboarding processes were also developed.ResultSite identification: Over 50 sites in Europe are currently onboarding. Sites are located primarily in western Europe. Program identification: Existing GAP programs that can be optimized in Europe will include accelerated study start‐up services, rater certification, transportation support, and recruiting programs (media toolkits, trial videos, social / earned media support, and regional recruitment summits). Programs that will need to be modified or developed include trial design input, prescreening support, education of primary care physicians, and advocacy group collaboration. Infrastructure development: 44 sites have returned surveys and metrics, 20 sites have been approved to join the network, and will be approached to sign the European Network Agreement.ConclusionIn partnership with leading clinical research sites in Europe, GAP has begun developing a European site network. The processes developed for GAP‐Net in North America will be leveraged to support a GAP European network that can reduce the duration and cost and improve the quality of AD clinical studies. GAP will intensify collaboration with site networks in other countries to share learning and, where possible, to implement GAP‐enabled trials. These efforts will further GAP’s aim of achieving a fully global network of sites to enhance speed, efficiency, and quality of AD clinical trials.
Poor sleep is associated with smaller hippocampal subfields in cognitively normal elderly individuals
Authors: Alperin Noam 
Published: December 2021

AbstractBackgroundSleep quality decreases in normal aging and is manifested in neurodegenerative diseases including Alzheimer’s disease (AD). Hippocampus is a critical structure for brain health and plays a major role in memory. Although recent studies have demonstrated that reduced hippocampal volume is associated with poor sleep quality, the relationship between sleep quality and volumes of hippocampal subfields (HSs) remains unknown. The objective of this study is to investigate associations between self‐reported sleep quality measures and HS volumes in cognitively normal elderly individuals.MethodSixty‐seven cognitively normal elderly individuals aged 60 to 83 years with self‐reported Pittsburgh Sleep Quality Index (PSQI) were classified into two groups: 30 normal sleepers with PSQI < 5 and 37 poor sleepers with PSQI ≥5. The two groups were equivalent in terms of age, gender, ethnicity, education, handedness and cognitive performance. HSs were segmented in very high resolution T2‐weighted MRI sequence (with an in‐plane resolution of 0.4×0.4 mm2 and 2 mm slice thickness) using the automatic segmentation of hippocampal subfields (ASHS) tool. The HS Volumes were normalized with respect to intracranial volumes. We compared HS volumes between subjects with normal and poor sleep quality. Furthermore, we evaluated associations between the HS volumes and different sleep quality measures, and between the HS volumes and performance of different cognitive tests.ResultCompared to normal sleepers, poor sleepers exhibited lower normalized volumes in the left cornu ammonis field 1 (CA1) (p=0.020), dentate gyrus (DG) (p=0.008) and subiculum (p=0.018). Global PSQI was significantly and negatively associated with the normalized volumes of the left CA1 (r=‐0.266), left DG (r=‐0.295) and left subiculum (r=‐0.276). Sleep duration was significantly associated with normalized volumes of the bilateral CA1 (left: r=0.428, right: r=0.438), DG (left: r=0.381, right: r=0.367), left CA2 (r=0.231) and subiculum (r=0.219). Verbal memory scores were associated with the normalized volumes of left CA1 (r=0.382).ConclusionWe found association between poor sleep quality and volume decreases in multiple HSs. Improving overall sleep quality, especially sleep duration, could prevent or slow volume loss of the HSs, which are associated with cognitive decline and onset of mild cognitive impairment (MCI) and AD.
Identifying predictive factors of patient dropout in Alzheimer’s disease clinical trials
Authors: Crimin Kimberly , Allen Patricia J , Abba Iman , Ahlberg Corinne , Benz Luke , Lau Hiuyan , Liu Jingshu , Melhem Fareed , Fisseha Nahome , Florian Hana 
Published: December 2021

AbstractBackgroundImproving retention of clinical trial participants plays a vital role in developing treatment and prevention strategies for Alzheimer’s disease (AD). Participant retention is critical to maintaining statistical power, preventing scientific error, and minimizing bias in research (Grill JD, et al., 2020). The purpose of this analysis was to identify factors that are predictive of participant dropout in AD trials using pooled data from randomized clinical trials run on the Medidata platform. These factors can be used to improve operational aspects of future trial design as well as to support patients with prevention strategies during future trials.Method8,103 AD patients from 7 completed Phase 3 clinical trials were included in the analysis. The follow‐up time across studies was 1.4 ± 1.6 years (m ± sd) and the dropout rate was 21.2 ± 10.8%. A limited set of clinical and operational data were standardized across trials using proprietary machine learning algorithms combined with human review. Factors were assessed by survival analysis using Cox proportional hazards modeling. A 70/30 train‐test split was used to evaluate model performance in the prediction at baseline of dropouts within 3, 6, and 12 months of the trial. Additional models specific to dropouts due to reasons other than adverse events (AE) or death were also explored.ResultThe models were observed to predict dropouts at an acceptable level above random guessing with an ROC‐AUC ≥ 0.60 within 3, 6 and 12 months. However, the models typically overestimated the probability of dropout, leading to more false positives and reduced precision overall (PR‐AUC < 0.24). Several patient and site factors were associated with increased risk of dropout, including age, race, certain medical histories and AEs (e.g. anxiety), friend as caregiver, low surrounding population density & the size of the clinical staff at the site. Significant interactions between factors were also identified.ConclusionThis study offers additional evidence that a combination of patient‐ and site‐specific factors influence risk of patient dropout in AD trials. These results both confirmed hypotheses of subject matter experts and suggest additional factors for consideration in planning future AD clinical trials, including supportive care for patients.
Effect of Alzheimer’s pathology on the functional architecture of memory networks during rest and task states in aging
Authors: Cassady Kaitlin , Adams Jenna N. , Chen Xi , Maass Anne , Harrison Theresa M. , Ziontz Jacob , Baker Suzanne L. , Jagust William J. 
Published: December 2021

AbstractBackgroundIntrinsic brain networks are relatively consistently organized between rest and task states in young individuals. We performed this study in order to determine whether the same is true in aging, and whether measures of AD pathology affect this relationship.MethodWe used task‐based (mnemonic discrimination task with object and scene stimuli) and rest fMRI to measure functional connectivity (FC) in an anterior temporal (AT) and posteromedial (PM) network in older (OA; N=49, 74±5 years, 31F) and younger adults (YA; N=24, 27±4 years, 9F). We calculated the correlation between rest and task FC states by conducting a Pearson’s correlation between the rest and task FC matrices for each participant. We used PiB‐PET to measure global Aβ (using threshold of 1.065 to classify OA as PiB+/‐) and FTP‐PET to measure tau within an AT and PM composite ROI in OA. We also measured recognition memory performance during the mnemonic discrimination task requiring discrimination of repeated stimuli from lures.ResultResting state and task FC in the ATPM network were less correlated in older compared to younger adults. In addition, less correlated rest vs. task FC was associated with higher levels of FTP in ATPM networks in PiB+ older adults. Finally, less correlated rest vs. task FC was associated with worse recognition performance (among all participants and OA alone) during the object trials.ConclusionThese findings link AD pathology to disruption of the functional architecture of intrinsic brain networks during rest and memory task states in OA. They also suggest that memory decline in some older adults may be influenced by the extent of change in functional architecture between rest and task demands. Overall, dynamic FC changes from rest to task may provide a novel mechanism in which aging impacts cognition.
How many Black men in cognitive intervention trials? A persistent barrier to equity
Authors: Forrester Sarah N , Thorpe Roland J , Hill Carl V , Whitfield Keith E 
Published: December 2021

AbstractBackgroundThere has been sparse attention paid to the cognition of older men and potential race differences in cognitive ability among older men. Men’s health disparities are likely to continue to increase in the next few decades, likely due to an aging baby boom cohort; increases in racial diversity in the US; and increases in life expectancy among both Black and White men. Our objective was to examine the completed cognitive intervention trials to ascertain the proportion of Black men and racial differences in such trials.MethodWe conducted a scoping review of reported cognitive intervention trials between the years 2000 and 2020. We searched PubMed, Google Scholar, CINHAL, Cochrane, and Clinicaltrials.gov for cognitive intervention trials using the following MeSH terms – “cognitive intervention”, “mild cognitive impairment”, “dementia”, “Alzheimer’s disease”, and “cognitive disorder”. Inclusion criteria included U.S, based interventions intended to improve cognition.ResultWe found 293 unique trials that met our search terms of which 66 were included for final analysis. The rest were excluded due to not being in the US, only including healthy participants, and use of non‐cognitive interventions. We were able to assess the number of Black men in 9 out of the 66 trials, because the trials were either all White (n=8) or all Black (n=1). Of the 9 trials we could assess, 8 had no Black participants (thus no Black men) and the one with all Black participants had 21% men. Of the remaining 57 trials, 32 did not report race and 25 included race and sex data but did not include race‐sex categories and thus we were unable to determine the number of black men included.ConclusionWe were unable to determine if cognitive intervention trials included sufficient proportions of Black men due to non‐reporting of race, race‐sex categories, and lack of inclusion of Black persons in trials. Our results beg the question of how we can understand cognitive health disparities and improve representation in trials if we don’t include the information that would allow us to make that determination.
Male sex is associated with an increased risk of developing cognitive impairments
Authors: Wang Ge , Li Wei 
Published: December 2021

AbstractBackgroundIt is inconclusive on how sex works as a risk factor for developing mild cognitive impairment (MCI) or dementia.MethodA secondary data analysis was performed on data collected from participants enrolled at Alzheimer’s Disease Research Centers funded by National Institute on Aging. There were two inclusion criteria: 1) participants were free of dementia at the baseline visit; 2) every participant must have at least one follow‐up visit. A Cox proportional hazards model was used to investigate how sex affects the risk of developing cognitive impairments.ResultDuring a follow‐up period of more than 10 years, male participants had a slightly higher incidence than female participants for either MCI or dementia. Not surprisingly, a higher prevalence was also observed in male than female participants for either MCI or dementia. Although both sexes had comparable lifespan in years, male participants had a higher mortality rate than their female counterparts.ConclusionThe male sex is associated with a higher risk for developing cognitive impairments along the aging process.
Feasibility of short imaging protocols for [18F]PI‐2620 tau‐PET in progressive supranuclear palsy
Authors: Song Mengmeng , Scheifele Maximilian , Barthel Henryk , van Eimeren Thilo , Beyer Leonie , Marek Ken , Eckenweber Florian , Palleis Carla , Finze Anika , Kaiser Lena , Kern Maike , Nitschmann Alexander , Biechele Gloria , Katzdobler Sabrina , Bischof Gerard N , Hammes Jochen , Jessen Frank , Saur Dorothee , Schroeter Matthias L. , Rumpf Jost‐Julian , Rullmann Michael , Schildan Andreas , Patt Marianne , Neumaier Bernd , Stephens Andrew W , Rauchmann Boris‐Stephan , Perneczky Robert , Levin Johannes , Classen Joseph , Höglinger Günter , Bartenstein Peter , Boening Guido , Ziegler Sibylle , Villemagne Victor L L , Drzezga Alexander , Seibyl John P , Sabri Osama , Brendel Matthias 
Published: December 2021

AbstractBackgroundDynamic 60‐minute positron‐emission‐tomography (PET) imaging with the novel tau radiotracer [18F]PI‐2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). We now aimed to investigate if shorter acquisition and static time windows of [18F]PI‐2620 tau‐PET can be used for imaging of patients with PSP.MethodWe evaluated 37 patients at five different centers with probable or possible PSP Richardson syndrome (PSP‐RS) together with ten HCs. [18F]PI‐2620 PET was performed by a dynamic 60 minute scan. Distribution volume ratios (DVRs, multilinear reference tissue model 2, cerebellar reference) were calculated using full and truncated scan durations (0‐60, 0‐50, 0‐40, 0‐30, and 0‐20 minutes p.i.). Standardized uptake value ratios (SUVrs, cerebellar reference) were obtained from static imaging windows with 20 minutes duration (20‐40, 30‐50, and 40‐60 minutes p.i.). All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP‐RS from HCs in predefined subcortical and cortical target regions (effect size, receiver operating area under the curve (AUC), multi‐region classifier). Finally, we tested if shorter [18F]PI‐2620 PET imaging can also be applied to patients with Alzheimer’s disease (n=11).ResultThe effect size of 0‐50 and 0‐40 DVR was equivalent to 0‐60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0‐30 or 0‐20 DVR. The 20‐40 SUVr indicated the best performance of all short static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP and healthy controls at a similarly high level for 0‐60 DVR (AUC: 0.96), 0‐40 DVR (AUC: 0.96), and 20‐40 SUVr (AUC: 0.94). The multi‐region classifier sensitivity of these time windows was consistently 86%. 0‐40 DVR showed similar performance in Alzheimer’s disease when compared to 0‐60 DVR.ConclusionShort dynamic acquisition and static imaging windows can be used for [18F]PI‐2620 PET imaging of PSP. 0‐40 minute dynamic scanning offers the best balance between accuracy and economic scanning and is may also be suitable for [18F]PI‐2620 PET imaging of Alzheimer’s disease.
Association of dual impairment in physical performance and cognition with cognitive change over two years in older adults
Authors: Peng Tao‐Chun , Chen Yen‐Ching , Chen Ta‐Fu , Chiou Jeng‐Min , Chen Jen‐Hau 
Published: December 2021

AbstractBackgroundDementia has a great impact in the ageing world. Much of the growing will happen in low and middle income regions, especially in Asia and Africa. Identifying the target population before clinical symptoms is most important for early intervention of preventing dementia. Recently, the concept of motoric cognitive risk syndrome has been introduced. However, the analogue of this syndrome is poorly evaluated. Therefore, we aim to explore the association of dual impairment in physical performance and cognition with cognitive impairment.MethodThis cohort study is part of the ongoing Taiwan Initiative of Geriatric Epidemiological Research. A total of 315 participants aged 65 and older were identified between 2015 and 2017 at the University Taiwan University hospital with a two‐ year follow‐up (2017‐2019). Dual impairment were defined as the concurrence of slow gait speed (< 1 m/s) and poor cognitive domain or low grip strength (< 28kg for men and < 18kg for women) and poor cognitive domain. Cognitive impairment was defined as the lowest tertile of the change of Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) over 2 years. Logistic regression models were used to evaluate the association between dual impairment and the change of cognitive function adjusted for age, sex, education, and apolipoprotein e4 status.ResultThe mean age of this population was 75.17 years old. Forty‐eight participants (15.24%) with dual impairment of low handgrip strength and low verbal fluency were identified. Multivariable analyses showed that dual impairment of low grip strength and low verbal fluency increased the risk of cognitive decline [adjusted odds ratios (aOR)=2.42, 95% confidence interval (CI)=1.20−4.88]. However, dual impairment of slow gait speed and low verbal fluency were not associated with cognitive decline (aOR=1.62, 95% CI=0.94–2.78).ConclusionOur findings indicate that older adults with dual impairment of low grip strength and low verbal fluency were at a higher risk of cognitive impairment, which emphasizes the importance of complexity in pre‐dementia syndrome. Further research is warranted to clarity the underlying mechanisms of cognitive impairment and opportunities for early intervention.
Classified biomarker panel with tau microtubule binding regions identifies pathophysiological changes in Alzheimer’s disease continuum
Authors: Horie Kanta , Barthelemy Nicolas R. , Sato Chihiro , Li Yan , McDade Eric , Bateman Randall J. 
Published: December 2021

AbstractBackgroundAccumulations of tau aggregates and amyloid plaques in brain are hallmarks of Alzheimer’s disease (AD). Recent studies in characterizing tau species, especially phosphorylated tau‐181 (p‐tau181) and p‐tau217 in AD brain and biofluids suggested that these species start increasing at preclinical stage, correlate with amyloid plaques, and improve the diagnosis. However, it is still unclear if these changes in p‐tau reflect tau pathology in AD. Recently, we identified truncated tau species containing microtubule binding regions, e.g., residues 243‐254 (MTBR‐tau243) and 299‐317 (MTBR‐tau299), associate with tau pathology in AD brain. In this study, we show how these MTBR‐tau change and correlate with p‐tau species in AD cerebrospinal fluid (CSF). We discuss the potential use of these composite biomarker panel to understand whole AD continuum.MethodWe established methods to quantify more than dozen of CSF tau species including MTBR‐tau and p‐tau, using immunoprecipitation or chemical extraction followed by mass spectrometry analysis. These methods were applied to CSF analyses of several sporadic AD cohorts. Subsets of the participants were assessed for brain tau aggregation measured by positron emission tomography (PET) to investigate the correlations with various CSF tau biomarkers.ResultCSF MTBR‐tau were specifically increased in amyloid positive group. Especially, MTBR‐tau299 showed the most significant increase even in preclinical stage and discriminated amyloid status (AUC=0.923), whereas the correlation with tau‐PET measure was moderate (Spearman r=0.458) and the increase was saturated at high tau‐PET measure. MTBR‐tau243 showed the best correlation with tau‐PET measure (Spearman r=0.759) in all tau species quantified in this study and no saturation was observed. MTBR‐tau299 was the most highly correlated with p‐tau217 (Spearman r=0.849), suggesting MTBR‐tau299 is highly corresponding to amyloid pathology. Notably, the phosphorylation occupancy at p‐tau217 was also saturated at high tau‐PET measure as seen in MTBR‐tau299.ConclusionMTBR‐tau complement p‐tau to classify biomarker panel to stage AD, reflecting tau as well as amyloid pathology in whole AD continuum. Of note, it remains to be addressed if p‐tau217 increases in response to amyloid plaques rather than tau tangles.
Executive dysfunction is the earliest sign of preclinical Alzheimer’s disease detected by regional Ab‐PET SUVr in the precuneus and posterior cingulate cortex
Authors: Ali Doaa , Barber Justin M. , El Khouli Riham H. , Gold Brian T. , Harp Jordan , Van Eldik Linda J. , Wilcock Donna M. , Jicha Gregory A. 
Published: December 2021

AbstractBackgroundAmyloid (Aβ) deposition occurs many years or even decades before the appearance of cognitive decline (preclinical Alzheimer’s disease (pAD)). The diagnosis of pAD is based on biomarker positivity using diagnostic tests such as amyloid‐PET that can provide regional quantification of Aβ deposition in the brain. The precuneus and posterior cingulate gyri are thought to represent the earliest brain regions affected by AD pathology. The present study sought to explore the associations of amyloid‐PET standardized uptake value ratio (SUVr) positivity with global, executive, and memory‐specific domain involvement in pAD.MethodNinety‐nine clinically‐normal, aged participants with Montreal Cognitive Assessment (MoCA) scores ≥ 23 that had undergone amyloid‐PET scanning were analyzed. The participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in MoCA, Trail Making Test (TMT), and California Verbal Learning Test‐II (CVLT‐II) scores were analyzed using two‐sided independent t test.ResultThe sample included 45 participants in the pAD group and 54 participants in the healthy control group that did not differ in age or education. Statistically significant between group differences were seen for TMT B, TMT B‐A and MoCA (p = 0.006, 0.001 and 0.034, respectively). No significant differences were seen between groups in delayed recall measures on the CVLT‐II.ConclusionWhile the prevailing view in the field suggests that early memory change is the hallmark of AD, the present data demonstrate that changes in executive function may be the earliest signs of pAD. Ongoing and future efforts at developing more sensitive tests for preclinical executive function deficits may serve as the most sensitive, low cost, non‐invasive clinical biomarkers of pAD.