bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline participant characteristics of GRADUATION: a study to evaluate once‐weekly subcutaneous administration of gantenerumab
Authors: Boess Frank , Lane Christopher , Scelsi Marzia A. , Delmar Paul , Hofmann Carsten , Tonietto Matteo , Klein Gregory , Kerchner Geoffrey A. , Baudler Monika , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to doses of up to 1,200 mg every 4 weeks (q4w) confirmed substantial Abeta removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of subcutaneous gantenerumab in early AD, using a target dose of 510 mg q2w (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (q1w) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous q1w administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience.MethodsIn this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg q4w, followed by 255 mg q4w and q2w for 12 weeks each, and a target dose of 255 mg q1w. This target dose is equivalent to the 1,020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a q1w dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography. Secondary objectives include assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, and cognitive and functional assessments.ResultsRecruitment for GRADUATION is complete. Participants were enrolled from Belgium, France, Germany, Italy, Poland, Spain, UK, and US. Detailed baseline characteristics will be presented.ConclusionThe GRADUATION study will determine the effect of q1w administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home.1. Ostrowitzki S, et al. Alzheimers Res Ther 2017;9:952. Klein G, et al. Alzheimers Res Ther 2019;11:101
MRI signatures of Brain Age in the Alzheimer’s disease continuum
Authors: Shah Jay , Ghisays Valentina , Chen Yinghua , Luo Ji , Li Baoxin , Reiman Eric M. , Chen Kewei , Wu Teresa , Su Yi 
Published: December 2022

AbstractBackgroundAge is the biggest risk factor for Alzheimer’s disease (AD). Substantial efforts to extract age signatures from magnetic resonance imaging (MRI) of the brain have achieved impressive accuracy and demonstrated these signatures were altered by neurological disorders including AD. In this work, we develop a deep learning model to characterize brain age signatures and examine their variation over the AD continuum.MethodA 3D deep ResNet model was implemented to learn the structural signatures of brain age in predicting the chronological age of the participants. The model was trained on 7372 T1‐weighted MRI scans from a combined lifespan cohort of 5848 cognitively normal participants (age: 8‐ 95 yrs) using a 10‐fold cross validation procedure. The model was then applied to the independent ADNI cohort (N=1175, 50‐98 yrs) to examine MRI derived brain age signatures variation in the AD continuum. The difference (∆age) between model predicted age and chronological age was used as the independent variable for group comparison using univariate ANCOVA tests, controlling for sex, education, and APOE4 gene dose, among five clinical groups: normal control (NC), normal to MCI converters (NC‐MCI), stable MCI (MCIs), MCI to AD converters (MCI‐AD), and AD patients.ResultThe ResNet model achieved an MAE=3.76 yrs and R2=0.93 across 10 folds in the lifespan cohort. In the baseline data of the ADNI cohort, model derived ∆age increased along the AD continuum as expected: NC (‐1.2yrs) < NC‐MCI (‐0.7yrs) < MCIs (‐0.3yrs) < MCI‐AD (0.7yrs) <AD (1.5yrs) (F=11.24, p<0.0001). Post‐hoc pairwise comparison results are summarized in Table 1/Figure 2. Although the difference between NC and NC‐MCI did not reach significance (p=0.24) for the baseline data, comparison between the two groups using data from all visits was significant (p=0.0009), suggesting more subtle differences.ConclusionA ResNet model was developed that captures the MRI signatures of brain age with high accuracy in age prediction. The model detected group level differences along the AD continuum in the expected direction. Subtle changes in brain signatures were observable in normal participants who later developed cognitive impairment. Our technique provides a novel approach to investigate the relationship between aging and AD.
Effects of Aging, Sex and Forgetfulness on Mental Rotation Performance
Authors: Schendel Krista , Lwi Sandy J. , Chok Jas M. , Hall Kathleen , Williams Garrett , Blank Michael , Geraci Kristin , Curran Brian , Herron Tim , Woods David L. , Baldo Juliana 
Published: December 2022

AbstractBackgroundThere is growing interest in the development of screening tests for AD and MCI that focus on non‐amnestic symptoms. Moreover, evidence suggests that declining mental rotation ability can be associated with prodromal Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI). Additional studies in healthy aging adults are therefore needed to determine whether computerized mental rotation tasks may prove useful in predicting cognitive decline.MethodHere, we report findings from a large group of aging adults (n = 276, 42% female, aged 56–89 years, M = 70.5) who were remotely administered a computerized mental rotation task as part of a larger California Cognitive Assessment Battery (CCAB). During the mental rotation task, participants had to decide as quickly as possible whether a presented letter was in its typical (e.g., R) versus mirror‐reversed (Я) orientation. Letters were presented either upright (at 0 degrees) or rotated (+/‐60, or +/‐120 degrees). Participants’ responses on the Cognitive Failures Questionnaire were also collected as part of the assessment battery.ResultResponse times (RT) and accuracy on the mental rotation task were captured and analyzed to determine whether any effects of age, sex, and rotation angle could be observed using this remotely administered mental rotation task. Analysis revealed that both age and sex were significantly associated with performance measures on this task. The expected pattern of longer response times with greater degree of stimulus rotation was also observed. Analysis of sex differences revealed greater accuracy overall by females, while males experienced smaller RT costs based on rotation angle. Finally, a significant relationship between forgetting scores and mental rotation response times was also observed.ConclusionIncreased age and forgetting scores were both associated with worse mental rotation performance. Continuing longitudinal assessment at 6‐month intervals is ongoing and will further establish trends in mental rotation performance during aging.
Genome‐wide association study on Alzheimer’s disease CSF profiles in the EMIF‐AD MBD and ADNI datasets
Authors: Neumann Alexander , Ohlei Olena , Dobricic Valerija , Vos Stephanie J. B. , Zetterberg Henrik , Visser Pieter Jelle , Tijms Betty , Sleegers Kristel , Bertram Lars ,   collaborators of the EMIF‐AD MBD and ADNI consortium
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown and disease mechanisms are often unclear. Using CSF biomarkers of AD as outcome may aid in gene discovery and in elucidating disease processes. We previously demonstrated that six CSF biomarkers (β‐amyloid, total/phosphorylated tau, NFL, YKL‐40, and neurogranin) can be robustly clustered into five profiles by principal components (PC) analysis, each representing statistically independent biological processes. Our goals here were: 1. To identify common genetic variants associated with these profiles; 2 To assess the role of associated variants in AD pathophysiology and 3. Explore potential sex differences.MethodWe performed GWAS analyses for each of the five biomarker PCs in two multi‐center studies, i.e.: the EMIF‐AD and ADNI. In total, 931 participants with no, mild cognitive impairment or AD had sufficient genetic and biomarkers information. Overall, we tested the effect of 7,433,949 common SNPs (MAF>1%; incl. X chromosome) and 19,511 protein‐coding genes. Genome‐wide significant variants were followed up with structural equation models to test whether any of the biomarker PCs mediate the effect of the variants on diagnostic status. We further tested sex interactions with a moderated mediation model.ResultFive loci showed genome‐wide significant association with the PCA‐based CSF profiles, three of which were previously described (APOE, TMEM160B and CHI3L), and two were novel (rs145791381 and GRIN2D). Mediation tests indicated that variants in the APOE region affect AD status via two statistically independent processes: amyloid and tau pathology, but not via neuronal injury/inflammation. Vice versa, TMEM106B, CHI3L, and rs145791381 affected AD only via neuronal injury/inflammation. GRIN2D was associated with synaptic functioning, but was unrelated to AD risk. PCA‐based CSF profiles did not differ between sexes, neither did associations between CSF profiles and diagnosis status. Interestingly, however, genetic effects were stronger in females for most pathways.ConclusionThe results suggest for the first time an involvement of an intergenic region on chromosome 9p21.3 (rs145791381) in AD‐related disease processes, as well as a role of the glutamate receptor GRIN2D in synaptic functioning. Furthermore, the study highlights the importance of sex differences in the genetics of AD.
NEUROPROTECTIVE POTENTIAL OF FINGOLIMOD AGAINST ALUMINIUM CHLORIDE INDUCED EXPERIMENTAL DEMENTIA IN RATS
Authors: Agrawal Mohit , Chandolia Priyanka 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is an age related neurodegenerative disease mainly characterized by progressive cognitive decline, synaptic loss, extracellular amyloid‐beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost are the deregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit. In the present study, we have explored the neuroprotective potential of Fingolimod (FTY720), against Aluminium Chloride (AlCl3) induced experimental dementia in the rats.MethodAlCl3 at the dose of (175mg/kg, p.o.) daily on first to 35th day. Spatial and non‐spatial memory was evaluated by using Morris water maze and object recognition test. Fingolimod (0.25 and 0.5 mg/kg, p.o.) was administered at weekly intervals after administered AlCl3 in rats. Administered AlCl3 in rats produced cognitive deficit and caused significant elevation in markers and oxidative stress and degenerative changes in hippocampus and cortical brain region.ResultOn the countatary, fingolimod treatment attenuate AlCl3 induced cognitive decline, reduced oxidative burden and able to preserve neuronal architecture and prevent neuronal loss in hippocampus and cortical brain region of the rats.ConclusionThe present study suggests that Fingolimod (FTY 720) show beneficial effects in treating dementia. Our data demonstrated that Fingolimod could be effective in the protection of toxicity induced by Aluminium chloride
Evaluating the DICE method to improve early recognition and treatment of neuropsychiatric symptoms in early Alzheimer’s disease
Authors: Eikelboom Willem S. , van den Berg Esther , Raso Francesco U S Mattace , van Bruchem‐Visser Rozemarijn L. , Goudzwaard Jeannette A , de Jong Frank Jan , den Heijer Tom , Driesen Jan J. M. , Vroegindeweij Lilian J.H.M. , Thomeer Elsbeth C. , Hoogers Susanne E. , Singleton Ellen H. , van Swieten John C , Ossenkoppele Rik , Coesmans Michiel , Papma Janne M. 
Published: December 2022

AbstractBackgroundWhile neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic.MethodA total of 60 community‐dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table‐1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL‐AD) and caregivers (Carerqol‐7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI‐Q & BEHAVE‐AD), NPS‐related distress (NPI‐Q), competence managing NPS (additional NPI‐Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group‐level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes.ResultWe found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table‐2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS‐related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement.ConclusionThis Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group‐level, but suggest that particular participants might benefit from this approach. Data will be re‐analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS‐related knowledge and management styles of participants.
Real world clinical perspective on PDE5i utility in dementia.
Authors: Elahi Fanny M 
Published: December 2022

AbstractBackgroundThere is clearly a large unmet need for more drug treatments in dementia due to Alzheimer pathology (AD) and in VCID. Mechanistic studies in rodents and in vitro support a benefit of PDE5 inhibitors in AD.MethodA Big data approach recently confirmed this potential benefit with an independent study incorporating multiple levels of biology with in silico network drug discovery for amyloid and tau endophenotypes, data mining from insurance records, as well as in vitro modeling using derived induced pluripotent stem cell (iPSC) neuronal models of AD.ResultsCollectively, this body of work is cause of optimism. However, a real‐world randomized clinical trial (RCT) of the PDE5i tadalafil in older people, incorporating biomarkers, detected no significant effect with respect to cerebral blood flow.ConclusionThese results raise multiple questions for the dementia clinician‐scientist. Do in vitro and in vivo preclinical paradigms provide non‐translatable findings because these systems are not capturing a key component of AD, such as human aging? Is it still worth pursuing PDE5i as a therapeutic route? What could be some factors that contributed to the negative RCT results and what should be emphasized in the design of a definitive RCT for this class of therapeutics? Finally, what role do biomarkers play in filling critical gaps in knowledge to bridge the path between bench and bedside.
Characteristics and Outcomes of Traumatic Brain Injury among Older Adults with and without Pre‐injury Dementia: an Israel National Trauma Registry Study
Authors: Gardner Raquel C. , Cohen‐Manheim Irit , Givon Adi , Radomislensky Irina , Bodas Moran ,   the Israel Trauma Group (ITG)
Published: December 2022

AbstractBackgroundOlder adults have the highest and fastest rising incidence of traumatic brain injury (TBI) compared to all other age groups. Few studies have examined the prevalence of pre‐injury dementia among older adults presenting with TBI. None have examined injury characteristics and outcomes specifically among those with pre‐injury dementia. Our aim was to describe prevalence of pre‐injury dementia among older adults hospitalized with TBI in Israel and to examine features of those with versus without pre‐injury dementia.MethodWe identified all TBIs recorded in the Israel National Trauma Registry from 2015‐2020 among adults age 65 years and older who were admitted to one of 15 trauma centers. We determined the prevalence of a diagnosis of pre‐injury dementia recorded in the registry and compared baseline demographics, injury features, and hospital outcomes among those with versus without pre‐injury dementia.ResultAmong N = 7,788 identified cases of geriatric TBI, 9.8% (N = 762) had pre‐injury dementia. Compared to those without pre‐injury dementia, those with pre‐injury dementia were significantly older (90% vs. 70% age >75 years), more female (58% vs. 47%), had higher rates of injury location of residential institution (24% vs. 7%) or home (63% vs. 58%), and higher rates of injury mechanism of fall (95% vs. 84%; all p<0.01). No differences were identified in Injury Severity Score (ISS) across groups (p = 0.19). However, those with pre‐injury dementia had lower rates of severe TBI (4% vs. 7% Glasgow Coma Scale <9), lower rates of polytrauma (10% vs. 13%), and lower rates of surgical intervention (9% vs. 13%), yet had higher rates of in‐hospital mortality (10% vs. 8%) and new institutionalization post‐discharge (11% vs. 4%; all p<0.02).ConclusionApproximately 10% of older adults admitted to hospitals in Israel with TBI have dementia compared to only 7% of older adults in the general population (per 2019 national health service data), suggesting that dementia is likely a risk factor for TBI in the elderly. Additionally, admission for a TBI resulted in 10% in‐hospital mortality and 11% new institutionalization post‐discharge among those with pre‐injury dementia. Geriatric TBI prevention, primarily through fall‐prevention, is of high public health importance in Israel.
Whole brain MRI‐free tau and amyloid PET quantification
Authors: Ward Tyler J. , Harrison Theresa M. , Murphy Alice , Baker Suzanne L. , Mormino Elizabeth C. , Koeppe Robert A. , Jagust William J. , Landau Susan M. 
Published: December 2022

AbstractBackgroundThe growing use of PET imaging in Alzheimer’s research and clinical practice has resulted in the need for PET quantification when an MRI is unavailable or contraindicated. The Desikan‐Killiany (DK) atlas in Freesurfer (FS) is often used in conjunction with a native space MRI to define regions of interest for tau and amyloid PET quantification. Here we developed a template‐space DK atlas for use in MRI‐free amyloid & tau quantification, and validated the performance of the template using MRI‐free florbetapir and flortaucipir SUVrs in relation to our gold standard native space SUVrs.MethodTo develop a template‐space atlas made up of 112 DK regions identical to those used in our native‐space, MRI‐dependent pipeline, we segmented T1 MRIs from a subset of 200 cognitively normal ADNI participants using Freesurfer 7.1. Each binary region was nonlinearly warped to template space, smoothed, and averaged across the 200 MRIs to create 112 ROI probability maps (Fig 1A). Each region probability map was normalized between 0 and 1 then merged together into a single template‐space atlas by ranking each voxel in relation to each ROI (Fig 1B). To calculate MRI‐free SUVrs, ADNI baseline flortaucipir (n=768) and florbetapir (n=1290) images were spatially normalized to PET‐only, tracer‐specific templates developed in subsets of ADNI scans. We examined several key amyloid and tau target SUVrs based on the MRI‐free atlas in relation to corresponding MRI‐dependent SUVrs calculated using our gold standard pipeline.ResultMRI‐free region‐wise cortical SUVRs were highly correlated with their MRI‐dependent counterparts for both florbetapir (average R2 across cortical ROIs = 0.80, cortical summary R2 = 0.84; Fig 2A) and flortaucipir (average R2 across cortical ROIs = 0.87, entorhinal R2 = 0.88, temporal metaROI R2 = 0.97; Fig 2B). Positive/negative status agreement between MRI‐free and MRI‐dependent approaches using previously‐validated MRI‐dependent thresholds was 91% (Aβ) and 92% (temporal metaROI tau).ConclusionAmyloid and tau SUVRs and +/− status calculated using a template‐space DK atlas are comparable to those calculated using our gold standard MRI‐dependent approach. This MRI‐free approach will be useful for region‐wise PET quantification when structural scans are unavailable.