bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain age estimation by structural MRI in superagers: a BrainAGE approach in elderly people with youthful episodic memory
Authors: Pascual Marta Garo , Gaser Christian , Strange Bryan A 
Published: December 2022

AbstractBackgroundAge‐related episodic memory decline is not the only trajectory of healthy ageing. Superagers are the living proof that an 80yo can have the memory of a 50‐60yo. We aim to estimate the biological brain age of superagers using the BrainAGE approach to understand the underlying ageing process. In the context of normal ageing, resistance refers to the avoidance of ageing effects and will translate into a deceleration of the ageing process, whereas resilience is the successful coping with age‐related changes and will translate into a similar estimated brain age and chronological age. We tested these hypotheses in this study.MethodA sample of 63 superagers (mean age 81.8 years ± 1.8 std, 60.3% women) and 55 age‐matched controls (mean age 82.4 years ± 1.9 std, 63.6% women) from the Vallecas Project cohort in Madrid, Spain, were selected according to their episodic memory score in the Free and Cued Selective Reminding Test. Superagers scored at or above the mean value of a 50‐56yo person, whereas controls scored within one standard deviation for their age. BrainAGE (“Brain Age Gap Estimation”) aggregates to a single value the complex multidimensional aging pattern within the whole brain by applying established kernel regression methods to anatomical brain magnetic resonance images (Franke and Gaser 2019). The BrainAGE score was calculated for both groups as the difference between chronological age and estimated brain age. Positive values indicate an acceleration of the ageing process and negative values indicate a deceleration of the ageing process.ResultThe BrainAGE score of superagers was ‐0.5 years, showing that their estimated brain age is lower than their chronological age whereas the estimated brain age of the control group is similar to their chronological age. The difference in BrainAGE between the superager and the control group is significant (p = 1x10‐6). This result indicates a deceleration in the brain ageing process of superagers compared to age‐matched controls.ConclusionSuperagers showed a slowing of the structural brain age‐related changes compared to the control group. These results suggest that superagers, selected for their youthful episodic memory, show whole‐brain resistance to the ageing process.
Biomarker‐based development for optimized ACI‐24, a novel candidate vaccine for the treatment and prevention of Alzheimer’s disease
Authors: Sol Olivier , Lê Bénédicte , Valatsou Elena , Delpretti Saskia , Rongere Julien , Vukicevic Marija , Gray Julian JG , Hliva Valerie , Kosco‐Vilbois Marie , Pfeifer Andrea , Streffer Johannes 
Published: December 2022

AbstractBackgroundAmyloid plaques and neurofibrillary tangles are the neuropathologic hallmarks of Alzheimer’s disease (AD) with the key constituents being Amyloid Beta (Abeta) and Tau protein, respectively. However, the initiation and propagation of neurodegeneration and neurotoxicity in Alzheimer’s disease remains incompletely understood despite recent important progress in clinical trials. It is apparent that small aggregates such as Abeta oligomers or fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42)) are of key importance for disease initiation with significant implications for translational medicine and success in clinical trial development.MethodACI‐24 is a vaccine targeting Abeta for the treatment and prevention of AD. Initial clinical data have demonstrated safety and an initial pharmacodynamic response, both in sporadic AD and people with Down syndrome (DS), a specifically vulnerable population predisposed to developing AD. Preclinical data have recently demonstrated that a new, optimized formulation of ACI‐24 has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42. Recent clinical trial results in AD, specifically with monoclonal antibodies targeting Abeta, have successfully employed translational biomarkers, including Amyloid PET, as key decision markers and predictors of clinical benefit.ResultWe present an innovative translational clinical trial design to understand the immunogenic properties of optimized ACI‐24 in sporadic AD and in people with DS. The biomarker‐based design, including multiple interim analyses, will enable (I) assessment of early safety and immunogenicity, (II) dose selection for early and meaningful readouts on translational biomarkers including Amyloid PET, (III) the safe transition into the more vulnerable DS population and (IV) informed transition into pivotal studies.ConclusionThe Alzheimer’s disease field needs new treatments and clinical trial approaches. Vaccination is a proven approach to managing diseases affecting global populations. The field of biomarker‐based translational medicine has been mobilized by the recent understanding of how to clinically evaluate targeting of toxic Abeta fragments and aggregates in trials using monoclonal antibodies. Here, we demonstrate how we utilize these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test optimized ACI‐24 as a novel Abeta vaccine candidate.
Telomere Length Variation in the Lewy Body Diseases and its Relationship to Epigenetic Age
Authors: Imm Jennifer L , Harvey Joshua , Smith Adam R. , Pishva Ehsan , Lunnon Katie 
Published: December 2022

AbstractBackgroundThe Lewy body diseases (LBDs), Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LBs). As both the LBDs and the shortening of telomeres are well established with aging it is reasonable to hypothesise some involvement of telomere shortening in the LBDs. There are few studies addressing telomere length changes in the LBDs and as these studies are often conflicting, we aim to rectify this disparity and establish whether there is a relationship between disease diagnosis, LB Braak staging and epigenetic age.MethodBulk cingulate gyrus and prefrontal cortex tissue was used to determine absolute telomere length using quantitative real‐time PCR. Alongside sample DNA, standards for either telomeric repeats or a housekeeping gene, ribosomal phosphoprotein P0 (36B4), for which the copy number was known were run. Calculation of absolute telomere length was achieved by dividing the telomere copies per reaction by the corresponding 36B4 copies per reaction. This value was then further divided by 92 to give the length per individual telomere. Linear regression was used to determine significance within each brain region controlling for age, gender and cellular composition. DNA methylation was assessed using the Illumina EPIC array and epigenetic age was derived using the Horvath skin and blood clock.ResultWe have used 136 PD, 307 PDD, 178 DLB and 302 control samples in two different brain regions in order to determine the relationship between telomere length, epigenetic age, neuropathology and clinical diagnosis.ConclusionWe have studied how telomere length varies not only in relation to epigenetic age in post‐mortem brain samples but also how it relates to clinical diagnosis and neuropathology in the LBDs.
NLRP3 regulates microglial metabolic function in Alzheimer’s disease
Authors: McManus Roisin M. , Komes Max P , Griep Angelika , Santarelli Francesco , Schwartz Stephanie , Khalil Michelle‐Amirah , Lauterbach Mario , Gomez‐Cabrero David , Tegner Jesper , Hiller Karsten , Latz Eicke , Heneka Michael T. 
Published: December 2022

AbstractBackgroundOur laboratory has demonstrated that the NLRP3 inflammasome has a critical part in the microglial innate immune response to Alzheimer’s disease (AD)‐related peptides, triggering the production of cleaved‐caspase‐1 and IL‐1β. NLRP3 activation was found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic mouse models of AD expressing amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology and neuroinflammation. Here, we set out to determine the genes and pathways under the influence of NLRP3, beyond the established release of IL‐1β and ASC that could be contributing to the progression of AD.MethodSingle cell RNA sequencing was performed on CD11b+ cells from the brains of aged wildtype, APP/PS1, NLRP3−/− and APP/PS1.NLRP3−/− mice. Microglia were prepared from the brains of 1‐day old wildtype and NLRP3−/− mice to assess real‐time metabolic function, phagocytosis assays and flow cytometric analysis. Targets were investigated in the post‐mortem brain tissue of those with and without AD. In a separate series of experiments, microglial cells and APP/PS1 mice were treated with novel NLRP3‐targeted inhibitors to confirm findings.ResultSingle cell RNA sequencing analysis found a unique cluster of microglia with pathways related to phagocytosis and glutamate metabolic signaling in APP/PS1.NLRP3−/− mice. Metabolic analysis found that NLRP3−/− microglia had enhanced mitochondrial and metabolic function. NLRP3−/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with cellular utilization of glutamate and glutamine. Importantly, we were able to replicate these findings in human cells and using NLRP3‐specific inhibitors in vitro and in vivo.
ConclusionWe have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate‐related metabolism, which was associated with enhanced phagocytic activity. This pathway is conserved between mouse and man. Critically, we can mimic this effect pharmacologically using NLRP3‐specific inhibitors. Together, our data strengthens NLRP3 as a master‐immune regulator and an important target in the treatment of AD and dementia.
Concordance and discordance in disease severity classification between clinician judgments and cognitive testing scores for Alzheimer’s disease in the United States Veterans Affairs Healthcare System
Authors: Li Mingfei , Wang Ying , Aguilar Byron J. , Morin Peter , Berlowitz Dan , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming 
Published: December 2022

AbstractBackgroundThe current standard of practice for assessment of Alzheimer’s disease (AD) severity in the Department of Veterans Affairs (VA) Healthcare System is primarily based on clinical examination and cognitive testing. We aimed to assess the consistency between clinician judgements of AD severity compared with that classified by cognitive test scores in the VA system.MethodWe identified medical notes for patients with mild, moderate, or severe AD from the VA electronic healthcare records (EHR) database between March 2008 and October 2021, using the natural language processing technology. Mini‐Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA) scores from the corresponding medical notes with physician judgments were classified and used for comparisons of severity levels. A binary variable was coded to indicate concordance or discordance for each paired comparison.ResultWe screened clinical notes from 51,809 AD patients and analyzed 8,888 clinical notes that had either an MMSE or MoCA test score from 5,150 AD patients (3.5% female; average age at 78.1±9.4 years). Clinician judgements and test‐score‐based classification of AD severity were concordant in 53.2% of comparisons (weighted Kappa = 0.39, 95% CI:0.38‐0.41, p = 0.009); whereas clinician judgments were less severe in 25.7% and more severe in 21.1% comparisons, relative to the test‐score‐based severity level. Clinician judgments were concordant with 54.1%, 51.8%, and 53.0% cognitive test‐score‐based classifications, of mild, moderate, and severe AD, respectively. Concordance was observed in 55.9% clinician judgments involving internist, 53.0% involving psychiatrist or neurologist, and 51.7% involving psychologist specialties, and in 50.4% involving nurse practitioners. Among discordant severity classifications, clinician judgments tended to be less severe than test scores (Figure).ConclusionExamination of VA EHR reveals that nearly one half of clinician judgments of AD severity are discordant with severity classification based on the MMSE or MoCA test scores. Discordance is more pronounced in the moderate relative to mild and severe AD categories but does not vary substantially over clinicians’ specialty background. Research will aim to find plausible explanations for the variation of concordance vs discordance by further examining the relative contributions of patient, clinician, and system characteristics in the process of AD clinical assessments.
A standardized protocol for detection of Amyloid Related Imaging Abnormality (ARIA) on 3T Philips Magnetic Resonance Imaging (MRI)
Authors: Pinter Nandor K , Ganji Sandeep , Johnson Brian , Huijbers Willem , Ajtai Bela , Dorn Ryu , Alnaji Baraa , Harlock Sarah , Westphal Erica , Friel Harry , Mechtler Laszlo 
Published: December 2022

AbstractBackgroundARIA is a common side effect of aducanumab, the first anti‐amyloid pharmacotherapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer’s disease. Regular MRI is required by FDA to detect and monitor different forms of ARIA during initiation of therapy. MRI protocols must be a) high resolution to detect abnormalities with high sensitivity, b) fast to accommodate workflow and ensure patient compliance and c) standardized to maximize data acquisition consistency across sites. Based on a vendor agnostic protocol recommendation by Benzinger et al (CTAD 2021), we propose specific parameters for 3T Philips systems, for an accelerated and enhanced protocol.MethodThe protocol was developed on a 3T Philips Elition X scanner, using 32‐channel head coil, and included 3D T1, 3D FLAIR, 2D DWI, 2D T2* and multi echo 3D Susceptibility Weighted Imaging (SWI) sequences.ResultAcquisition voxel resolution of 3D T1, 3D FLAIR, T2* and DWI matches current recommendations. 3D SWI resolution is 0.7x0.7x2mm. Compressed‐SENSE (C‐SENSE) acceleration is applied on 3D T1, 3D FLAIR, T2* and 3D SWI. SENSE is applied on DWI (Figure 1). Total acquisition time including the additional 3D SWI scan is 11 minutes, 6 minutes faster than the original recommendation. Qualitative assessment of images showed high signal‐to‐noise and contrast‐to‐noise. Images were free of acceleration related artifacts. Automated slice prescription localizer ensures better reproducibility for longitudinal assessment.ConclusionImaging protocol standardization is necessary to ensure consistent accuracy for diagnosing ARIA. Broad recommendations leave room for variability, therefore specific parameters are needed to achieve cross‐platform standardization. Our protocol is applicable for 3T Philips systems with compressed‐SENSE capability and 32‐channel head coil. The recommended C‐SENSE values maintain image quality with shorter exam time. This is more comfortable for patients and easier to fit into the workflow. The higher sensitivity of SWI can improve thresholds for therapy monitoring and provide additional quantitative measurements.
AB1601 topline results – Phase 2 study of ABvac40 in patients with amnestic mild cognitive impairment (a‐MCI) or very mild Alzheimer’s Disease (Vm‐AD).
Authors: Molina Elisabet , Castillo Sergio , Lacosta Ana M , Allué Jose A , Fandos Noelia , Montañés María , Romero Judith , Sarasa Leticia , Boada Mercè , Sarasa Manuel 
Published: December 2022

AbstractBackgroundImmunotherapy against amyloid β (Aβ) has emerged as a promising treatment option for Alzheimer’s disease (AD). Araclon‐Biotech is developing an active vaccine against Aβ40 peptide, one of the most abundant peptides in senile plaques and the dominant peptide in vascular deposits, that has been associated with earlier onset of dementia. The immunogen peptide of ABvac40 (Aβx‐40) does not contain the epitope recognized by T cells whose activation was considered the primary cause of aseptic meningoencephalitis. In Phase‐1 (NCT03113812), ABvac40 generated a long‐lasting antibody response after only three‐monthly‐immunizations.In 2017 Araclon‐Biotech initiated a Phase‐2, 24‐month, multicenter, randomized, double‐blind, placebo‐controlled trial in patients with a‐MCI or Vm‐AD to investigate the safety, tolerability, and immune response of repeated subcutaneous injections of ABvac40 as well as explore the effect of treatment on biomarkers and cognition (Part A) (NCT03461276). In July 2020, a protocol amendment was approved whereby the blind phase (Part A) was shortened from 24 to 18‐months and an additional 18‐months cross‐over study (Part B) was added.MethodPatients initially receiving placebo during Part A will be crossed over to receive ABvac40, whereas patients initially receiving ABvac40 will be given matching placebo plus a booster. Assignment to treatment groups will remain blinded for investigators and patients until the end of Part B. It is noteworthy that when the blind will be opened (18‐month visit), the average follow‐up will be of 23 months (close to the 24 months initially planned).Result124 patients aged 55 to 80 have been included (a‐MCI, n = 80; Vm‐AD, n = 44). Baseline demographics and characteristics were reasonably well balanced. A total of 101 patients have completed Part A and 77 of which have finally transitioned to Part B. Part B is progressing as scheduled.ConclusionTop line results for Part A will be presented in the congress.
A biomarker profile of elevated CSF p‐tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
Authors: Groot Colin , Smith Ruben , Stomrud Erik , Binette Alexa Pichet , Leuzy Antoine , Wuestefeld Anika , Wisse Laura EM , Palmqvist Sebastian , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Hansson Oskar 
Published: December 2022

AbstractBackgroundDifferent tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p‐tau typically being elevated at subthreshold levels of tau‐PET binding. To capitalize on the temporal order of tau biomarker‐abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid‐β‐positive (A+) individuals with elevated CSF p‐tau levels but negative tau‐PET scans and assessed longitudinal changes in tau‐PET, cortical thickness and cognitive decline.MethodIndividuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER‐2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut‐offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p‐tau217 (P; >110 pg/ml) and [18F]RO948 tau‐PET SUVR within a temporal meta‐ROI (T; SUVR >1.40). Resulting groups were: A+P‐T‐ (concordant, n=30), A+P+T‐ (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A‐ CU individuals (A‐ CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau‐PET SUVR, cortical thickness and cognition between the A+P+T‐ group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education.ResultLongitudinal change in tau‐PET was faster in the A+P+T‐ group than in the A‐ CU and A+P‐T‐ groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T‐ group showed slower rate of increases in tau‐PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T‐ and A+P‐T‐ groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups.ConclusionThese findings suggest that the A+P+T‐ biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T‐ group represents an interesting target‐group for early anti‐tau interventions and for examining the emergence of tau aggregates in early AD.
Optimized ACI‐24, an amyloid beta (Abeta) vaccine that safely drives immunity to oligomers and Pyroglutamate Abeta, key pathological species of Alzheimer’s disease (AD)
Authors: Fiorini Emma , Vukicevic Marija , Carpintero Rakel , Rincon Marcela , Lopez‐Deber Pilar , Piot Nicolas , Ayer Maxime , Rentero Inmaculada , Siegert Stefanie , Babolin Chiara , Knittel Delphine , Gollwitzer Eva , Bravo‐Veyrat Sophie , Giriens Valérie , Morici Catherine , Beuzelin Marie‐Gabrielle , Gesbert Anthony , Rivot Sebastien , Chuard Nathalie , Attanasio Vanessa , Delpretti Saskia , Donati Piergiorgio , Streffer Johannes , Pfeifer Andrea , Kosco‐Vilbois Marie 
Published: December 2022

AbstractBackgroundAmyloid immunotherapy has received recent clinical validation with monoclonal antibodies. Vaccines, such as optimized ACI‐24, are designed to produce a broader, robust antibody response against multiple pathologic forms of Abeta with the added advantage to reduce treatment frequency. Optimized ACI‐24 builds on the initial safety, immunogenicity and pharmacodynamic data of ACI‐24 that has been studied in AD and Down Syndrome‐related AD. Optimized ACI‐24 is formulated with the additional immune cell help via a non‐Abeta, universal T‐helper cell peptide, aiming to insure sustained antibody production, particularly against pathological Abeta species, such as oligomers and truncated pyroglutamate.MethodOptimized ACI‐24 was generated using the SupraAntigen® platform. Mice and non‐human primates were immunized and sera/plasma obtained to measure titers against Abeta1‐42, pyroglutamate (Abeta3‐42) and oligomers. Epitope mapping, immunohistochemistry on different human tissues, including AD brains were performed.ResultImmunization of mice and cynomolgus monkeys with optimized ACI‐24 resulted in potent antigen specific IgG levels. The polyclonal antibody response was observed to mature over time with higher affinity IgGs emerging as well as an increase in titers of IgGs that recognized the highly neurotoxic Abeta species including truncated pyroglutamate and pathological Abeta oligomers. Epitope mapping confirmed the induction of a broader spectrum of antibodies recognizing the N‐terminal containing and the truncated species of pathological Abeta, as compared to the previously clinically tested Abeta vaccines. In addition, target engagement was demonstrated as the immunized monkey sera labeled Abeta plaques in AD patient brain sections while did not show any binding to other human tissues.ConclusionThese preclinical data illustrate that optimized ACI‐24 generates IgGs with a broader N‐terminal Abeta sequence recognition than offered by clinically tested mAbs or Abeta vaccines. This unique binding profile for the pathogenic forms of Abeta, including truncated pyroglutamate and toxic oligomers, is encouraging as it combines the targets of mAbs, such as Aducanumab and Donanemab, recently linked to clinical benefits, and thus, the potential of enhancing plaque reduction. The presented data support the fast progression of optimized ACI‐24 into clinical development as a disease modifying treatment with potential for prevention in AD and Down Syndrome‐related AD.