bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time‐based measures for quantifying disease modification in Alzheimer’s disease
Authors: Raket Lars Lau 
Published: January 2025

AbstractBackgroundThe advent of disease‐modifying therapies in Alzheimer’s disease (AD) necessitates a nuanced understanding of how therapies impact disease processes. Over the past decades, AD clinical trials have primarily relied on classical statistical analysis methodology such as the mixed model for repeated measures (MMRM) to estimate treatment effects. These conventional treatment effect quantifications are given as group differences in clinical outcome measures at a single visit. While this classical approach of estimating treatment effects is well established, the resulting quantifications have shortcomings in relation to data utilization, meaningfulness, cumulative benefit summarization, post‐trial implications, and cross‐trial comparability.MethodProperties of conventional treatment effect quantifications from the MMRM were compared with two time‐based quantifications from the progression model for repeated measures (PMRM)1 and a latent time‐disease progression model. Results were illustrated and compared using data from the TRAILBLAZER‐ALZ 2 trial of donanemab.ResultThe MMRM had fewest assumptions, followed by PMRM and then the laten‐time quantifications. PMRM and latent‐time quantifications utilized information across visits better than the conventional MMRM quantification and produced greater power to detect treatment effects. Compared to conventional quantifications, the time‐based quantifications of treatment effects offered several desirable properties in terms of meaningfulness, cumulative benefit summarization, post‐trial implications, and cross‐trial comparability.ConclusionTime‐based estimates, particularly those derived from PMRM and latent time disease progression models, offer a set of desirable properties that complement conventional treatment effect quantifications. This study advocates for the inclusion of time‐based measures in the evaluation of disease modification in AD, providing a more comprehensive and nuanced perspective for guiding future clinical trial methodologies and result interpretations.References:1. Raket, L. L. (2022). Progression models for repeated measures: Estimating novel treatment effects in progressive diseases. Statistics in Medicine, 41(28), 5537‐5557.
How to handle use of additional medication for Alzheimer’s Disease during randomised clinical trials?
Authors: Dethlefsen Claus , Johannsen Peter 
Published: January 2025

AbstractBackgroundPhase 3 randomized clinical trials within Alzheimer’s Disease (AD) typically last over 18 months. Post‐baseline participants can use additional treatment for Alzheimer’s disease, potentially impacting the cognitive ability as evaluated by the primary endpoint. Consequently, this could overestimate or underestimate the treatment effect, depending on the distribution of usage between treatment arms.MethodThe ICH E9 (R1) addendum’s estimand framework provide a means of precisely defining the clinical question of interest, in particular detailing how intercurrent events such as ‘use of additional AD medication’ should be handled and how to interpret the estimated treatment effect. Donohue et al (2020) suggested to use a treatment policy strategy for initiation of symptomatic treatments, based on the observation that placebo subjects did not experience an improvement after initiation of symptomatic treatment. The EMA guideline for Alzheimer’s disease (2018), recommends using a hypothetical strategy for initiation of symptomatic treatment.ResultUse of additional AD medication will qualify as an intercurrent event only as long as the medication is considered to have an effect. Symptomatic AD medication is assumed to have no effect when the patient is no longer exposed. Therefore, we suggest to allow for the intercurrent event ‘use of additional AD medication’ to have both a start and a stop date, and, when applying a hypothetical strategy, only measurements that are considered affected by the intercurrent event will be substituted by outcomes corresponding to the hypothetical scenario were additional AD medication has not been initiated.ConclusionUsing estimands clarifies the interpretation of treatment effects in clinical trials allowing usage of additional AD medication.
Discovery and Preclinical Development of SM15685, a Novel Highly Selective Oral DYRK1A/B Inhibitor as a Potential Therapeutic for Alzheimer’s Disease
Authors: Mak Chi‐Ching , Mittapalli Gopi , Nora Chelsea , Creger Emily , Turner Lewis , Eastman Brian , Hofilena Brian , Vakiti Ramkrishna , Benardo David , Taylor Graeme , Hill John S , Bossard Carine 
Published: January 2025

AbstractBackgroundDYRK1A overexpression, common in neurodegenerative diseases like Alzheimer’s (AD), contributes to neurofibrillary tangles via Tau protein hyperphosphorylation and amyloid plaque formation, key AD hallmarks. Therefore, DYRK1A has been regarded as a novel target for neurodegenerative diseases. However, developing DYRK1A selective inhibitors has been a difficult challenge due to the highly conserved ATP‐binding site of protein kinases, particularly among the CMGC family. Here we describe SM15685, a novel highly selective and potent oral DYRK1A/B inhibitor, which reduces Tau hyperphosphorylation both in vitro and in vivo.MethodCompound selectivity and potency were evaluated in kinase panels and cellular target engagement assays. Tau phosphorylation (pTau) was measured in cell‐based assays. Pharmacokinetics (PK) were evaluated in rodents and pharmacodynamics evaluated in 3‐month‐old JNPL3 female mice (P301L human Tau overexpression) treated orally with SM15685 or Vehicle for 7 days (7 mice/group). pTau at Thr212 was biochemically quantified in subcortical brain and spinal cord fractions.ResultSM15685 was developed by utilizing structure‐based drug design and via iterative medicinal chemistry optimization cycles to achieve high potency, selectivity against the closely related CLKs and GSK3β, and good oral PK profiles characterized by brain‐penetration. SM15685 selectively and potently inhibited DYRK1A kinase activity (IC50 = 1 nM) with >90% inhibition at 1μM and only inhibited <2% of the full kinome. Selectivity and potency for DYRK1A and DYRK1B were confirmed in cellular target engagement assays (IC50 = 18 and 55 nM, respectively). SM15685 reduced pTau at the Threonine 212 site (IC50 = 14 nM). In pharmacokinetic studies, SM15685 demonstrated high oral bioavailability (%F >70) and good brain‐penetration in rodents (Kpuu >0.6). Compared to vehicle, JNPL3 mice treated with SM15685 at 45mg/kg showed significant reduction of pTau in both subcortical and spinal cord fractions in a pharmacodynamic model (p<0.05, T‐test).ConclusionSM15685, a highly selective and potent, oral, brain‐penetrant, DYRK1A/B inhibitor with the ability to significantly reduce Tau phosphorylation, has potential as a treatment for chronic tauopathies such as AD. These studies support further evaluation of SM15685 as a therapeutic option for AD and other diseases characterized by Tau hyperphosphorylation.
Association Between the Retinal Biomarkers and Cognitive Impairment in Community‐dwelling Older Adults in Taiwan
Authors: Chu Ting‐Wen , Hsieh Yi‐Ting , Chiou Jeng‐Min , Liu Yao‐Lin , Chen Jen‐Hau , Chen Yen‐Ching 
Published: January 2025

AbstractBackgroundThe early detection of preclinical dementia is crucial, prompting investigations into retinal biomarkers using optical coherence tomography (OCT). Inconsistent and limited longitudinal studies have been done to clarify the association between the retinal nerve fiber layer (RNFL) and ganglion cell‐inner plexiform layer (GC‐IPL) thickness and cognitive function over time. This study aims to explore the association between retinal biomarkers and cognitive function over time in non‐demented older adults.MethodThis seven‐year prospective cohort study included 264 non‐demented older adults at baseline (2015‐2017) from the ongoing Taiwan Initiative for Geriatric Epidemiological Research. Cognitive function underwent biennial follow‐ups to 2022, with assessments including global and domain‐specific cognition (memory, attention, executive function, and verbal fluency) measured using the Montreal Cognitive Assessment–Taiwanese version (MoCA‐T) and a battery of neuropsychological tests. Retinal data were collected using OCT at baseline. Generalized linear mixed models were utilized to examine the relationship between the RNFL, GC‐IPL thickness, and cognitive function, adjusting for apolipoprotein E ε4 status, age, sex, education years, and age‐related macular degeneration.ResultAt baseline, the performance of global cognition (MoCA‐T) decreased as GC‐IPL deviated from the mean (77.1 μm) (quadratic GC‐IPL: β= ‐0.32 x 10‐2; 95% CI: ‐0.61 x 10‐2 to ‐0.03 x 10‐2). Similar findings were found for memory performance (quadratic GC‐IPL: β= ‐0.19 x 10‐2; 95% CI: ‐0.31 x 10‐2 to ‐0.06 x 10‐2), and executive function (quadratic GC‐IPL: β= ‐0.07 x 10‐2; 95% CI: ‐0.14 x 10‐2 to ‐0.003 x 10‐2) over seven years. These results remained significant in females after stratification by sex. Notably, no significant association was observed between RNFL thickness and cognition.ConclusionWe found a non‐linear relation between GC‐IPL thickness and poor performance of global cognition, memory, and executive function, particularly among women. These findings highlight the significance of GC‐IPL thickness as an early biomarker of cognitive impairment, informing strategies for timely intervention in aging populations.
FDG‐PET and Amyloid PET scans: benefits beyond Alzheimer´s Disease. It´s really useful in daily practice? Clinical case review
Authors: Orrego Shenda , Sava Mihaela , Garcia Maria Pilar , Manzano María Sagrario 
Published: January 2025

AbstractBackgroundbiomarkers are essential in order to make a diagnosis with a high level of accuracy in patients with cognitive and behavior complaints. However, molecular imaging biomarkers not always provide an answer in daily clinical practice.Methodsretrospective and descriptive study in patients with Amyloid PET (APscans) implemented according to rational use of this technic, between January 2019‐November 2023 in Neurology Department, Infanta Leonor Hospital, Madrid, Spain.We included: first visit date, type of diagnosis, date, age, sex, neuropsychiatric symptoms, doctor requesting the diagnosis, CT/MRI scans (atrophy or vascular signs), NPS values (GDS),18F‐FDG PET scans (divided into normal, AD pattern, not AD pattern, indeterminate). The study was approved by the Research Committee of ILH. Statistical analysis was made with Dataset and SPSS 22.0.Resultstotal of 51 patients (54.9%females) were included. Mean of age 61.058, SD:8.329The mean of months till diagnosis was 10.82, SD:10.133. 74.5% cases were GDS 3 in the first visit.Positive APScans:39.22%, negative APScans:50.98%, not made yet:1.96%, not made:7.84%In the negative APScans only 26.92% could obtain a diagnosis with a high level of accuracy (Lewy body dementia 11.54%; FTD. 15.38%). But in 23.08% the results were not conclusive and the patients remains without a diagnosis in the follow up.In FDG‐PET‐scans we observed an impairment of glucose metabolism in 72.55% of patients. 58.82% FDG‐PET‐scans have a not AD pattern, being indeterminate in 73.33%.49.02% patients have history of depression, 3.92% psychosis, sleep disorders 1.96%, anxiety 3.92%, suicidal ideation 1.96%. Positive APScans has depression in 50% of cases vs 57.69% of negatives(p>0.05). Psychosis was present in 10% of positive APScans vs 0% of negatives(p>0.05). These symptoms did not predict the positive or negative results in APScansIn structural neuroimaging we observed 55% of patients with atrophy in MRI scans. A vascular pathology in MRI (lacunar strokes or leukoaraiosis):56.86%. Vascular pathology in structural neuroimaging predicted the higher probability to have a negative APScan (57.69%). Probably the small size could impact in all these results.ConclusionIn patients with cognitive and behaviour complaints, biomarkers are essential to make a diagnosis. However, when an APScan is negative and FDG‐PET‐scan indeterminate, diagnostic uncertainty, in real life, remains a serious unresolved issue
The Swedish registry for behavioural and psychological symptoms of dementia (BPSD)
Authors: Jönsson Linus , Londos Elisabet , Wibom Moa , Nägga Katarina 
Published: January 2025

AbstractBackgroundBehavioural and psychological symptoms (BPSD) are common in major cognitive disorders and an important driver of suffering and high care needs. The Swedish BPSD registry was founded in 2010 to develop an evidence base for quality improvement in the care of patients with BPSD. Here we describe the process of establishing and operating the registry, the patient population included, and data collected since the start of the registry in 2010.MethodsThe Swedish BPSD registry provides a framework for documenting the occurrence of behavioural disturbances, formulating individual caring and treatment plans and following up the patients and capturing health outcomes. Symptoms are recorded by the neuropsychiatric inventory ‐ nursing home (NPI‐NH) scale, and data is entered by trained staff, mainly at institutional care facilities. Triggering factors for BPSD are also recorded, as well as care objectives and targeted symptoms.ResultsBetween 2010 and 2023, 324,900 registrations were made in 110,684 persons. The number of patients active in the registry each year is 20‐25,000. Alzheimer’s disease was the most common diagnosis, 33%, followed by vascular dementia 17%, mixed 8%, DLB/PDD in 3% and FTD in 1,5%. Pain was the most cited trigger factor in all symptoms, except for night‐time and appetite/eating disturbances. The most frequently used care objective was affirmation/security, especially to manage agitation/aggression. Median survival was 24.0 months for men, 30.5 months for women.ConclusionsThe Swedish BPSD registry provides a unique view of the final stages in the disease course of dementia, with specific focus on the role of behavioural disturbances and their management. The scale, data completeness, long duration and possibility of linkage to other health registries is to our knowledge unparalleled and a great potential as a resource for data‐driven research.
Exploring the Therapeutic Effect of Perampanel, a Selective AMPA Receptor Antagonist, on Pathophysiological Changes in hAPP‐J20 Transgenic Alzheimer’s Mice
Authors: Liao Keng Ying , Hsin Yue Loong , Han Xu , Chen Wen‐Ying , Liu Wentai 
Published: January 2025

AbstractBackgroundThe initiation of amyloid plaque deposition signifies a crucial stage in Alzheimer’s disease (AD) progression, which often coincides with the disruption of neural circuits and cognitive decline. While the role of excitatory‐inhibitory balance is increasingly recognized in AD pathophysiology, targeted therapies to modulate this balance remain underexplored. This study investigates the effect of perampanel, a selective non‐competitive AMPA receptor antagonist, in modulating neurophysiological changes in hAPP‐J20 transgenic Alzheimer’s mice.MethodPerampanel was administered to hAPP‐J20 mice and their age‐matched wildtype littermates, aged 20‐25 weeks, during the critical amyloid plaque deposition period in the hippocampus. We continuously monitored the local field potential of the hippocampal CA1 region using long‐term wireless telemetry (sampled at a rate of 2 kHz), capable of calculating rates of high‐frequency oscillations (HFOs) to gauge potential epileptiform activity. To evaluate cognitive function, Morris water maze test was conducted. Glutamatergic pyramidal cells and GABAergic interneurons was quantified to assess neuronal health, and the hippocampal concentration of neuropeptide Y (NPY) was measured as an indirect indicator of mossy fiber sprouting.ResultTreatment with perampanel resulted in a significant rescue of GABAergic interneuron depletion and reduced the pathological increase of HFOs, indicative of restored excitatory‐inhibitory balance. In line with the restored excitatory‐inhibitory balance, it also attenuated neuronal sprouting labeled by NPY. Additionally, perampanel administration led to a substantial decrease in amyloid plaque accumulation in the hippocampus, though the observed memory deficit in transgenic mice did not change significantly.ConclusionOur findings reveal that perampanel, an established antiseizure medication, exerts multifaceted neuroprotective effects in the AD mouse model. The preservation of interneurons, reduction of pathological neural hyperactivity, and decreased amyloid plaque burden highlighted the potential of targeting glutamatergic pathways as a therapeutic strategy. The study warrants further investigation of perampanel as a promising candidate for ameliorating the pathophysiological and cognitive deficits associated with AD.
The role of the insula predicting memory performance in Alzheimer's disease amyloid positive and negative: a clinical cohort study
Authors: Coleman Michelle M , Haut Marc W , Teixeira Camila Vieira de Ligo , Keith Cierra M , Mehta Rashi , Phelps Holly , Ward Melanie , Miller Mark , Navia R. Osvaldo , Marano Gary D , Wang Xiaofei , Pockl Stephanie , Rajabalee Nafiisah , McCuddy William T , D’Haese Pierre‐Francois , Wilhelmson Kirk 
Published: January 2025

AbstractBackgroundKnown areas of Alzheimer’s pathology, including the hippocampus, entorhinal cortex and medial temporal cortex, have been well‐demonstrated as demonstrating atrophy in Alzheimer’s disease (AD). Using surface‐based morphometry measures, recent studies have suggested that the insula may play a role in memory function. Differences in patients based on amyloid biomarkers are increasingly being studied, particularly comparing individuals who were clinically diagnosed as AD but have negative amyloid biomarkers with those who are positive for amyloid. Atrophy may be similar in the entorhinal cortex between individuals who are amyloid positive versus amyloid negative, despite differences in memory. Here, we aimed to investigate the role of the insula in memory in a cohort of patients (aMCI and dementia) who were positive for amyloid with those who were negative for amyloid.MethodWe retrospectively analyzed clinical data from 161 aMCI and dementia patients (A+ = 106, A‐ = 55) and 41 healthy participants. Participants completed MRI and cognitive measures. Analysis of cortical thickness and gyrification index of the AD signature areas and the insula were completed using CAT12 and the DKT40 atlas. Memory performance was assessed using the California Verbal Learning Test short form, with long‐delay‐free recall as the variable of interest. Pearson’s correlations and stepwise linear regression were run using signature areas' significant correlations and interactions (adjusted p<0.001).ResultSignificant correlations with memory performance included insula gyrification and entorhinal and inferior parietal thickness (r=.25, r=.23, and r=.22, respectively). The interaction of insula gyrification with entorhinal thickness demonstrated significant results in predicting memory performance, accounting for 11% variance, even controlling for age. The interaction of reduced entorhinal cortex thickness and increased insula gyrification best explains delayed recall.ConclusionIn our well‐characterized clinical cohort of aMCI and dementia with positive and negative amyloid biomarkers, insula gyrification interaction with entorhinal thickness best predicted memory performance measured by CVLT long delay. This finding suggests that, regardless of amyloid status, reduced entorhinal cortex thickness and increased insula atrophy (measured by gyrification, not thickness), impact delayed memory. Studies are necessary to understand the insula's function in memory as well as gyrification and thickness variations across brain regions and their role in cognition.
New high throughput fully automated plasma p‐Tau217 immunoassay
Authors: Szabo Miklos , Wynveen Paul , Knutson Chris , Salvati Mike , Hoffmann Katie , Curtis Kara , Dumke Ben , Patzlaff Jason , Nichkova‐Doseva Mikaela 
Published: January 2025

AbstractBackgroundHyperphosphorylated Tau is a pathologic hallmark of the neurofibrillary tangles in Alzheimer’s Disease (AD). p‐Tau217 is a promising blood‐based biomarker in AD research, drug development, diagnosis, disease monitoring, and patient care. Several assays for p‐Tau217 in plasma have been previously described, however there is a need to make this test easily available to the clinical laboratories around the world and more accessible to the patients and the clinicians. We describe the development of a precise and highly sensitive plasma phosphorylated Tau (Thr 217) high‐throughput immunoassay on the new Beckman Coulter DxI 9000TM Access Immunoassay Analyzer.MethodThe prototype p‐Tau217 assay is a two‐step sandwich assay using an alkaline phosphatase‐conjugated anti‐tau monoclonal antibody (MAb), with an anti‐p‐Tau217 MAb bound to paramagnetic particles. EDTA plasma sample, reaction buffer, and MAb‐coated particles are incubated and washed. This is followed by addition of the ALP‐conjugate with another incubation and wash step before a chemiluminescent substrate is added. The light generated is directly proportional to the p‐Tau217 concentration in the sample. Through the capabilities of the DxI 9000 analyzer, assay time to first results is ∼48 minutes with a throughput of 225 test/hour. For this study, 66 EDTA plasma samples, consisting of 40 AD and 26 age‐matched healthy controls, were evaluated. Analytical sensitivity (lower limit of quantitation) and discrimination between AD positive and healthy control populations were evaluated.ResultThe prototype p‐Tau217 assay has a targeted analytical measuring range of ∼10 fg/ml to approximately 2000 fg/mL. All (100%) healthy control samples were quantified, and a 20% within‐run lower limit of quantitation (LLOQ) was estimated at 10 fg/mL with a 10% LLOQ estimated at 30 fg/mL. The ratio of the mean concentration of p‐Tau217 in the AD samples (520.9 fg/mL) compared with the mean concentration of p‐Tau217 of the age‐matched healthy controls (129.3 fg/mL) was 4.0.Conclusionp‐Tau217 is a promising blood‐based biomarker in AD research, drug development, diagnosis, disease monitoring, and patient care. The prototype p‐Tau217 assay provides fast, highly sensitive, precise, and relatively cost‐effective results in an automated immunoassay on the high‐throughput Beckman Coulter DxI 9000TM Access Immunoassay Analyzer.