bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring biological response profiles to amyloid antibodies in clinical practice using Quantitative Systems Pharmacology
Authors: Grant Athena , Short Shaina M , Geerts Hugo 
Published: January 2025

AbstractBackgroundWith the approval of several anti‐amyloid antibodies and a robust pipeline of new amyloid‐based therapies, attention turns towards questions related to real‐world clinical practice. Here we explore the impact of several biological pathways on the amyloid biomarker response of AD patients using a Quantitative Systems Pharmacology (QSP) approach with the ultimate objective to find measurable biomarkers for responder identification.MethodUsing a well‐validated QSP biophysically realistic model of amyloid aggregation, we performed sensitivity analysis to identify key drivers of amyloid biomarkers both in a longitudinal observational context and after treatment with specific amyloid antibodies. One Factor at a Time (OFAT), Pareto plots and Big Data classification algorithms in large virtual patient trials were used.ResultNot unexpectedly, in observational studies the major driver of amyloid aggregation (age of decrease in CSF Ab42 and maximal SUVR readout) included parameters of the amyloid aggregation, notably the exponential weighting factor of the aggregate order on the backward (monomer dissociation) rate constants. Smaller contributions of the forward rate constants, synthesis of APP and microglia‐mediated clearance of amyloid species were found.The same parameter was the major driver of SUVR response in trials with donanemab (dona) versus aducanumab (adu) and lecanemab (leca) with opposite effects on oligomers and protofibrils reduction. In contrast, parameters associated with secondary nucleation and flow from interstitial fluid (ISF) into cerebrospinal fluid (CSF) were driving ARIA‐E lability with opposing directions between adu versus dona and leca versus dona. The contribution of the different processes to the biomarker responses of the three antibodies were smaller in non‐APOE4 patients, except for the ARIA‐E liability where they were more pronounced.ConclusionThis approach can be used with the pharmacology of different therapies (including novel amyloid antibodies, gamma‐secretase modulators and oligomerisation inhibitors), to identify pathways characterizing individual patient responses.
What makes ‘hard decisions’ hard? Decision‐making in dyads of people living with Alzheimer’s disease and their care partners
Authors: Largent Emily A. , Erickson Claire M. , Gupta Anjali , Kleid Melanie , Harkins Kristin , Stites Shana D. , Peterson Andrew H. , Karlawish Jason , Clapp Justin 
Published: January 2025

AbstractBackgroundPeople living with Alzheimer’s disease and related dementias confront numerous decisions that affect their wellbeing, as well as that of their family members. Research demonstrates the importance of family involvement in such decision making, yet there is a lack of knowledge about how patients and families work together to make decisions and how families can best provide decisional support.MethodsSemi‐structured interviews were conducted separately with 15 patients diagnosed with mild cognitive impairment (MCI) or mild dementia, identified through a National Institute on Aging‐funded Alzheimer’s Disease Research Center, and 14 care partners. As part of a study of decisional support, interviewees were asked to describe a hard decision they had faced. Data analysis was guided by a constructivist grounded theory approach and consisted of iterative rounds of coding with checks for intercoder reliability.ResultsPatients and care partners most frequently identified the patient no longer driving as a hard decision; other hard decisions included changing the patient’s living arrangements or surrendering responsibility for their finances. Though interviewed separately, dyad members frequently identified the same hard decision. Hard decisions were characterized by tension between the patient’s independence or identity and the safety of the patient or others; the tension was nearly always resolved in favor of safety, particularly safety of others. Despite characterizing these as “decisions,” patients often felt they had no meaningful choice and implied that the outcome was inevitable. Consistent with these findings, both patients and care partners typically indicated that care partners initiated these decisions and denied engaging in substantive deliberation before enacting changes. Patients and care partners described hard decisions as emotionally difficult because they were confronted with the progression of the patient’s disease. Even as they acknowledged the importance of safety, patients grieved their loss of independence and diminished sense of self. Care partners expressed empathy for the patient’s losses and grieved alterations to the relationship.ConclusionsHard decisions are associated with undesirable outcomes more than with difficult decision‐making processes. When disease progression necessitates change, patients and care partners grieve even as they acknowledge change is appropriate. They may benefit from others acknowledging this grief.
MicroRNA‐502‐3p, a novel regulator of GABA function in Alzheimer’s disease
Authors: Sharma Bhupender , Torres Melissa , Rodriguez Sheryl , Kumar Subodh 
Published: January 2025

AbstractBackgroundIn various neurological disorders, including Alzheimer’s disease (AD) and AD‐related dementia, there is a notable reduction in gamma‐aminobutyric acid (GABA)ergic neurons, which represent the most abundant inhibitory neurons in the human brain. This study explores molecular association between miR‐502‐3p and the function of GABAergic neurons in AD.MethodThe investigation commenced by examining the status of GABA receptor proteins and miR‐502‐3p in postmortem AD brains. Subsequent in‐vitro experiments were conducted using the mouse hippocampal neuronal (HT22) cells, transfected with miR‐502‐3p agomiRs and antagomiRs. In‐silico analysis, performed to select miR‐502‐3p potential targets. Thereafter targeting of the GABRα1 gene by miR‐502‐3p were confirmed through a different technique, including QRT‐PCR, western blotting and ELISA, cell viability, miRNA in‐situ hybridization, immunoblotting, and immunostaining techniques were used to confirm the effect of miR‐502‐3p overexpression on the GABRα1 level and GABRα1 proteins.ResultReduced levels of GABA receptor subunits correlating with Braak stages were identified in AD postmortem brain samples compared to control. We found upregulated miR‐502‐3p expression in AD postmortem brain samples, correlating with Braak stages. In‐silico analysis, revealed multiple binding sites of miR‐502‐3p at GABRα1 mRNA. The targeting of the GABRα1 gene by miR‐502‐3p were confirmed through luciferase assay, QRT‐PCR, western blotting and ELISA for GABRα1. Elevated miR‐502‐3p levels showed toxic effects on HT22 cells and reduced cell viability. Furthermore, miRNA in‐situ hybridization, immunoblotting, immunostaining and whole cell patch‐clamp analysis confirmed that miR‐502‐3p overexpression (miR‐502‐3p agomiRs) suppressed GABRα1 mRNA and protein levels. Conversely, suppression of miR‐502‐3p (miR‐502‐3p antagomiRs) resulted in the restoration of GABRα1 levels, an increase in GABA current, and an overall enhancement of GABA function. Additionally, enhanced levels of proteins associated with AD were found with miR‐502‐3p overexpression and reduced with miR‐502‐3p suppression.ConclusionThe study uncovered an inverse correlation between miR‐502‐3p levels and GABA subunit proteins. Notably, inhibition of miR‐502‐3p demonstrated a protective effect on GABA function. Collectively, these findings suggest that miR‐502‐3p could serve as a promising therapeutic target for enhancing GABAergic neuron function in neurological disorders, including AD and AD‐related dementia.
Preparing home health clinicians to educate caregivers of persons living with dementia
Authors: Albrecht Tammi , Endicott Sarah , Kehl‐Floberg Kristen E , Schroeder Molly , Sayavedra Noelia , Mahoney Jane , Carlsson Cynthia M. , Walaszek Art 
Published: January 2025

AbstractBackgroundThe majority of persons living with moderate to severe dementia live in their homes despite the challenges of increasing care needs as dementia progresses. Caregivers are not prepared to understand and manage common medical concerns, such as incontinence, dehydration, and impaired mobility. Health care clinicians need training and tools to better prepare caregivers for these responsibilities. The goal of this program was to address this need by developing an educational program for home health clinicians who treat and support persons living with moderate to severe dementia in their homes.MethodsParticipants included registered nurses, physical therapists, occupational therapists, speech therapists, and social workers from two home health agencies. Trainings were held throughout a two‐year period. Outcomes measured included clinician knowledge, attitudes, and self‐efficacy gathered via surveys at baseline, immediately after training, and six‐months post‐training. Outcomes measured also included caregiver burden, caregiver self‐efficacy, and use of medical services and community resources gathered via surveys at baseline and six‐months post‐training.ResultsTwenty‐one clinicians were trained; 19 completed the baseline survey and 11 completed the post‐training survey. The clinicians implemented the caregiver training with 29 caregivers; 24 completed the baseline survey and 11 completed the six‐month post‐training survey. Clinicians demonstrated improvements in knowledge and self‐efficacy post‐training. Clinicians experienced significant improvements in attitudes as measured by the Dementia Attitudes Scale post‐training, especially in comfort and familiarity with caring for persons living with dementia. Caregivers reported similar levels of caregiver burden and self‐efficiency at baseline and six‐months post‐training. Caregivers reported overall satisfaction with the training they received from home health clinicians.ConclusionPersons living with dementia and their caregivers are impacted by changes in cognition, function, and physical health as dementia progresses. Home health clinicians are well‐positioned to help address these needs. The training provided to clinicians led to improvement in attitudes and confidence in the care of persons with dementia. Family caregivers reported a high level of satisfaction with the training; however, a small sample size and the effects of the COVID‐19 pandemic affected the ability to identify changes in caregiver burden, caregiver self‐efficacy, and use of medical and social services.
Role of ApoE polymorphism in Dementia
Authors: Agarwal Rachna , Kushwaha Suman , Tripathi Chandra Bhushan 
Published: January 2025

AbstractBackgroundApoE polymorphism especially APOE ε4 play a central role in AD pathophysiology through Aβ‐dependent and Aβ‐independent neuropathogenic pathway in the Alzheimer’s disease.MethodA cross‐sectional study was performed on non diseased and diseased subjects with stroke from outpatient services of Neurology department of Institute of Human Behavior & Allied Sciences (IHBAS), New Delhi (India). Subjects diagnosed with various dementias including Alzheimer’s disease, non AD dementias and dementia with Behavior & Psychological symptoms were taken. APOE genotyping was done in all subjects by ARMS‐PCR method.ResultThe most common allele APOE ε3ε3 was observed across all dementia groups (AD, non AD dementia. Dementia with BPSD & forgetfulness, whereas ε2ε4 was least commonly observed. Multivariable logistic regression analysis showed that the presence of APOE ε4 genotyping is significantly increasing the risk of AD three times more as compared to other alleles (Adjusted Odds Ratio: 3.07, 95% CI: 1.39 ‐ 6.78). The age and gender did not emerge out as significant contributors in AD. In group of AD with BPSD, the most common Behavior & Psychological symptoms observed was paranoid & delusional ideation.ConclusionAPOE ε4 is a risk factor for Alzheimer's disease.
Parsing disease heterogeneity using normative modelling and Generative Adversarial Networks (GANs)
Authors: Chintapalli Sai Spandana , Govindarajan Sindhuja Tirumalai , Shou Haochang , Huang Hao , Davatzikos Christos 
Published: January 2025

AbstractBackgroundStructural and functional heterogeneity in the brains of patients with Alzheimer's disease (AD) leads to diagnostic and prognostic uncertainty and confounds clinical treatment planning. Normative modelling, where individual‐level deviations in brain measures from a reference sample are computed to infer personalized effects of disease, allows parsing of disease heterogeneity. In this study, GAN based normative modelling technique quantifies individual level neuroanatomical abnormality thereby facilitating measurement of personalized disease related effects in AD patients.MethodWe adapt the pix2pix GAN to translate a subject with disease to a corresponding subject without disease. We train this model using a dataset comprising of healthy controls and synthetically simulated patients. Healthy controls (n=6000) are selected from the ISTAGING consortium. Our neuroanatomical brain measures are the 10 region of interest (ROI) volumes (covering left and right frontal, parietal, occipital, temporal lobes as well as deep brain structures) computed using a multi‐atlas segmentation technique. To simulate patients, for each healthy control we introduce 10‐30% atrophy or expansion in a random combination of ROIs while preserving clinical covariate effects. The model learns to synthesize patient‐specific controls by removing disease‐related variations from patient’s brain measures (Figure 1). Deviation of the patient from the synthesized disease‐free control acts as an image‐based biomarker that is sensitive to disease effects and severity. For performance assessment, we select 200 controls (CN) and 200 AD participants (PT) from the OASIS dataset and compute their deviations across the 10 ROI volumes using the model pretrained on the ISTAGING dataset. Logistic regression is used to assess the overall discriminative power of the derived deviations in AD classification.ResultLarger deviations in PT compared to CN suggest disease related abnormality in brain measures (Figure 2.a). Additionally, GAN’s deviations provide a considerable gain over raw ROI volumes in AD classification as quantified using the 5‐fold AUC scores (Figure 2.b).ConclusionGAN‐based normative modelling technique introduced here is a useful tool to parse heterogeneity in brain measures at an individual level. We see that self‐supervised training of the model using pseudo‐synthetically simulated patient data that is agnostic to disease patterns can help detect real disease related effects.
Cross sectional dopamine transporter imaging and myocardial sympathetic scintigraphy study in patients with dementia with Lewy bodies
Authors: Hirano Shigeki , Tang Zhihui , Koizumi Yume , Izumi Michiko , Kitayama Yoshihisa , Yamagishi Kosuke , Tamura Mitsuyoshi , Ishikawa Ai , Kashiwado Kouichi , Iimori Takashi , Mukai Hiroki , Yokota Hajime , Horikoshi Takuro , Uno Takashi , Kuwabara Satoshi 
Published: January 2025

AbstractBackgroundDopamine transporter (123I‐FP‐CIT) single‐photon emission tomography (SPECT) and 123I‐meta‐iodobenzylguanidine (123I‐MIBG) image play roles as indicative biomarkers in diagnosing patients with dementia with Lewy bodies (DLB). Brain‐ and body‐first subtypes of DLB were hypothesized implying that subset of DLB may have normal 123I‐FP‐CIT or 123I‐MIBG results, respectively. The purpose of this study was to explore the diagnostic sensitivity of two combination imaging modalities (123I‐FP‐CIT SPECT and 123I‐MIBG image) in patients with DLB and examine the clinical difference between brain‐ and body‐first subtype.MethodPossible DLB patients, defined by the fourth consensus DLB criteria, who underwent both 123I‐FP‐CIT SPECT and 123I‐MIBG image was retrospectively collected. Semi‐automated software and their results were utilized to define abnormality for both scans. Demographic data, cognition, motor, and core features were compared between the brain‐first and body first DLB subgroups.ResultOf the 114 patients with DLB, 66 underwent both scans. Mean (SD) age was 74.1 (7.1) years, male was predominant (62.1%), min‐mental state examination total score was 21.7 (4.8) and unified Parkinson’s disease rating scale motort subscore was 14.7 (4.8). Thirty‐six (54.5%) patients showed both abnormal scans and four patients (6.1%) were both normal scans. Seventeen patients (25.8%) showed abnormal 123I‐FP‐CIT result with normal 123I‐MIBG result (brain‐first DLB), nine patients (13.6%) showed normal 123I‐FP‐CIT result with abnormal 123I‐MIBG result (body‐first DLB). No clinical differences were observed between brain‐first and body‐first DLB subtypes.ConclusionApproximately 40% of DLB patients displayed normal result in either image. Normal results of a single imaging test may not refute the possibility of DLB.No clinical difference was observed between brain‐ and body‐first DLB subtypes.
Exploring potential of Allopurinol in Dementia of Alzheimer’s type
Authors: Kumar Amit , Sharma Diksha , Silakari Pragati , Grewal Amarjot Kaur 
Published: January 2025

AbstractBackgroundDementia is a mental condition defined by a severe loss of intellectual ability that interferes with one’s occupational or social activities. The rapid increase in the number of patients with dementia and Alzheimer’s disease (AD) will result in tremendous consequences for our society and economy. Hypoxanthine is a purine compound that is implicated in the progression of AD. The conversion of hypoxanthine into uric acid by xanthine oxidase reductase (XOR) leads to the formation of superoxide species that increase oxidative stress. The aim of the present study is to investigate the protective effect of allopurinol on STZ‐induced Alzheimer’s‐type dementia.MethodA docking study was done to evaluate the interaction of allopurinol with AChE. Once the interaction was confirmed, the study used Swiss albino mice. The test drug was administered to STZ mice for a total of 7 days (16‐22 days). Animals were subjected to the Morris Water Maze (MWM) training trials for 4 days (Days 19‐22). On the 21st and 22nd days, we performed the step‐down passive avoidance test. On the 23rd day, retrieval trials were conducted on MWM and step‐down passive avoidance, and animals were sacrificed and the whole brain extracted for biochemical and histological investigations.ResultSTZ‐induced mice showed decreased performance in MWM, stepdown‐passive avoidance, and altered biochemical and inflammatory cytokines. The histopathological study revealed severe infiltration of neutrophils and amyloid deposition. In the study, allopurinol treatment mitigated STZ‐induced cognitive decline via behavioural, biochemical, and histopathological changes.ConclusionThe results suggest that the neuroprotective effects of allopurinol in STZ‐induced Alzheimer’s‐type dementia might be attributed to anticholinesterase, antioxidative, and anti‐inflammatory effects.
Clinical performance of the Lumipulse G NfL CSF assay in cases with AD and FTD
Authors: Agüero Pablo , Téllez Raquel , Gonzales Alicia Ruiz , Wagner Sonia , Querejeta Agustín , Mahillo Ignacio , Ruiz Andrea , Sainz María José , Cremades‐Jimeno Lucía , Sanchez‐Juan Pascual , Gómez‐Tortosa Estrella 
Published: January 2025

AbstractBackgroundNeurofilament light chain (NfL) is a fluid biomarker of axonal damage reported to be elevated in cases with dementia, and particularly in FTD. In this study we evaluate the performance of a recently developed NfL assay to be analyzed through the Lumipulse chemiluminescent platform, which is frequently available in clinical settings for the study of AD core biomarkers.MethodWe evaluated CSF NfL levels using the Lumipulse G600II platform (Fujirebio, Iberia) in 70 cases, including 33 patients with AD (supported by CSF biomarkers consistent with an A+T+(N)+ classification scheme), 26 with confirmed FTD (typical phenotype and CSF with a A‐T‐ profile), and 11 controls. NfL was also determined in plasma samples of the same cases by single molecule array (SIMOA) with a Quanterix assay. We analyzed the correlation of NfL as measured in these two samples by the two different platforms and their value to discriminate between AD and FTD cases.ResultNfL in CSF was higher in FTD (mean‐SD= 2417‐2326 pg/mL) than in AD cases (1144‐594, p=0.07) and controls (809‐327, p=0.03), with no differences between AD and controls. The same applied for plasma NfL with more remarkable statistical differences: FTD (mean‐SD= 37‐21) vs AD cases (19‐7, p>0.001) and vs controls (18‐7, p=0.007). There was a significant linear correlation between NfL values in CSF and plasma in all cases (Pearson R=0.84, p<0.001). By groups, the correlation was higher in FTD cases (R=0.83) and controls (R=0.89) than in AD cases (R=0.46). The best discrimination between FTD and AD cases for CSF NfL was obtained at 1671 pg/mL (AUC: 0.675, 59% sensitivity, 90.6% specificity), while levels of 1395 pg/mL obtained the best discrimination between FTD and controls (AUC: 0.777, sensitivity 64%, specificity 100%).ConclusionThe Lumipulse NfL CSF assay could be useful in clinical settings to improve discrimination among dementia subtypes and controls. Elevated NfL CSF levels are highly specific of FTD and correlate well with plasma levels. Furthermore, NfL levels may support an underlying neurodegenerative process in cases with ambiguous phenotype and an A‐T‐(N)‐ CSF profile.