bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Safety and Tolerability of IGC‐AD1 in Alzheimer’s Patients: Insights from CYP2C9 Polymorphism Assessment
Authors: Sulvaran Marian A , Arbelaez Maria Juanita , Gutiérrez Evelyn , Tangarife Maria Alejandra , Rao Jagadeesh S , Venegas Margarita , Sánchez Laura Tatiana , Shahnawaz Saadia , De Jesus William Julio , Pujals Karen Y , Grimaldi Claudia , Hong Elliot , Mukunda Ram 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) affects millions of Americans, with potential future increases without breakthroughs in treatment. IGC‐AD1, a novel formulation comprising of delta‐9 tetrahydrocannabinol (“THC”) and melatonin, is being studied in AD‐associated agitation. THC is predominantly metabolized by cytochrome P450 and specifically by CYP2C9. We present the comparison of Adverse Events (“AE”) between two polymorphisms of CYP2C9, intermediate (“IM”) and normal metabolizers (“NM”).MethodsThirteen Puerto Rican AD patients participated in a three‐cohort MAD, Phase‐1 safety, and tolerability trial (IND146069, NCT04749563). In Cohorts‐1, 2, and 3, one mL of IGC‐AD1 was administered QD, BID, TID, respectively, for 14‐days, with a minimum washout period of 4‐days between cohorts. CYP2C9 genotyping was assessed. Active Participants were grouped by phenotypes, Intermediate, or Normal. The IM group was assessed by genotype (*1/*2, *1/*3). Frequency of Adverse Events (“AE”s) was evaluated by group. Chi‐squared was used to compare differences between groups (SPSSv.28).ResultsSeven patients were IM (allele *1/*2 = 4, allele*1/*3 = 3), while five were NM. Both groups IM and NM presented somnolence (IM: 57%; NM: 80%, p = 0.63), hypertension (IM: 43%; NM: 20%, p = 0.50), dizziness (IM: 43%; NM: 40% p = 0.94), and falls (IM: 29%; NM: 40% p = 0.74). No serious adverse events were reported.ConclusionIn this limited sample size and trial, there were no significant differences in AE frequencies between the two CYP2C9 phenotypes IM and NM, suggesting that IGC‐AD1 has a safety profile that does not vary greatly, based on these two CYP2C9 polymorphisms. This analysis and initial results are important because the pharmacokinetics of THC are different for IM and NM. We continue to study these and other polymorphisms of CYP2C9 to understand their impact on AEs as it is crucial for personalized treatment strategies for the aged AD population.
Relationship between Anticholinergics and Cognitive Measures Important to the Diagnosis of Dementia
Authors: Keshk Noha , Khalil Hussein , Campbell Noll L 
Published: January 2025

AbstractBackgroundOver half of ambulatory older adults are prescribed at least one anticholinergic medication to address a myriad of conditions, including incontinence, allergies, anxiety and insomnia. Longitudinal studies suggest an association between anticholinergic exposure and risk of dementia. Prior studies often rely on crude exposure measures (use vs. non‐use), lacking detailed analysis of anticholinergic effects across different cognitive domains indicative of dementia. This study adopts a more comprehensive exposure measure, considering dosage, duration, and strength, to explore its association with a spectrum of cognitive assessments commonly used in diagnosing dementia.MethodA retrospective observational design was employed, analyzing one‐year electronic prescription data of 735 participants (age, 70.12±6.33; 75.2% Female; 88.3% White) recruited in two clinical trials (BrainSafe and R2D2 studies). Anticholinergic exposure was quantified using total standardized daily doses (TSDD). Outcomes were cognitive test scores of phonemic fluency, semantic fluency, symbol digit modalities, oral trail making (OTMT Part A and B), and hopkins verbal learning test (HVLT) collected at baseline. Generalized Linear models were applied to evaluate the impact of TSDD on cognitive performance, and Least Square means with Tukey’s adjustment were utilized to compare effects across anticholinergic subclasses. Subclasses compared were antimuscarinics, antihistamines, skeletal muscle relaxants and antidepressants. Covariates included in all the models are age, gender, ethnicity, educational level, and Charlson Co‐morbidity Index (CCI) Scores.ResultHigher anticholinergic exposure was associated with poorer performance in semantic fluency test (p‐value = 0.0002) and OTMT‐A (p‐value = 0.0034). The comparison between anticholinergic subclasses showed that antimuscarinic only users performed significantly better in HVLT total recall test than those using a combination of antihistamines and antimuscarinics (p‐value = 0.0037), after adjusting for TSDD and other covariates. Both antihistamine users and antimuscarinic users exhibited worse outcomes than antidepressant users in semantic fluency (p‐value = 0.008 and p‐value = 0.005, respectively).ConclusionThis study indicates an adverse dose‐duration effect of anticholinergic drugs on language, complex attention, executive functioning, and processing speed. Specifically, antimuscarinics users and antihistamine users demonstrated inferior performance in language, processing speed, and executive function compared to those on antidepressants. Additionally, combination use of antihistamines and antimuscarinics may lead to worse memory recall compared to the use of antimuscarinics alone.
Lingual Taste Neuroepithelium Precursor Hippocampal Implantation: A Novel Neurosurgical Intervention Hypothesis for Alzheimer’s Dementia
Authors: Ismail Youssef A. , Mohamed Hazim , El‐Satar Youssef M. Abd , Haitham Youssef , Walid Mohammad 
Published: January 2025

AbstractBackgroundLingual taste cells (LTCs) are taste buds' sensory cells that modulate gustation. This study’s aim is to assess whether it can be successfully implanted in hippocampus, modulating learning and memory deficits observed in Alzheimer’s Dementia (AD).MethodsRetrospective trials on rodents i.e., rats and guinea pigs showed that LTCs have been detected to demonstrate similarities with neurons, releasing neurotransmitters, synapsing and even antagonizing pathologies associated with AD. We mapped how it possibly can enhance cognitive function and memory deficits. Previous literature will be demonstrated in this study supporting and/or opposing therapeutic perspective.ResultsLTCs are classified into type I (glial‐like), type II receptor, and type III presynaptic cells. Preliminary evaluation noted that only type III LTCs possess conventional synapses, and transmission of taste stimulus from type II to nerve fiber requires a non‐conventional pathway, by subsurface cisternae and specialized mitochondria and also suggesting neurotransmitters. Type II LTCs have been identified to secrete acetylcholine, and type III’s have also serotonin (5‐HT), γ‐aminobutyric acid (GABA), and noradrenalin. Type II LTCs have been also found to express taste receptor type 1 member 1 (T1R1) and 3 (T1R3), been involved in the detection of glutamate gustatory stimulus from afferent nerve fibers. In long‐withstanding AD patients, decreased intracellular and increased extracellular adenosine triphosphate (ATP), by ATP synthase deficiency and P2X7 respectively, have been evident. Purinergic signaling in LTCs is also evident, type II has been recognized to secrete ATP by Panx1 with taste stimulation, and hydrolyzed by nucleoside triphosphate diphosphohydrolase‐2 (NTPDase2), expressed on the membranes of type I LTCs, which constitute the majority of cells within each bud. ATP also activates sour‐sensitive type III LTCs via P2Y4, causing vesicular release of 5‐HT and GABA, which in turn induce negative feedback on ATP release from type II LTCs. Glutamate also activates ionotropic glutamate receptors, N‐methyl‐D‐aspartate receptor (NMDAR), in type III LTCs, secreting 5‐HT and inducing previous feedback.ConclusionLTCs possess set of characteristics that could possibly compensating learning and memory impairment in AD, even in neuroplasticity in autism spectrum disorder (ASD), multiple sclerosis (MS) and other neurodegenerative diseases.
Subtypes of Longitudinal Progression Trajectories Among Cognitively Impaired Older Adults with A+N+ Biomarkers: Trajectory Clustering Analysis
Authors: Park Sangyong , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Chumin Evgeny J. , Jung Gijung , Kim Kyung Tae , Choi Hyeji , Kim Yoon Hee , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Jun‐Young , Risacher Shannon L. , Sporns Olaf , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young 
Published: January 2025

AbstractBackgroundWe investigated heterogeneities in clinical progression trajectories among cognitively impaired (CI) older adults who were positive for both beta‐amyloid (Aβ) and neurodegeneration biomarkers of Alzheimer’s disease (AD) using trajectory clustering analysis. We then compared clinical and neuroimaging variables across clusters with different clinical trajectories.MethodCI older adults, consisting of individuals with mild cognitive impairment (MCI) or mild AD dementia were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). All participants underwent comprehensive clinical assessment, and multi‐modal neuroimaging including 11C‐PiB PET, 18F‐FDG PET, and MRI with resting‐state functional MRI (fMRI). Among them, participants who were both amyloid positive (A+) and neurodegeneration positive (N+), including those with hypometabolism and cortical thinning in AD‐vulnerable regions, as well as hippocampal atrophy, were included. A subset of participants underwent 18F‐AV1451 PET to measure brain tau deposition. Group‐based trajectory modeling (GBTM) using the Clinical Dementia Rating (CDR)‐Sum of boxes (SOB) measured at baseline and longitudinal follow‐up up to four years, was used to identify clusters among A+N+ CI participants.ResultA total of 86 A+N+ CI individuals were included for the final analysis. A GBTM, based on longitudinal CDR‐SOB, identified two clusters with different trajectories: Cluster A (N = 54 [62.8%]) with slow progression and Cluster B (N = 32 [37.2%]) with rapid progression (Figure 1). No significant differences among age, sex, educational years, clinical diagnosis, global CDR, and APOE e4 carrier status were observed between the two clusters at baseline. These two clusters did not differ regarding global tau deposition and Braak Stages in a subset of participants (N = 34). However, at baseline, network segregation measure for the whole cortex and sensory‐motor network, and functional connectivity (FC) within the sensory‐motor network, differed between the two clusters after adjusting for age, sex, and education.ConclusionOur study identified two clusters with heterogeneous clinical progression trajectories even among CI older adults who exhibited both Aβ and neurodegeneration biomarkers. Further studies are necessary to elucidate the relationship between resting‐state FC measures and AD subtypes with different clinical trajectories.
Emotional valence in rapid automatized naming for early detection of Alzheimer disease
Authors: Lafenthaler Sandra , Höller Yvonne , Bergmann Jürgen , Kirschner Margarita , Frey Vanessa , Rossini Fabio , Trinka Eugen , Staffen Wolfgang 
Published: January 2025

AbstractBackgroundAlzheimer disease (AD) worsens naming abilities as the disease progresses. It is argued that traditional naming tests, commonly used to aid in staging AD severity, may overestimate semantic abilities. This study explored whether a more challenging naming task can distinguish between healthy adults and those with amnestic mild cognitive impairment (aMCI) or mild AD.MethodIn a cross‐sectional study, 16 individuals with aMCI, 15 with mild AD, and 20 healthy controls (see Table 1 for demographic details) performed a rapid automatized naming (RAN) task with emotionally balanced object and action pictures. Naming performance was assessed by response times (RTs) and accuracy (error rates). Regression analyses examined the relationship between RTs/error rates and group, sex, age, education, anxiety, and depression. Receiver operating characteristic (ROC) curves evaluated the discriminative ability of the RAN task.ResultPatients with aMCI and mild AD showed significantly slower RTs and higher error rates compared to healthy controls (all p‐values < .001). Naming performance was especially impaired for negative stimuli compared to positive and neutral ones in healthy controls (p < 0.001) and aMCI patients (p < 0.01). However, this effect was absent in the AD group. Regression analyses revealed significant associations between RTs/error rates and group (both p‐values < 0.001), but not for age, sex, education, anxiety, and depression (see Table 2). ROC analysis demonstrated moderate diagnostic accuracy in classifying mild AD versus healthy controls (AUC of 0.887 for RTs; AUC of 0.854 for error rates; see Figure 1), but not in classifying aMCI versus healthy controls.ConclusionThe RAN task reliably detects variations in naming ability across different stages of cognitive decline associated with AD. We observed an inhibitory effect of negative valence on lexical retrieval processes, which appeared to be dependent on the degree of cognitive impairment, as it was no longer evident in our AD group. Further research with larger sample sizes is warranted. A significant limitation of our study is the lack of standardization of our visual stimuli. It is possible that the ratings for emotional valence derived from written words may not precisely reflect the emotional responses of our participants.
Kirrel3 is associated with disordered sleep in presymptomatic Alzheimer’s disease mice.
Authors: Singh Surjeet , Hadad Niran , Dunn Amy R , Kaur Harpreet , Kravchenko Julia A. , O'Connell Kristen , Hohman Timothy J. , Pack Allan I , Kaczorowski Catherine C. 
Published: January 2025

AbstractBackgroundSleep dysfunctions are highly comorbid with Alzheimer’s disease (AD), though often associated with later stages of AD, sleep disruptions have been noted to appear decades before the onset of cognitive symptoms. Here, we provide the first evidence that genetic factors interact with AD mutations to influence sleep behavior even before the onset of cognitive symptoms.MethodTo identify novel genetic factors underlying disordered sleep that precede cognitive decline in our AD‐BXD mouse genetic reference panel (n = 179 mice across 25 strains, 7‐months‐old), we first used sleep phenotypes measured in the PiezoSleep chambers and performed quantitative trait loci (QTL) mapping and discovered Kirrel3 as the novel gene candidate associated with disordered sleep. To further evaluate the causal role of Kirrel3 in susceptibility to sleep decline in the presence of Alzheimer’s disease pathology, we generated mice heterozygous for the Kirrel3 gene with and without the 5XFAD transgene, and then did sleep phenotyping in these mice (n = 153, 7‐months‐old).ResultWe found that in AD‐BXD mouse population sleep was highly heritable (h2RIx̄ = 22% – 71%) and varied by light/dark cycle, sex, and the presence of the 5XFAD transgene. This implies high heritability of sleep that lays within the heritability observed in humans. Using QTL mapping we then identified Kirrel3 as a novel genetic factor underlying disordered sleep that precedes AD‐related cognitive decline in mice. Further evaluation of sleep changes in Kirrel3 heterozygous mice revealed a significant reduction in total sleep and sleep during dark cycle, for both sexes but only in the presence of 5XFAD transgene.ConclusionRecent GWAS studies in humans nominated Kirrel3 (aka Neph2) as a potential AD risk gene and as a regulator of sleep behavior (independent of disease). In this study we identified Kirrel3 as a novel genetic factor contributing to disordered sleep that precedes cognitive decline in our AD‐BXD mouse genetic reference panel. Further, using Kirrel3 heterozygous mice, we provide, first evidence for the causal role of Kirrel3 in sleep regulation only in the presence of 5XFAD transgene.
Classifier algorithms to characterize various stages of Alzheimer’s disease based on analysis of circulating brain‐enriched and inflammation‐associated microRNAs
Authors: Kunwar Arzu , Ablordeppey Kenny K , Goldman Jacob , Mireskandari Alidad , Kumar Gyanendra , Kiefer Michael , Wolk David A , Sheinerman Kira S. , Umansky Samuil R. 
Published: January 2025

AbstractBackgroundMinimally invasive diagnostic tools are crucial to characterize heterogeneous mild cognitive impairment (MCI), pre‐MCI, and Alzheimer’s disease (AD) cohorts. Our approach is based on targeted selection and quantitative analysis of microRNAs enriched in the brain and detectable in blood plasma. Here, we report the comparative analysis of 24 microRNAs comprising CogniMIR panel in 200 plasma samples with our Gen1 and Gen2 software algorithms towards distinguishing cognitively unimpaired (CU), MCI and AD cohorts.MethodThe expression of 24 brain‐enriched and inflammation‐associated microRNAs were analyzed in 200 plasma samples collected at the Univ. of Pennsylvania’s ADRC from 76 CU, 85 MCI, and 39 AD study participants. RNA from plasma samples was isolated using the MagMAX mirVana kit (ThermoFisher). microRNA concentrations were measured by qPCR using custom plates (Qiagen) pre‐plated with lyophilized miRCURY LNA‐based primers. Performance of classifier algorithms in differentiating clinically distinct groups was evaluated using Gen1 (self‐validation) and Gen2 (five‐fold cross validation) algorithms.ResultAUC generated with Gen1 for differentiation of CU Aβ‐/APOE4‐ vs AD APOE4+ was 91%, while the mean of five‐fold cross validation AUC for the same cohort was 85%. Similarly, the self‐validation AUC for CU Aβ‐/APOE4‐ vs MCI Aβ+/APOE4+ was 82%, while the five‐fold cross validation AUC was 77%. Further, the self‐validation AUC for CU Aβ‐/APOE4‐ vs CU Aβ+/APOE4+ was 85%, whereas the AUC generated with the five‐fold cross validation for the same groups was 61%. These analyses demonstrate higher self‐validation performance metrics as compared to the five‐fold cross validation metrics. It is likely that self‐validation (Gen1), which utilizes the full sample set for the analysis, provides an overestimation of the classifier’s performance. Whereas, in the five‐fold validation (Gen2) 20% of samples are held back during the classifier training step and used for testing evaluation; this process is repeated five times with different withheld subsets, and the performance results are averaged out.ConclusionDiamiR’s Gen2 classifier algorithm offers a more reliable estimate of generalized performance compared to our Gen1 classifier. The data generated in this study further support the development of assays based on brain‐enriched and inflammation‐associated microRNAs detectable in the blood. A larger study is ongoing.
Liver‐specific changes in Ppp1r3b expression impact cognitive function and neuroinflammation in mice
Authors: Punnuru Varnitha , Wu Jacqueline , Rodrigues Amrith , Wilson Aisha , Mahmood Malaika , Lo Emily , Rader Daniel J. , Corder Gregory , Creasy Kate Townsend 
Published: January 2025

AbstractBackgroundCardiometabolic disorders represent a pressing public health challenge and confer heightened susceptibility to age‐related cognitive decline, including increased risk of developing Alzheimer’s disease (AD). There is a strong genetic component underlying risks for these conditions, and human Genome‐Wide Association Studies (GWAS) have associated the PPP1R3B genetic locus with both cardiometabolic dysfunction and AD. PPP1R3B protein is primarily expressed in liver hepatocytes, regulating liver glycogen metabolism. However, there is no clear understanding of its genetic association with AD or its role in the brain. We aim to investigate the molecular mechanisms underlying the association of PPP1R3B with AD and to clarify how liver metabolic dysfunction contributes to neurological symptoms.MethodHepatocyte‐specific Ppp1r3b deletion (KO), over‐expression (OE), and wild‐type (WT) control mice underwent baseline learning and memory assessments by Y‐maze and Novel Object Recognition, and blood samples were collected. Mice were aged to 1 year then underwent additional cognitive assessments and were subsequently euthanized. Brain, liver, and blood samples were collected for assessments of metabolic and neurological dysfunction.ResultHepatocyte‐specific Ppp1r3b KO mice displayed impaired spatial memory recall as early as four months. Mice with hepatocyte Ppp1r3b OE showed no differences in memory compared to WT mice. Brain section immunohistochemistry revealed KO mice exhibited increased activation of microglia in memory‐related brain regions compared to both OE and WT mice. WT mice had some activated microglia while OE mice had less, suggesting OE protection from age‐related microglia dysfunction. Lipidomics performed on brain, liver, and blood samples revealed significant changes in lipid species that suggest a connection between liver metabolic dysfunction and observed cognitive phenotypes.ConclusionHepatocyte‐specific Ppp1r3b KO mice develop glucose intolerance and liver metabolic dysfunction that coincides with impaired memory and learning behaviors. After a year of aging, brains from KO mice have increased microglia activation, and altered circulating, brain, and liver lipid profiles that may contribute to the cognitive dysfunction. These data support the role of a liver‐brain axis connecting liver metabolic disease and cognitive impairment. Future studies aim to further clarify the role of specific lipids involved in cardiometabolic disease and AD.
Caregiver‐Driven Cognitive training (CDCT) – A feasible approach to dementia care in the Indian Population
Authors: Kanmani S Aparna , Kumar Keshav J , Sivakumar PT , Mathuranath PS 
Published: January 2025

AbstractBackgroundDementia care is incomplete without active caregiver involvement. Yet, existing cognitive interventions often overlook this crucial aspect. This study aims to develop and evaluate the feasibility of a Caregiver Driven Cognitive Training (CDCT) program in the Indian context, recognizing caregivers as essential partners in the care process.MethodIn Phase I, the CDCT Program was meticulously crafted through a comprehensive literature review and expert input, resulting in nine tailored cognitive tasks spanning attention, executive function, memory, and language domains. Caregivers, whether family members or professionals, were trained as co‐therapists with guidance from neuropsychologists. Phase II involved a pilot test (n = 5), using a quasi‐experimental research design (n = 5) by recruiting a dyad ‐ 1 patient with dementia (with a diagnosis of AD/FTD) + 1 caregiver. Eligible and consenting dyads were allocated (1:1) to the CDCT group or Treatment as usual (TAU) group and received intervention for five weeks. A thus modified CDCT was used in Phase III data collection (n = 32), utilizing the NIMHANS Neuropsychological Battery for Elderly (NNB‐E) and caregiver‐reported scales to assess outcomes assessed at three points: baseline, post‐intervention, and one month follow‐upResultThe CDCT Program yielded encouraging results, with participants demonstrating improved cognitive function, particularly in attention, executive function, and memory, post‐intervention compared to a Treatment as Usual (TAU) group. Additionally, CDCT participants exhibited enhanced quality of life, increased independence in daily activities, and reduced symptom severity. Caregivers reported subjective improvements in confidence, error detection, self‐correction, communication, and insight. The program received high feasibility ratings from caregivers, indicating its suitability for the Indian population. The quantitative and qualitative evidence of the same shall be presented.ConclusionThe CDCT program represents a paradigm shift in dementia care, emphasizing the active involvement of caregivers as co‐therapists. This approach not only enhances patient outcomes but also empowers caregivers, fostering a sustainable model of cognitive care tailored to the Indian socio‐cultural context.