bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of later‐life emergent affective dysregulation with neuroinflammatory biomarkers in dementia‐free older adults
Authors: Ghahremani Maryam , Ismail Zahinoor 
Published: January 2025

AbstractBackgroundNeuroinflammation has emerged as a significant factor in the pathogenesis of dementia. Elevated levels of proinflammatory and anti‐inflammatory cytokines such as interleukin‐6 (IL6), interleukin‐10 (IL10), and tumor necrosis factor‐alpha (TNFα) have been observed in the cerebrospinal fluid and plasma of patients with Alzheimer’s disease, associating with cognitive decline and dementia. Here, we explored the cross‐sectional association between plasma inflammatory biomarkers and the affective dysregulation domain of Mild Behavioral Impairment (MBI), a validated neurobehavioral syndrome capturing later‐life emergent and persistent neuropsychiatric symptoms (NPS).MethodData from dementia‐free older adults were acquired from the Health and Aging Brain Study: Health Disparities (HABS‐HD). MBI‐affective dysregulation (MBI‐affect) was operationalized based on a diagnosis of depression and/or anxiety within 5 years of baseline. Comparator groups included participants with no previous diagnosis of depression or anxiety (No‐affect) and those with a diagnosis >5 years prior to baseline (Non‐MBI‐affect). Plasma concentrations of inflammatory biomarkers IL5, IL6, IL10, and TNFα were obtained using single molecule array (SiMOA) technology. Linear regressions modeled the cross‐sectional association between NPS group (predictor) and inflammatory biomarker level (outcome), adjusted for age, sex, education, race, and cognitive diagnosis (normal cognition or mild cognitive impairment (MCI)).ResultThe sample comprised 74 MBI‐affect (age = 62.4±7.5; 81.1% female; 23.0% MCI), 143 Non‐MBI‐affect (age = 64.3±7.1; 76.2% female; 21.0% MCI), and 396 No‐affect participants (age = 66.7±8.9; 51.8% female; 13.6% MCI). Those with MBI‐affect had significantly higher baseline levels of plasma IL6 (b = 3.10, 95%CI:1.01‐5.19, p = 0.004) and TNFα (b = 1.66, 95%CI:0.43‐2.89, p = 0.008) compared to No‐affect, after multivariable adjustment. Biomarker levels in Non‐MBI‐affect did not differ significantly from the No‐affect group. For IL5, while MBI‐affect participants did not significantly differ from No‐affect (b = 0.03, 95%CI:‐0.002‐0.07, p = 0.06), the magnitude and direction of the effect were similar to the other biomarkers (Table 1).ConclusionCompared to No‐affect, MBI affective dysregulation was associated with higher levels of inflammatory biomarkers IL6 and TNFα, while Non‐MBI‐affect showed no association. The link between MBI affective dysregulation and neuroinflammation further informs our understanding of the biological underpinnings of MBI. These findings add to the evidence base for MBI as a clinically relevant approach to identify high‐risk individuals for cognitive decline and incident dementia.
Maternal Care and Offspring Development Trajectories in Mice: Effects of Alzheimer’s Disease Genotype and Maternal Age
Authors: Prakapenka Alesia V , Parpala Sophia , Cary Mallica , Ramirez Edith , Kujawa Stacy , Hawkey Andrew 
Published: January 2025

AbstractBackgroundPregnancy and birth uniquely alter female physiology, biology, and behavior. Contrasting findings on pregnancy and AD risk association suggest that confounding variables (e.g., age at birth) mediate pregnancy’s role in AD risk. We aim to elucidate the impact of age at first birth on female behavioral and brain health at middle‐age in the triple‐transgenic AD mouse model. Since strain and genotype differences in maternal care and offspring development exist, maternal care and offspring development trajectories as a function of genotype and maternal age were assessed.MethodsWildtype (WT; C57BL/6J) and AD virgin females were paired with WT males for pregnancy and birth to occur at 2‐m‐o. Gestational weight gain and litter characteristics (i.e., pup number, sex ratio, body weight) were recorded. Maternal care measures included retrieval of four pups to nest following 5‐min separation on postnatal day 2 (PND2) and evaluation of maternal activities for two hours on PND3 and PND17. Offspring development was assessed by righting reflex (PND5‐8) and negative geotaxis (PND10‐13) tests.ResultsAll mice were pregnant and gave birth, with two WT litters lost after birth. AD dams tended to have increased gestational weight gain compared to WT dams [p < 0.1]. Gestational weight gain was similar across genotypes after accounting for pup number and lost litters. All dams successfully retrieved pups on the retrieval task. Genotype by pup interaction [F(3, 36) = 2.814, p = 0.05] indicated that latency to retrieve increased with each subsequent pup in AD versus WT dams. Preliminary analyses suggest AD dams spent more time digging during the task compared to WT dams, which may modulate observed pup retrieval differences. Dam genotype impacted offspring development trajectories, whereby WT litters exhibited longer righting reflex latencies and shorter negative geotaxis latencies compared to AD litters.ConclusionsFindings suggest that maternal care and offspring development trajectories differ as a function of AD genotype in 2‐m‐o dams. Ongoing study evaluates 5‐6‐m‐o and 8‐9‐m‐o maternal ages. Future work will assess age at first birth effects on maternal health outcomes (e.g., behavior, neuropathology) in these dams at middle‐age, correlating to observed maternal care and offspring development measures.
Tinnitus and hearing loss in people with dementia
Authors: Machado Mariane Gomes , Machado Thais Helena , Caramelli Paulo , de Resende Luciana Macedo 
Published: January 2025

AbstractBackgroundTinnitus has variable prevalence in the general population and is often associated with some degree of hearing loss. There are few studies on tinnitus in people with dementia. The objective of the study was to investigate the occurrence of tinnitus complaints in patients with dementia and evaluate possible relationships with hearing acuity.MethodObservational study carried out with individuals treated at a cognitive neurology outpatient clinic. The inclusion criteria were patient being monitored for dementia, patient’s ability to answer the question “Do you feel tinnitus/noise in your ears or head?” and respond to audiometry. Descriptive analysis was performed. Research Ethics Committee 5626511.ResultOverall 187 patients with mild to moderate dementia who answered the anamnesis questions. Among these patients, 70 (37.43%) reported tinnitus and had a mean age of 66.71 years, 33 (47.14%) women and 37 (52.85%) men. It was possible to perform audiometry on 62 patients, due to difficulties in carrying it out due to dementia. Of the 62 patients who complained of tinnitus and underwent audiometric evaluation, hearing loss was detected in 54 (87.10%).ConclusionIn our study, 37.43% of patients with dementia complained of tinnitus. The prevalence of tinnitus complaints in the general population varies greatly, ranging between 4.4 and 15.1% in adults and 22.2% in older adults. Changes and severity of mental status and type of dementia may worsen the perception of tinnitus. The vast majority of tinnitus patients had some degree of hearing loss. The complaint of tinnitus is strongly associated with hearing loss in previous studies. Hearing rehabilitation may be a recommended treatment for patients with dementia, hearing loss and tinnitus. In addition to improving hearing acuity, rehabilitation can reduce the perception of tinnitus, as this symptom can lead to changes in mood and behavior that are difficult to manage. The perception of tinnitus in people with dementia may be greater compared to the general population. More studies need to be carried out to better characterize the tinnitus reported by people with dementia of different types and stages to better define management by professionals.
Cerebrovascular pathology and neurovascular coupling impairment in aged‐mouse model of Alzheimer’s disease
Authors: Promkan Moltira , Phikulthong Kamonchat , Kimseng Rungruedee , Pauss Kate , Lee Tiffany , Weekman Erica M. , Nelson Peter T , Wilcock Donna M. , Sompol Pradoldej 
Published: January 2025

AbstractBackgroundVascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials. Therefore, we aim to characterize cerebrovascular amyloid angiopathy (CAA), vascular degeneration, and cerebrovascular function in an aged Tg2576 mouse model of AD.MethodWT and Tg2576 (∼ 2 years of age) were housed in a reversed light cycle room. Cranial window surgery and cranial window installation were performed. After 3 weeks of recovery, the animals were acclimated to an intravital multiphoton imaging platform. To visualize beta‐amyloid in the brain, Methoxy‐X04 (10mg/kg) was injected the day before the imaging. Cerebrovasculature was visualized by intravascular retro‐orbital injection of rhodamine‐dextran (5% V/W in saline). This procedure was done while the animals were under anesthesia and securely head‐fixed prior to the imaging. Z‐stack imaging was performed, and vascular structure was analyzed by using FIJI or ImageJ. Neurovascular coupling was performed to investigate vascular function in awake mice. While imaging penetrating arteriole, air‐puff stimulation of contralateral whiskers was conducted and increased vascular diameter is used as an indicator of hyperemic neurovascular function.ResultInvestigation of cerebrovascular pathology including CAA, vascular straightness, and vascular blebbing are ongoing. During whisker stimulation, vascular diameter was relatively reduced in Tg2576 compared to WT control mice.ConclusionAged Tg2576 exhibits comorbidity of amyloid plaques, cerebral amyloid angiopathy, small vessel pathology and cerebrovascular dysfunction similar to human brain. This aged Tg2576 could be used as a preclinical translational mixed vascular/AD model.
Screening for the Spectrum of Cognitive Impairment in Primary Care: Development of a Machine Learning Informed, Workflow‐Friendly Care Model
Authors: Williamson Jeff D. , Jaeger Byron C , Bateman James R. , Benayoun Marc D. , Boehm Amy , Cleveland Maryjo , Kirkendall Eric D , Mielke Michelle M. , Pajewski Nicholas M. , Rigdon Joseph D , Snyder Heather M , Weiss Matthew G. , Yelton Paul D , Craft Suzanne 
Published: January 2025

AbstractIntroductionOver 9 million Americans are projected to have dementia by 2030, and adults with mild cognitive impairment (MCI), a potential pre‐cursor to dementia, will also rise. With recent and emerging clinical trial evidence for interventions to slow the progression of MCI to dementia, identification of persons in primary care with undiagnosed early‐stage cognitive impairment may provide opportunity for preventive intervention.MethodsA Machine Learning (ML)‐based prediction model trained using data from the electronic health record was applied to patients without formal diagnoses of cognitive impairment who were currently seen in selected primary care practices. The ML model is a super learner ensemble of prediction models, combining predictions from boosted trees, oblique random forests, and Cox regression trained using patient records from 2017‐01‐01 to 2018‐12‐31. We externally validated the super learner’s discrimination, calibration, and fairness using records from 2019‐01‐01 to 2020‐12‐31 (no overlapping patients). Patients for whom the model triggered an alert were recommended by their primary care practitioner to undergo cognitive assessment, consisting of a 30‐minute remotely‐administered tablet‐based cognitive battery. Patients also underwent blood collection for AD biomarkers (ptau217, Ab42, neurofilament light, GFAP), and neuroimaging (MRI, amyloid PET).ResultsIn the testing cohort, the super learner obtained a concordance statistic (95% confidence interval) of 0.822 (0.810, 0.835), higher than any of the individual ML models (Figure 1), and its predicted risk aligned with observed risk in calibration slope plots (Figure 2). Results of cognitive testing plus expert adjudication of the first 75 patients will be presented by proportion of patients adjudicated as not impaired versus MCI. We will also report categories of therapy such as behavioral (sleep, exercise, etc.), medical (hypertension control, alcohol cessation), or pharmacologic (anti‐amyloid therapy) that were recommended based on cognitive, imaging, biomarker, and medical findings. Also reported will be initial feedback on workflow and provider satisfaction with this screening and care model from primary care providers.ConclusionWhile predictive models of undiagnosed cognitive impairment are imperfect, they can facilitate scalable and feasible primary care screening models leading to effective care plan design for patients with early cognitive impairment and without adversely affecting workflow.
Effective Practices for Enrolling Underrepresented Groups in Early Alzheimer’s Disease Trials: Insights from the Aducanumab Program
Authors: Showell Shardae , Murphy Jennifer , Gillis Cai , Maserejian Nancy N , Mayuram Sangeetha , Wilson Jenna , Farrell Aimee , King Katie , DaCosta Savine , Wilson Kate , Lovelace Kerry , Vigario Andrew , Dawson Katherine , Dent Gersham 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impairment of daily functioning. It disproportionately affects certain racial and ethnic groups, with African Americans and Hispanics being 2 and 1.5 times more likely to develop Alzheimer’s disease compared to white non‐Hispanic Americans, respectively. Despite higher disease prevalence in these groups, enrolling these patients in Alzheimer’s disease clinical trials has been challenging, and they have historically been underrepresented. For the aducanumab program, we developed strategies to boost enrollment of African American and Hispanic participants. Here, we share insights from employing these strategies to further advance the enrollment of underrepresented groups in Alzheimer’s disease clinical trials.MethodTo boost enrollment of African American and Hispanic participants, we developed a cross‐functional work stream, incorporating members from clinical development, epidemiology, clinical operations, patient engagement, clinical trial diversity, and clinical country site management to collaborate on diverse recruitment and enrollment strategies. We executed and measured the impact of these strategies through the screening, enrollment, and retention of participants from these groups.ResultThe creation of intentional recruitment practices and site‐led strategies increased screening and randomization of underrepresented populations. Successful strategies included brain awareness education programs and faith‐based initiatives to build a trusting relationship with communities, mobile research unit initiatives to combat access barriers, and tailored site‐led programs that engaged populations in specific geographic/demographic locations. In parallel, targeted site communications and study‐wide webinars provided rationale for the goals and strategies of the trials, explaining the critical scientific need to include biological data from diverse populations.ConclusionEmploying a wide range of operational interventions, incentivizing strategies, outreach initiatives, and site educational events enhanced the recruitment and enrollment of underrepresented populations in an aducanumab clinical study. Clinical trials that are representative of the overall Alzheimer’s disease population may aid in producing results that better reflect real world outcomes.
Associations Between Alzheimer’s Disease and Stroke: Clinical Studies of NA‐831 for AD and NA‐911 for Stroke
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern 
Published: January 2025

AbstractBackgroundNA‐831 is a candidate for the treatment of Alzheimer’s Disease (AD). NA‐911 is an analog of NA‐831, serving as an IGF‐1 and GLP‐1 agonists. Animal studies of NA‐911 are evaluated for the treatment of by hypoxic‐ischemic injury, hemorrhagic stroke, and chronic neurodegenerative disordersMethodFor NA‐831: A randomized clinical trial of NA‐831 was performed in 112 participants with mild and moderate AD, half received the drugs and half received placebo. The patients with MCI received 10 mg of NA‐831 or placebo orally per day. The patients with mild and moderate AD received 30 mg of NA‐831 or placebo orally per day. Subjects with MCI to meet the NIA‐AA core clinical criteria, CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline. MMSE score ≥22. Subjects with mild & moderate AD to meet the NIA‐AA core clinical criteria. MMSE: 17‐21.For NA‐911: We conducted animal studies of NA‐911 on adult male Sprague‐Dawley rats using the middle coronary artery occlusion (MCAO) method. This method is designed to mimic neurological and behavioral signs and symptoms of stroke in humans. Details of the animal study method will be described.ResultsNA‐831 showed a significant improvement for patients with mild and moderate AD with the ADAS‐Cog‐13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT). CIBIC‐Plus showed 78% patients improved (p = 0.01; ITT). mNA‐831 was well‐tolerated at 30 mg/day.In the animal study of NA‐911, the area of infarct in animals treated with vehicle was 43.4±7.4 mm2 (n = 13, Treatment with NA‐911 (3 mg/kg/h) significantly reduced the area of the infarct to 17.3 ±5.4 mm2 when compared to its vehicle treated group (n = 15, * P<0.05). It has been shown that progenitor cells residing in the SVZ are potentially able to replace the loss of nervous tissue after stroke.ConclusionAn association of Alzheimer’s disease and stroke has been suggested with clinical studies of NA‐831 and NA‐911. However, whether this association is causal requires further evaluation.
Concordance between visual interpretation of [18F]flortaucipir pet images and the Universal centaur scale
Authors: Moscoso Alexis , van Essen Martijn , Mainta Isminni , Camacho Valle , Rodríguez‐Fonseca Omar , Silva‐Rodríguez Jesús , Perissinotti Andrés , Franzmeier Nicolai , Grothe Michel J. , Frisoni Giovanni B , Garibotto Valentina , Schöll Michael 
Published: January 2025

AbstractBackgroundPositron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this clinically approved definition of tau PET positivity and a recently proposed universal scale—CenTauR—for the standardized quantification of abnormal tau aggregates.MethodWe included 1849 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (A4 study, ADNI, OASIS‐3, and HABS) with available [18F]flortaucipir PET (mean age: 72.2 y, 55% females). Three trained readers scored each [18F]flortaucipir PET scan as positive/negative using an FDA‐approved visual interpretation method. Visual reads were compared to [18F]flortaucipir PET quantification using the Universal CenTauRz scale. Specifically, we analysed concordance by 1) performing a receiver operating characteristic (ROC) curve analysis of continuous CenTauRz (CTRz) values discriminating between positive/negative visual reads; and 2) computing sensitivity and specificity when using a previously proposed cut‐point of 2 CTRz.ResultConcordance between visual interpretation and continuous CTRz measures was limited (AUC = 0.82 for CU and AUC = 0.87 for CI, Figure 1). When using a previously proposed cut‐point of 2 CTRz, this quantitative approach yielded a sensitivity of 49% [95% CI, 42% to 57%] and a specificity of 95% [93% to 96%] in CU individuals and a sensitivity of 73% [95% CI, 66% to 79%] and a specificity of 94% [95% CI, 90% to 96%] in CI individuals. Visual‐positive, CenTauRz‐negative individuals were more frequently Aβ‐positive than visual‐negative, CenTauRz‐positive individuals (87% vs 48%, p<0.001).ConclusionVisual interpretation of [18F]flortaucipir PET images and quantification using the universal CenTauRz scale exhibited limited agreement, particularly among CU individuals. Tau‐PET positivity based on visual interpretation aligns better with the presence of Aβ‐pathology. Visual interpretation seems to be more sensitive to early tau aggregation compared to universal CenTauRz quantification. Future analyses will compare clinical outcomes associated to each definition of tau‐PET positivity.
Psychometric properties of the Memory Alteration Test (M@T) using a confirmatory factor analysis and a Rasch model
Authors: Carbajal Alicia Boluarte , Boluarte Arantxa Sánchez , Santisteban Brian Florentino , López Angel Zegarra , Boluarte Sofía Sanchez 
Published: January 2025

AbstractBackgroundBackground. According to the World Health Organization, dementia is one of the leading causes of disability in the elderly, imposing a significant burden on global public health. It is estimated that dementia affects over 55 million people worldwide, with 60% of them living in low‐ and middle‐income countries. Early detection of cognitive impairment is crucial for timely intervention and management. In this context, neuropsychological assessment tools play a vital role in identifying individuals at risk. The Memory Alteration Test (M@T) has emerged as a promising tool due to its high sensitivity for early detection of dementia and MCI. To build on this, our study aimed to analyze the psychometric properties of the M@T, in order to ensure its validity and reliability in clinical settings.MethodThe study was conducted among 352 participants over 60 years of age, recruited from Municipal Elderly Care Centers in four socioeconomically distinct districts of Lima, Peru. The M@T captures five domains of memory: encoding, temporal orientation, semantic memory, free recall and cued recall. For this, we proposed a unidimensional model and a multidimensional model with 5 factors, using a confirmatory factor analysis and a Rasch modeling.ResultThe majority of participants were women (82.9%), with a notable proportion reporting a clinical history of hypertension (33.2%). The internal structure analysis and Rasch modeling exhibited a unidimensional structure with good fit and adequate reliability (GY = .897, ord = .934). On the other hand, the 5‐factor multidimensional model showed a poor fit with unreliable scores (GY = .174‐.785, ord = .576‐.898). Likewise, the Rasch analysis demonstrated that the test measures a general memory ability reliably (Rp = .813), while the multidimensional model showed that the scores in each domain were not consistent (Rp = .358‐.707).ConclusionThe findings suggest that the M@T operates as a unidimensional factor, emphasizing the importance of considering the total score rather than individual dimensions. This underscores the need for caution when interpreting results, particularly when employing multidimensional models, which may not accurately capture the underlying structure of the test. Ultimately, a unidimensional approach offers a more parsimonious and reliable means of assessing cognitive function using the M@T.