bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized trial of over‐the‐counter hearing aids for adults with cognitive decline due to Alzheimer’s Disease and related dementias
Authors: Mueller Kimberly D , Chin Nathaniel A. , Williams Victoria J. , McAlister Courtney B. , Souza Pamela E. 
Published: January 2025

AbstractBackgroundHearing loss occurs commonly with age and is more prevalent among adults with Mild Cognitive Impairment (MCI) or Alzheimer’s Disease and related dementias (ADRD) than among older adults with typical cognitive abilities. Over‐the‐counter (OTC) hearing aids are a recently approved, lower‐cost method of hearing treatment which can be accessed directly by patients. However, there are almost no data which can guide whether to recommend this treatment for adults with MCI or ADRD. OTC aids also have technology constraints that may limit their benefit for wearers with ADRD, who have specific communication and rehabilitation needs.MethodParticipants in this randomized clinical trial will be recruited at the time of diagnosis of either MCI or early ADRD. The trial design embeds a brief hearing assessment within the structure of a memory assessment at Geriatrics and Neurology clinics, in both urban (Madison, WI) and rural (La Crosse, WI) settings. Trial participants will be randomized to receive either OTC aids or communication strategies tailored for adults with cognitive decline. To maximize access for patients (including patients from rural or underserved areas), treatment will be delivered via telehealth. Outcomes will be measured at baseline and after one month of use of the OTC hearing aids or communication strategies. The primary outcome is subjective assessment of dyadic communication by the listener’s primary communication partner. Additional outcomes include hearing‐related quality of life and a novel assessment of communication ability using structured conversation analysis.ResultThis presentation will describe the trial design, expertise and roles of the multidisciplinary study team, mechanism of treatment delivery via telehealth, and planned outcome measurements.ConclusionResults of this trial will provide important evidence to guide treatment recommendations in community‐dwelling older adults with MCI or early ADRD. This project will also establish feasibility of conducting hearing assessment as part of a memory assessment.
Lecanemab Slows Amyloid‐Induced Tau Pathology as Supported by CSF MTBR‐tau243 in Clarity AD
Authors: Wildsmith Kristin R , Sachdev Pallavi , Horie Kanta , Reyderman Larisa , Charil Arnaud , Kanekiyo Michio , Yin Han , Li David , Koyama Akihiko , Dhadda Shobha , Irizarry Michael C. , Kramer Lynn D 
Published: January 2025

AbstractBackgroundLecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau243) is an emerging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) [Horie et al. Nat Med. 2023;29:1954‐1963]. In order to evaluate effects of lecanemab on MTBR‐tau243, CSF was analyzed in a subset of early AD participants from the phase 3 (Clarity AD) trial.MethodCSF from n = 167 early AD participants from Clarity AD was analyzed using an IP‐MS based method [Horie et al. Nat Med. 2023;29:1954‐1963.]. Pearson correlation analysis was performed to assess relationships between CSF MTBR‐tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.ResultBaseline correlation analysis show that CSF MTBR‐tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1‐6, whole cortical grey (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptau181, total tau, neurogranin, NfL, Aβ40 and Aβ42; plasma markers: pTau217, pTau181, Aβ42/40, NfL and GFAP). CSF MTBR‐tau243 has a higher correlation with Tau PET SUVR (r = 0.74, WCGROI) vs. amyloid PET Centiloids (r = 0.39, WCG ROI). Levels of CSF MTBR‐tau243 increased over time in early AD (placebo). Treatment with lecanemab slowed the rate of increase of MTBR‐tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). While the results have limitations due to sample size and do not reach statistical significance, at 18 months lecanemab slowed the rate of increase in CSF MTBR‐tau243 by 44% vs. placebo.ConclusionThese results support that CSF MTBR‐tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab‐associated amyloid removal slows the formation of tau pathology in the brain.
Association among Cognitive Stress Appraisal, Chronic Stress, and Cognition in Cognitively Normal Older Adults: Preliminary Findings
Authors: Aduen Paula , Badillo‐Cabrera Alex L , Vila‐Castelar Clara , Noriega‐Makarskyy Daisy , Munera Diana , Lucas John A. , Kirschbaum Clemens , Slavich George M , Quiroz Yakeel T. 
Published: January 2025

AbstractBackgroundCharacterizing stress can inform our understanding of direct and indirect pathways impacting mental and physical health outcomes, including age‐related cognitive decline. Chronic stress has been strongly associated with increased risk for cognitive decline, and hair cortisol concentration (HCC) has emerged as a viable neuroendocrine biomarker for its quantification. Cognitive appraisal of stress (CAS) provides key insight into the cognitive framework for responding to a given stressor. We implemented a multi‐pronged approach to evaluate chronic stress and examined its relation to cognition in older adults.MethodParticipants were 22 cognitively normal individuals (x̄ MMSE = 29.33, 0.92; x̄ age: 67.3 ± 8.8 years old, 17.0 ± 2.9 years of education, 54.5% female, 92.6% Non‐Hispanic White). Participants completed the Stress and Adversity Inventory (STRAIN) assessing lifetime stressor exposure and the Primary and Secondary Cognitive Appraisal Scale (PSCAS). HCC was used as a neuroendocrine biomarker of chronic stress. A brief cognitive battery assessing episodic memory and executive functions (Digit Span, HVLT‐R, Trail Making Test, Letter Fluency) and mood/anxiety measures were completed. To correct for skewness, log‐transformed HCC values were used for Pearson and partial correlation analyses controlling for age and education.ResultLifetime stressor exposure and CAS were not significantly related to cognitive performance (all ps > 0.05). There was a marginally significant association between HCC and executive functions (r = ‐0.41, p = 0.08). Total lifetime stressor count, chronicity, and severity were unrelated to symptoms of depression and anxiety (all ps > 0.05). Although lifetime stressor exposure and mood were not significantly related to HCC, higher HCC was associated with higher perceived control of stress (r = 0.45, p = 0.03).ConclusionHCC may be more sensitive to CAS rather than to objective stressor exposure. This highlights the potential of interventions targeted at improving coping in those with chronic stress. Results are preliminary, and the present study will explore impact of social and structural determinants of health on chronic stressor exposure, appraisal, and cognition.
Chronic Pain in Latin America: Prevalence, Risk Factors, and Their Association with Dementia
Authors: Hernandez Hernan , Caviedes Ariel , Oyanedel Lorena , Franco Teresita Ramos , Olavarria Loreto , Ibañez Agustin , Santamaria‐Garcia Hernando , Custodio Nilton , Montesinos Rosa , Bruno Martin Alejandro , Slachevsky Andrea , Ochoa‐Rosales Carolina , Duran‐Aniotz Claudia , Gonzalez‐Silva Carolina 
Published: January 2025

AbstractBackgroundChronic pain (CP) is defined as the persistence of pain beyond the expected recovery period of an injury, or alternatively, with a duration exceeding three months. It has been recognized as a risk factor for dementia in European and North American cohorts. However, in Latin America (LA), there remains a significant gap in understanding CP prevalence, its risk factors, and its association with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Our study aims to shed light on the impact of CP on the LA population, along with its implications for AD and FTD.MethodWe analyzed data from the National Health Survey (NHS) conducted in Chile in 2009‐2010 and 2016‐2017. This study comprised 2179 subjects from the 2009‐2010 survey and 1447 subjects from the 2016‐2017 survey. Additionally, we assessed CP in LA patients with dementia (AD and FTD) using a concise 6‐question survey, which evaluated the presence, duration, frequency, location, and intensity of pain. Our patients are from Chile, Peru, Argentina, and Colombia, all of whom actively participate in the Multicenter Consortium to Expand Dementia Research in Latin America (ReDLat).ResultOur analysis revealed from the Chilean NHS that the prevalence of CP increased by approximately 30% across both surveys among individuals aged 20 to 70. Key factors associated with CP in the Chilean population include reduced mobility, anxiety, depression, malnutrition, socioeconomic disadvantage, and lower educational attainment. The results also suggest an association between CP and the presence of dementia in the Chilean population that warrants further detailed investigation. In the analysis of the ReDLat cohort, we observed that patients with AD report experiencing CP at a higher proportion (53.6%) than patients with FTD (31.3%) and control subjects (34.8%).ConclusionThis study highlights the substantial impact of CP on the LA population, particularly in AD patients. To our knowledge, this is the first study in LA to investigate the prevalence and risk factors associated with CP. Additionally, our findings suggest that CP is associated with the pathology of dementia, emphasizing the critical need for further research in this area.
An Innovation to Address Brain Health and Dementia in Individuals with Intellectual and Developmental Disabilities
Authors: Pettis Jennifer , Tracy Karen K 
Published: January 2025

AbstractAdults with intellectual and developmental disabilities (I/DD) and their caregivers may face many barriers to obtaining an accurate assessment of cognitive decline. For example, primary care providers may mistake manifestations of new cognitive impairments or dementia for symptoms of the underlying disability. Pre‐existing cognitive impairments, communication challenges, unfavorable reactions by members of the care team to adults with pre‐existing cognitive deficits, and lack of understanding regarding common behaviors and needs of adults with I/DD can further complicate assessments. Furthermore, mainstream cognitive screening and assessment tools are not appropriate for many of the more than 7 million people living with I/DD in the United States. To address this unmet need and better equip primary care teams to appropriately address brain health in adults with I/DD, the Gerontological Society of America (GSA) developed a new companion resource to supplement The GSA KAER Toolkit for Brain Health.The four steps in the KAER framework—Kickstart, Assess, Evaluate, and Refer—are intended to improve health‐related outcomes and well‐being for people living with dementia and their families. The Toolkit includes practical approaches, educational resources, and validated clinical tools that help primary care teams implement initiatives related to brain health and timely detection of cognitive impairment. GSA developed the companion publication addressing the unique needs of adults with I/DD. The publication, Addressing Brain Health in Adults with Intellectual Disabilities and Developmental Disabilities: A Companion to the KAER Toolkit for Primary Care Providers, aims to:• Raise awareness of unique needs of adults living with I/DD.• Equip and encourage caregivers and health care teams to engage in appropriate brain health conversations with adults with I/DD.• Promote brain health conversations and early detection of changes in cognitive and adaptive function for adults with I/DD.• Assist with the identification of community supports and resource networks aimed at enhancing function and quality of life for adults with dementia and I/DD.This presentation will provide insights into the KAER framework and how, when combined with The GSA KAER Toolkit for Brain Health, the new companion can support person‐centered brain health promotion, early detection of dementia, and dementia care planning for individuals with I/DD.
Age associated changes in behavioral and memory functions in genetically heterogeneous mice UM‐HET3
Authors: Kaur Harpreet , Badenoch Bretton , Reifsnyder Peter C. , O'Connell Kristen MS , Miller Richard A. , Harrison David E. , Kaczorowski Catherine C. 
Published: January 2025

AbstractBackgroundPrevious studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.MethodBoth male and female UM‐HET3 mice at age of 11 months (middle‐aged) and 25 months (old) were used in this study. Complete blood count, grip‐strength, Rotarod, visual acuity, startle response, voluntary wheel running activity and contextual fear conditioning assays were performed on these mice. Further, a correlation analysis was performed on blood cells and contextual fear memory (CFM) to identify signatures associated with age related cognitive decline.ResultOur results showed significantly lower body temperature, decrease in hemoglobin, changes in blood related parameters (including RBC, hematocrit, platelets, MPV, WBC), reduced visual acuity, reduced grip strength (not normalized by BW) and impaired memory functions in older mice when compared to middle‐aged mice. We found no correlation between blood cells and CFM in middle‐aged mice, but the percentage of neutrophils (R = 0.794, p = 0.009) and lymphocytes (R = ‐0.734, p = 0.022) were found to be associated with CFM in older male mice. A reduced startle reactivity was also observed in older male and female mice which is likely to be the result of impaired hearing, although these mice were not tested for hearing loss. No statistical significance was observed in Rotarod performance and in wheel running activity when middle aged mice compared to old UM‐HET3 mice.ConclusionOur study showed that UM‐HET3 mice exhibit age related impairment in sensory and memory functions as compared to middle aged mice. In older mice, reduced memory correlates with increased percentage of neutrophils and decreased lymphocytes in blood, suggesting a possible role of white blood cells in age‐related memory decline in UM‐HET3 mice. However, further studies are needed to understand the mechanisms driving age‐related decline in cognition with focus on changes in immune cells for developing therapies to slow down the rate of cognitive decline in normal aging as well as neurological disorders such as Alzheimer’s disease.
AD04 – modifying Alzheimer’s Disease by modulation of neuroinflammation
Authors: Abraham Carmela R , Schneeberger Achim , III Agustin F Santana , Hoffmann Thomas , Fischer Anita , Trembleau Sylvie 
Published: January 2025

AbstractBackgroundWe aim to repurpose the widely used adjuvant and immunomodulator AlhydrogelTM at a specific dose and schedule (AD04) as a disease‐modifying treatment for mild Alzheimer’s disease (AD). AD04 is a potent adjuvant commonly used in vaccines and allergy immunotherapies to augment the magnitude and durability of the immune response. Our preliminary data come from a clinical Phase 2 study in which AD04 served as a control arm. In this study, AD04 showed promising results in delaying hippocampal atrophy and cognitive decline, as well as improving the quality of life in patients with mild AD. A global statistical test (GST) was used to compare the treatment effect of AD04 to other drugs/drug candidates. GST used is a combination of ADAS‐cog, ADCS‐ADL and the CDR‐sb. As such, it combines three important perspectives of three different aspects of AD progression. The effect size seen with AD04 is comparable or better than that of most other available treatments. However, the precise mode of action of subcutaneous (s.c.) administration of AD04 on the brain has not been deciphered.MethodAged (24 mo) C57BL/6 mice were injected s.c. with AD04 or with PBS, three times, and 3‐5 days after the last injection they were tested for fear conditioning. One day later, the mice were sacrificed, and hippocampi and peripheral organs were subjected to proteomics. Young (10wks) mice were used as controls.ResultIn the fear conditioning test, AD04‐treated old mice, exhibited an improved freezing behavior compared with the PBS‐injected mice. Proteomics analysis of the hippocampi revealed that peripheral AD04 administration modulated the production of proteins involved in lipid metabolism regulation and affected microglial phenotype into a phagocytic type.ConclusionBased on these preclinical results we conclude that AD04 administration induces microglia to phagocytose brain debris, such as apoptotic neurons, synapses and degraded myelin in the aged brain, and in the AD brain also Abeta, extracellular tau tangles and oxidized lipids. By changing the microglial phenotype, AD04, indirectly reduces the neuroinflammation induced by Abeta, tau and neuronal debris, leading to an anti‐inflammatory milieu in the brain which protects and rescues the hippocampus from neurodegeneration.
A Brief Digital Neuropsychological Protocol – IV: Relations Compared to Comprehensive Paper and Pencil Neuropsychological Assessment
Authors: De Anda‐Duran Ileana , Bazzano Lydia , Harville Emily , Fernandez‐Alonso Camilo , Banks Russell , Tobyne Sean , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro , Swenson Rodney , Libon David J. 
Published: January 2025

AbstractBackgroundA typical paper/pencil neuropsychological evaluation to assess for mild cognitive impairment (MCI) and dementia is lengthy. There is a need for a brief, digitally administered/scored neuropsychological protocol that can differentiate patients who are cognitively normal versus MCI and dementia. This need is particularly acute with the advent of disease‐modifying medications to treat MCI and early Alzheimer’s disease (AD).MethodThe Digital Assessment of Cognition (DAC) assesses memory with a 6‐word Philadelphia (repeatable) Verbal Learning Test [P(r)VLT]; executive abilities with three trials of 5 digits backward (BDST); and language/lexical access abilities with the ‘animal’ fluency test. 105 ambulatory care/memory clinic patients were assessed. DAC outcome measures include words recalled, recognition discriminability, BDST serial recall, and ‘animal fluency output; and separate episodic and executive summary indices. A portion of this sample (n = 70) underwent traditional, paper and pencil assessment.ResultCluster analysis (Table 1) classified participants into groups suggesting normal (NL = 25), dysexecutive MCI (n = 25), amnestic MCI (n = 11), mixed MCI (n = 24), and dementia (n = 25) cognitive abilities. Concordance between cluster classification and clinical diagnosis using a lengthy paper/pencil protocol was 90%. The ANOVA for the episodic memory summary index found no difference between NL/dMCI groups; all other groups differed. The ANOVA for the executive index found no differences between NL/aMCI, and dMCI/mixed MCI groups; all other groups were differentiated from each other. Within‐group, dMCI patients scored lower on the executive versus the memory index (p<0.001); aMCI patients scored lower on the memory versus executive index (p<0.001); NL patients scored higher on the executive versus the memory indices (p< 0.021); and mixed MCI patients did not differ on either index. The DAC memory index was correlated with CVLT‐short form delayed free recall (r = 0.648; p< 0.001) and recognition discriminability (r = 0.625, p<0.001) scores. The DAC executive index significantly correlated with WMS‐IV Symbol Span (r = 0.620, p<0.001; Trails B (r = 0.477, p< 0.001), and letter fluency (r = 0.538, p<0.001).ConclusionThe DAC is able to identify clinically meaningful groups, showed diagnostic concordance with lengthy paper/pencil assessment, and is positively correlated with traditional paper and pencil tests. The DAC provides a reasonable means to screen for patients with putative MCI and dementia.
Phase 3 Trial of Oral Anti‐Amyloid Agent ALZ‐801/Valiltramiprosate in APOE4/4 Homozygotes with Early Alzheimer’s Disease: Baseline Characteristics and Prevalence of Comorbid Cerebral Amyloid Angiopathy
Authors: Power Aidan , Watson David , Abushakra Susan , MacSweeney Emer , Porsteinsson Anton P. , Sabbagh Marwan N. , Liang Earvin , McLaine Rosalind , Boada Mercè , Snædal Jón , Flint Susan , Pak Winnie , Hey John A. , Tolar Martin 
Published: January 2025

AbstractBackgroundALZ‐801/valiltramiprosate, an oral small molecule inhibitor of amyloid oligomer formation, is being evaluated in a Phase 3 trial in APOE4/4 Early AD subjects (APOLLOE4). Topline results are expected in 3Q 2024. APOE4 is a major risk factor for Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) with a gene‐dose effect. APOE4/4 subjects with CAA are at higher risk of amyloid related imaging abnormalities (ARIA) with anti‐amyloid antibodies, including ARIA‐E (effusion/edema) and ARIA‐H [lobar microhemorrhages (MH), macrohemorrhages, and superficial siderosis (SS)]. APOE4 carriers are also at higher risk of hyperlipidemia and cardiovascular disease (CVD). Baseline prevalence of CAA and CVD risk factors were analyzed.MethodThis Phase 3 trial (NCT04770220) enrolled 325 APOE4/4 Early AD subjects (MMSE ≥22, 50‐80 years); 313 had baseline MRIs with central readings. Subjects with MH and SS were enrolled; ARIA‐E was exclusionary. Subjects with CAA (>4 MH, any siderosis, any macrohemorrhage) were compared to rest of population.ResultStudy population was 51% female, age 69 years, MMSE 26, 65%/MCI, 82% Caucasians. CAA group included 47/313 subjects (15%) of study, was mostly male (70% vs 45%), older (71 vs. 68 years, p = 0.004), more advanced (MMSE 25 vs 26, p = 0.018; ADAS‐cog 27 vs. 23, p = 0.002) with more severe deep WMD (p = 0.015). Both groups had similar prevalence of hypertension, diabetes, obesity, hyperlipidemia, and statin use but with higher coronary artery disease prevalence (17% vs. 8%, p = 0.049) and anti‐platelets use (38% vs 22%, p = 0.026) in the CAA group. No anticoagulants were allowed.ConclusionALZ‐801 showed no ARIA‐E in prior AD studies allowing its evaluation in the high‐risk APOE4/4 homozygotes. This pivotal APOLLOE4 Phase 3 trial of ALZ‐801 enrolled homozygous APOE4/4 subjects with higher CAA burden than anti‐amyloid antibody trials. The APOE4/4 CAA subjects were older with more advanced AD and higher rates of CAD and antiplatelets use than non‐CAA subjects, which may increase brain edema and microhemorrhage risk, requiring heightened vigilance with anti‐amyloid antibodies. If this Phase 3 trial is positive, ALZ‐801 could become a potentially safer alternative to anti‐amyloid antibodies for this population. The Phase 3 results are expected in 3Q 2024.