bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discussion and Documentation of Hearing Difficulty by Providers in the Presence of Cognitive Concerns‐ study of the Medicare Annual Wellness Visit and Medial Record
Authors: Powell Danielle , Nothelle Stephanie , Smith Jamie , Oh Esther S , Reed Nicholas S , Wolff Jennifer 
Published: January 2025

AbstractBackgroundHow clinicians discuss, document, and diagnose health concerns within a visit shapes patient perceptions of their health conditions. Undiagnosed hearing loss among older adults with dementia or cognitive concerns may exacerbate neuropsychiatric symptoms and care challenges. This study investigates clinician documentation of hearing concerns and whether documentation, diagnosis, and referral vary for older adults with dementia/cognitive concerns.MethodWe use patient‐level health and demographic information from the electronic medical record and associated clinician visit notes for Medicare beneficiaries who indicated hearing concerns for the first time at an Annual Wellness Visit (AWV) between 2017‐2022 at a large academic health system. We analyzed the text of a random sample of AWV clinical notes to evaluate clinical documentation of hearing concerns/loss and placement of hearing‐related referrals. Logistic regression models investigate odds of clinician documentation of hearing concerns or diagnosis by diagnosed dementia (from ICD codes) or cognitive concerns (from AWV health risk assessment).ResultAmong 2,593 beneficiaries who reported hearing concerns at an AWV (mean age 78.8 years, 56.6% female), 6.5% had a concurrent dementia diagnosis, nearly 40% indicated congruent cognitive concerns, and 20% had a prior diagnosis of hearing loss in the medical record. Text analysis (Table 1) of clinician visit notes from a random sample of patients (n = 474) found hearing concerns were less frequently documented for those with (versus without) diagnosed dementia (44.2% vs 30.2%). Clinicians were half as likely to comment on hearing (OR:0.51; 95%CI:0.34,0.76) or indicate known hearing loss in the AWV note (OR:0.56; 95% CI:0.38,0.84) for those with vs. without dementia (Table 2). Regardless of dementia status, about 8‐10% were recommended/received a referral to hearing care; only 50% with index hearing concerns received a diagnosis of hearing loss in the medical record following the AWV.ConclusionClinicians are less likely to document hearing concerns and incorporate hearing concerns as a health problem at the AWV for patients with dementia. The complex care needs of dementia may inhibit clinician ability to attend to other patient health concerns‐ like hearing. Opportunity to embed hearing and communication educational interventions which support clinicians in addressing patient‐collected health risks can improve overall dementia care.
Path integration deficits are related to Alzheimer’s disease pathology
Authors: Colmant Lise , Boyer Emilien , Gérard Thomas , Huyghe Lara , Quenon Lisa , Kunz Lukas , Axmacher Nikolai , Lefèvre Philippe , Hanseeuw Bernard J 
Published: January 2025

AbstractBackgroundThe medial temporal lobe (MTL) is the first cortical region affected by tauopathy in Alzheimer’s disease (AD) and is implicated in spatial orientation. In early AD stages, navigation deficits, including path integration deficits, could be present, even before memory deficits. We investigated whether these deficits were related to AD pathology (amyloidosis and/or tauopathy) using a path integration task, the “Apple Game”.MethodDuring the task, participants navigated through a virtual arena and were asked to return to a starting location after visiting one intermediate location. Two subtasks were tested: with a proximal cue (landmark‐supported path integration, LPI), and without (pure path integration, PPI). We recruited 90 participants (mean age: 69): 66 clinically normal (CN) and 24 patients with mild cognitive impairment (MCI). We classified them according to amyloid status: Aβ+ (n = 34) or Aβ‐ (n = 56) based on amyloid‐PET or CSF measurements. All participants underwent [18F]MK‐6240 Tau‐PET to disclose tau pathology in the MTL (entorhinal cortex and hippocampus). Task performances were analyzed in relation to amyloid status and MTL tauopathy using linear‐mixed‐effect models. First, we evaluated the error according to amyloid status, neuropsychological status, subtask, and their interactions. Then, we evaluated the error and its components (rotation and distance errors) according to MTL tauopathy, and amyloid status for each subtask. Education, gender, and video game experiences were adjusted for.ResultPreclinical AD individuals (CN, Aβ+) had a deficit in pure path integration (p = 0.02) compared to CN Aβ‐ individuals, but not in landmark‐supported path integration (Fig. 1). The amyloid status did not influence performances among MCI patients. Rotation errors depended on MTL tauopathy in PPI (p = 0.02) and LPI (p = 0.0004) (Fig. 2), whereas distance errors depended on age in PPI (p = 0.004), and on the age (p = 0.015) and MTL tauopathy (p = 0.02) in LPI.ConclusionWe detected a specific deficit in pure path integration in a virtual environment, in preclinical AD, suggesting a deficit to integrate self‐motion cues. Furthermore, we decomposed the path integration performances into rotation and distance errors, and found that rotation errors were associated with MTL tauopathy, possibly reflecting impairment of grid cells; whereas distance errors mainly increased with older ages.
A framework for automated speech and language analysis in Spanish‐speaking Latinos
Authors: Garcia Adolfo M. 
Published: January 2025

AbstractBackgroundAutomated speech and language analysis (ASLA) represents a powerful innovation for detecting and monitoring persons with or at risk for dementia. Given its cost‐efficiency and automaticity, its impact can be vital for under‐resourced communities, such Spanish‐speaking Latinos. However, ASLA markers are understudied in this group and may differ from those established in widely studied populations (e.g., English speakers). Here I will describe a novel framework to boost ASLA research among Spanish‐speaking Latinos.MethodWe have created hypothesis‐driven metrics to capture semantic and episodic memory alterations via (semi‐) spontaneous speech in Latinos. Our initial work includes measures of word selection patterns during verbal fluency, speech timing proxies of word retrieval effort, and algorithms quantifying egocentric/exocentric references in discourse. These metrics have been incorporated into the TELL app, our web‐based speech testing platform. Initial analyses have been performed on 60 Latinos with Alzheimer’s disease (AD), 65 with mild cognitive impairment (MCI), and 50 with behavioral variant frontotemporal dementia (bvFTD), including tests of cross‐linguistic generalizability with English speakers.ResultsCompared with healthy controls, AD and MCI (but not bvFTD) patients exhibit atypical vocabulary patterns during verbal fluency tasks, favoring high frequency and conceptually unspecific words, separated by longer pauses. These alterations discriminate between persons with and without these disorders (AD: AUC = .89; MCI: AUC = 81), and they predict atrophy of and hypo‐connectivity among temporo‐parietal regions implicated in semantic memory. Cross‐linguistic generalizability between English and Spanish‐speaking AD patients was maximal (AUC = .79) when based on speech timing features (e.g., pause duration, articulation rate). Finally, bvFTD (but not AD) patients showed abnormally exocentric discourse, with increased reliance on third‐person references and reduced reliance on first‐person references when describing daily activities.ConclusionOur initial findings attest to the usefulness of hypothesis‐driven ASLA features to identify persons with AD, MCI, and bvFTD among the Latino population. The framework will now be leveraged in a large multicentric effort across the ReDLat consortium to establish the most robust markers in large, heterogeneous samples. This work will help us streamline ASLA research as an avenue for more equitable clinical testing of dementia in Latin America and beyond.
Genetic variation of tandem repeats as a cause of Alzheimer’s Disease
Authors: Trujillo Alejandro Martin , Jadhav Bharati , Garg Paras , Altman Gabrielle , Manigbas Celine , Shadrina Mariya , Sharp Andrew J 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a common neurodegenerative disorder affecting >35 million people worldwide. Despite extensive genetic studies, the identified factors only explain a small fraction of the heritable risk of AD. This suggests the contribution of yet‐unknown genetic factors to the development of AD, such as tandem repeats (TRs). TRs are stretches of DNA consisting of two or more contiguous copies of a sequence of nucleotides (motif) arranged in a head‐to‐tail pattern (e.g., CAG‐CAG‐CAG). Recent studies indicate that rare expansions of short tandem repeats (STRs, motif size 1‐10 bp) as well as common copy number variation of variable number tandem repeats (VNTRs, motif size >10 bp) can act as risk modifiers for AD. However, despite this evidence, there has been no comprehensive evaluation of TR variation in large cohorts of AD patients. Therefore, we hypothesize that variation in TR sequences can contribute to the development of AD in a fraction of cases.MethodTo uncover the link between TR variation and AD, we are performing a comprehensive profiling of TR variation using whole genome sequencing (WGS) data generated by the UK Biobank (https://www.ukbiobank.ac.uk/). This involves estimating copy numbers in ∼220,000 polymorphic loci, including 77,000 STRs and 150,000 VNTRs, across ∼349,000 genomes (∼9,000 cases and ∼340,000 unrelated controls) using novel bioinformatic approaches, followed by extensive quality control to ensure the reliability of our estimates. Subsequently, we will use the resulting high‐confident estimates to identify TR alleles that exhibit significantly different copy numbers in AD patients compared to controls.ResultTo date, we have successfully designed efficient pipelines for profiling both STRs and VNTRs using WGS on a large scale to be executed on the UK Biobank cloud‐based environment (https://ukbiobank.dnanexus.com). Using these pipelines, we have generated copy number estimates in approximately 200,000 UK Biobank samples, including ∼1,200 AD cases.ConclusionBy leveraging the power of large cohorts and innovative methods, our study aims to explore the contribution of one of the most abundant and polymorphic, and yet understudied, genetic elements in the genome to AD, expanding our understanding of the genetic risk factors and mechanisms underlying this condition.
The inhibition of necroptosis prevents neuronal death in a mouse model of Alzheimer’s disease pathology
Authors: Moonen Sebastiaan , Koper Marta J , Ronisz Alicja , Ospitalieri Simona , Vegh Zsuzsanna , T’Syen Dries , Rabe Sabine , Staufenbiel Matthias , De Strooper Bart , Balusu Sriram , Thal Dietmar Rudolf 
Published: January 2025

AbstractBackgroundAs neurodegenerative diseases advance, postmitotic neurons are affected by disturbed proteostasis and the accumulation of misfolded proteins. This renders neurons sensitive to cell death, ultimately leading to progressive neuron loss. Multiple studies show the involvement of distinct pathways of regulated cell death (RCD) in neurodegenerative diseases, such as necroptosis. In human AD, activation of necroptosis has been shown to contribute to the neurodegenerative process. However, despite considerable research efforts, it is still not clear which mechanism exactly underlies neuronal loss in AD.MethodsWe studied necroptosis activation in mouse models of AD pathology and primary mouse neurons after the addition of pTau seeds. Immunohistochemistry was used to study neuronal loss and the presence of the activated necroptosis‐related proteins pRIPK1, pRIPK3 and pMLKL. TAU22 and TAU58 mice were used to assess the influence of Tau pathology, APP23 for amyloid pathology, and APP23xTAU58 for both Tau and amyloid pathology, representing more closely human AD neuropathological changes. APP23xTAU58 mice were subjected to intraperitoneal injection of the necroptosis‐inhibiting drugs dabrafenib or ponatinib from two to six months old, followed by neuropathological assessment and behavior testing using the social preference and social novelty test, T‐maze, and fear conditioning.ResultNecroptosis activation was detected in mice developing Tau pathology and in primary mouse neurons stimulated with AD pTau seeds. APP23xTAU58 mice showed the highest necroptosis activation, while no significant upregulation was observed in APP23 mice. The necroptosis‐related proteins (pRIPK1, pRIPK3, pMLKL) were present in neuronal granulovacuolar degeneration (GVD) bodies, predominantly in CA1 and subiculum of the hippocampus, entorhinal cortex, amygdala, parietal and frontal cortex. In the subiculum and amygdala, the number of neurons showing pMLKL‐positive GVD lesions was associated with neuronal loss, as seen in human AD. Both dabrafenib and ponatinib reduced the number of neurons showing pMLKL‐positive GVD bodies, prevented neuronal loss, and ameliorated social recognition memory.ConclusionTaken together, these results point to “GVD‐necroptosis”, as a presumably delayed form of necroptosis, and a mechanism underlying AD pathology‐related neuronal loss. Necroptosis inhibition as shown here in APP23xTAU58 mice is a novel approach to ultimately prevent “GVD‐necroptosis” induced neuronal death.Funding: SAO/FRA and FWO.
The association between tau pathology and later stages of memory processing is mediated by medial temporal lobe atrophy in typical Alzheimer’s Disease
Authors: Wuestefeld Anika , Cui Salena , Das Sandhitsu R. , Xie Long , McGrew Emily , Yushkevich Paul A. , Wisse Laura , Wolk David A ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundTau pathology is closely related to cognitive decline in Alzheimer’s disease (AD). Neurodegeneration is the putative mechanism by which tau leads to cognitive deficits. However, there is limited work on the associations between tau, neurodegeneration, and specific cognitive domains. We investigate potential mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration for different cognitive domains in amyloid‐β‐positive (Aβ+) adults.MethodWe included 325 positron emission tomography (PET) Aβ+ individuals across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (age: 72±8 [55–90]; 51.1% female, education: 16±2 years). Hippocampal volume and cortical thickness were measured from T1‐weighted structural magnetic resonance imaging in typical AD regions (Fig. 1). Using flortaucipir‐PET, tau was quantified for two composite regions (MTL, neocortical). Included cognitive measures are shown in Fig. 1. Mediation analyses between tau‐PET, thickness/volume, and cognition were performed. Cognitive measures were adjusted to isolate the function of interest (Fig. 1).ResultHigher tau‐PET uptake and lower thickness were associated with lower performance on all cognitive measures.In simple mediations, tau‐immediate recall associations were mediated by MTL, parietal, and temporal regions (Fig. 2A). Tau‐delayed recall associations were mediated by MTL regions. Tau‐late recall and tau‐recognition associations were mediated by MTL and parietal regions. Tau‐fluency and tau‐executive functioning associations were mediated by MTL and parietal regions, as well as temporal regions for fluency.Complex mediations investigated significant mediators simultaneously (Fig. 2B+3). Depending if MTL/neocortical tau remained significant when covarying for the other tau measure in a regression, the complex mediation models focused on MTL and/or neocortical regions (Fig. 2B description). Hippocampus mediated the tau‐late recall and tau‐recognition associations. Brodmann area 35 mediated the tau‐delayed recall association. Tau‐fluency was, at a trend level, mediated by inferior temporal thickness. Tau‐executive functioning did not demonstrate a mediation effect, potentially due to limited frontal atrophy. All mediators were partial mediators explaining up to 23% of variance.ConclusionThe results suggest that MTL tau pathology, partially mediated by macrostructural changes, lead to impairments in specific memory domains in early AD. Impairments in fluency and executive functioning, however, seem more likely to follow from tau‐induced effects in neocortical regions.
Commonalities in the lipid profile shift in ApoE ε4 risk variant and mild cognitive impairment highlight acyl chain remodeling
Authors: McIntire Laura Beth , Mares Jason , Costa Ana Paula , Lazarian Artur , Wartchow Krista Minéia , Dartora William , Nuriel Tal , Menon Vilas 
Published: January 2025

AbstractBackgroundAt least one‐third of the identified risk alleles from Genome Wide Association Studies of Alzheimer’s disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. BIN1 which is also known as Amphiphysin 2; and PICALM which are involved in phosphoinositide metabolism and binding rank just below the highest risk gene variant of Apolipoprotein E (ApoEε4), a cholesterol and phospholipid transporter. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, CSF, blood and multiple mouse models of AD. We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of transcriptomics and lipidomics in the Religious Order Study‐Memory Aging Project (ROS‐MAP) as well as models of disease.MethodLipidomic data in ROS‐MAP was generated using the Biocrates AbsoluteIDQ p180 platform, a multiplexed targeted metabolomic assay covering lipids and metabolites including acylcarnitines, glycerophospholipids and sphingolipids. We confirmed global lipid dysregulation of acyl chain remodeling using pharmacological inhibitors of lipid modifying enzymes in cell models overexpressing amyloid precursor protein (APP) and identified similarly dysregulated lipids in an animal model of AD overexpressing APP harboring the Swedish mutation in a targeted lipidomic panel of over 600 lipid species.ResultOur analysis of transcriptomic data from ROS‐MAP lead to identification of multiple genes in the pathway for acyl chain remolding, Lands Cycle, which were associated with cognitive decline independently of amyloid and tau pathologies. Coordinate changes in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and the ApoEe4 genotype which showed a correlated lipid profile shift. WGCNA analysis identified dysregulated lipids within a single module which are substrates and products in the Lands Cycle for acyl chain remodeling.ConclusionOur studies highlight the critical dysregulation of acyl chain remodeling in ApoEe4 carriers and MCI in human brain which could be modeled in mouse and cell models of disease. A coordinated lipid profile shift in both ApoEe4 carriers and MCI suggest pathological changes in lipid metabolism underly early disease and highlight lipid dyshomeostasis as a tractable target for early disease modifying intervention.
Carbonic anhydrase inhibitors (CAIs) decrease cardiac amyloid β pathology, mitigating neuro‐signaling maladaptive remodeling and improving cardiac function in Tg2676‐ AD mouse model
Authors: Elia Andrea , Parodi‐Rullan Rebecca M , Vazquez‐Torres Rafael , Carey Ashley M , Fossati Silvia 
Published: January 2025

AbstractBackgroundFDA‐approved carbonic anhydrase inhibitors (CAIs) have been shown to attenuate Aβ pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), suggesting a key role for CAs as a novel and previously unexplored target for AD therapy. Amyloid β accumulation severely impairs the cerebral neuro‐signaling pathway with a progressive loss in neurotrophic factors (NTFs, i.e., NGF and BDNF), potentially also affecting the cardiac nervous system and culminating in lethal heart dysfunction. Yet, no studies have proposed the use of CAIs for treating and preventing the systemic and cardiac effects of amyloidosis and AD.MethodsHere, we explored for the first time, the protective effects of a chronic CAIs therapeutic regimen against cardiac amyloid pathology, neuronal fibers’ loss, and heart neurotrophic dysregulation in Tg2576 mice, a widely used model of AD and cerebral amyloidosis.ResultsCardiac fibrosis enhancement along with progressive Aβ deposition in the heart seriously affected the cardiac neuro‐signaling pathway culminating in a robust decline of BDNF expression associated with myocardial adrenergic nerve fibers and regenerated nerve endings impoverishment (stained with TH and GAP‐43 respectively) in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. These degenerative mechanisms severely compromised heart function, evidenced by a decline of both ejection fraction and fraction shortening percentage in Tg2576 animals. Accordingly, we observed that human Aβ40 or Aβ42 oligomers’ treatment drastically reduced BDNF and GAP‐43 expression in human neuronal cells and human cardiomyocytes. Notably, long‐term CAIs treatment in Tg2576 mice reduced Aβ accumulation in the heart tissue and reverted cardiac neuro‐signaling pathway adverse remodeling, thus ameliorating heart function, as evidenced through echocardiographic analysis. These in vivo results were validated by in vitro experiments both in neuronal and cardiac cells.ConclusionThese findings suggest a new beneficial role of CAIs in preventing the Aβ‐induced cardiovascular remodeling and neuro‐signaling deregulation for the first time in the Tg2576 model of AD. Taken together with the positive effects of CAIs on cerebrovascular function and cognition, this study paves the way for future clinical trials aimed at repurposing FDA‐approved CAIs to prevent and correct both central and peripheral pathologies induced by AD and amyloidosis.