bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compensatory versus Rehabilitative Dysphagia Management Approaches are More Frequently Recommended in Hospitalized Persons with Alzheimer’s Disease and Related Dementias
Authors: Robison Raele Donetha , Broadfoot Courtney , Gustafson Sara , Yee Joanne P. , Burdick Ryan , Butz Nicole , Gilmore‐Bykovskyi Andrea L , Kind Amy J. , Rogus‐Pulia Nicole M. 
Published: December 2023

AbstractBackgroundPersons with Alzheimer’s disease and Related Dementias (AD/ADRD) frequently develop difficulty swallowing (dysphagia). Two general categories of dysphagia management approaches are initiated by Speech‐Language Pathologists (SLP): compensatory (e.g., modifying fluid/food characteristics) and rehabilitative (exercise‐based). While compensations may improve swallowing safety (no airway invasion) and efficiency (no residue) in the short term, they do not actively target swallowing muscles (e.g. rehabilitative approaches) to induce lasting change in physiology. Additionally, compensatory recommendations are often based on clinical examinations (Desai, 2020) that do not permit visualization of swallowing possible with instrumental assessment (e.g. videofluoroscopic swallow study, ‘VFS’) which may lead to recommendations that are misaligned with swallowing physiology. This study aimed to elucidate whether the frequency of compensatory versus rehabilitative recommendations differs based on VFS findings. Specifically, we sought to characterize: 1) dysphagia management recommendations and 2) VFS findings contributing to these recommendations in a cohort of hospitalized patients with AD/ADRD.MethodThe retrospective sample included all inpatients (n = 122) with AD/ADRD (≥50 years) referred for a VFS at an academic hospital in 2014. AD/ADRD was determined by a diagnosis in the EHR and/or if the patient was taking medication(s) prescribed for AD/ADRD. Dysphagia management recommendations and VFS outcomes including swallowing safety (Penetration‐Aspiration Scale (Rosenbek, 1995) ‘PAS’ scores), efficiency (oropharyngeal residue), and biomechanical impairments (as identified by the SLP) were abstracted from the EHR. The absence (PAS scores 1,2, or 4) or presence (PAS scores 3,5,6, 7, or 8) of airway invasion was further classified (Steele, 2017). Descriptive statistics were calculated to analyze the data.ResultAll recommendations were compensatory with no rehabilitative treatments offered (Table 1). Across recommendations, pharyngeal phase impairments (e.g., pharyngeal delay) and inefficiency (e.g., vallecular residue) on VFS were more common than oral phase impairments/inefficiency. While relatively infrequent, airway invasion was most observed in the pill, solid, and liquid modification groups (Table 2).ConclusionIn this cohort, all dysphagia treatment recommendations were compensatory approaches focused on optimizing swallowing safety and efficiency. While these recommendations were aligned with VFS findings reflecting pharyngeal phase impairments/inefficiency, they highlight a missed opportunity to address swallowing impairments by directly targeting underlying physiology with a rehabilitative approach.
Implementing new technologies to enhance specimen quality and researcher value at the National Centralized Repository for Alzheimer’s Disease and Related Dementias
Authors: Edler Michael C. , Mitchell Colleen M. , Smith Samantha N. , Denton Michael A. , Sullen Katharina , Ayres Elizabeth , Shaffer Trent B. , Bantel Andrew P. , Bever Thomas , Case K. Rose , Schwantes‐An Tae‐Hwi , Nudelman Kelly N. H. , Hobbick Chris C. , Faber Kelley M. , Foroud Tatiana M. 
Published: December 2023

AbstractBackgroundThe National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) was established in 1990 at Indiana University with the mission to support research focused on the etiology, early detection, and development of therapeutics for ADRD. NCRAD has been funded by the National Institute on Aging (NIA) since 1990 and is an integral international resource for clinical information and biological materials. As ADRD research has advanced, NCRAD and the NIA have worked together to expand the number and type of biological specimens available to the research community. NCRAD currently houses DNA, RNA, CSF, plasma, serum, stool, brain tissue, LCLs, PBMCs, fibroblasts and iPSCs from individuals with ADRD and healthy controls. NCRAD and the NIA have invested in technologies to standardize specimen processing, enhance specimen quality, and increase specimen distribution to researchers. Paired with this, all data generated from NCRAD specimens must be made available to other researchers through approved data warehouses.MethodDNA extractions are performed with standardized Chemagen chemistries on the Chemagic360 platform. Genotyping is performed with SNP Type™ assays on Juno™ and Biomark™ platforms. Automated specimen storage is executed by a Hamilton® BiOS M. Biofluid handling and sub‐aliquoting are carried out on Janus®, Biomek, and STARlet liquid‐handling platforms.ResultDNA extraction quality, consistency, and throughput increased after adopting the Chemagic360 platform. Custom SNP fingerprint genotyping of DNA specimens upon intake and distribution ensured specimen identity was not lost due to collection site errors or specimen swaps during processing. Additionally, APOE and LRRK2 G2019S genotyping has provided researchers banking specimens with valuable ADRD‐related genetic information. Automated, high‐density storage has permitted the banking of more specimens, allowing for onboarding of additional studies. Storage automation reduced the handling of specimens that could introduce warming events, contributing to confounding preanalytical variables.ConclusionRecent investments in new technologies have allowed NCRAD to accelerate ADRD research by supporting a broader range of biological specimens, increasing the number of specimens banked, limiting the effects of preanalytical variables, and shortening the time to distribute specimens. The broad availability of NCRAD specimens and the data generated from these specimens, has resulted in over 700 peer‐reviewed publications.
Regional correlation analysis between neuronal metabolism and synaptic density using [18F]FDG and [11C]UCB‐J
Authors: DiFilippo Alexandra H , McLachlan Max , Jonaitis Erin M. , Ennis Gilda E. , McVea Andrew K , Bettcher Brecca , Pasquesi Mary‐Elizabeth , Thor Yer , Davenport Nancy J , Grover Ethan , Hudson Sarah , Barnhart Todd E , Betthauser Tobey J , Engle Jonathan W , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T. 
Published: December 2023

AbstractBackgroundNeuronal hypometabolism measured with [18F]FDG PET scans can be used to identify neurodegeneration as part of the AT(N) (amyloid, tau, neurodegeneration) framework in AD. PET imaging of synaptic vesicle glycoprotein SV2A using [11C]UCB‐J provides an index of synaptic density, which has been shown to decrease during neurodegeneration. The purpose of this study was to examine the regional relationship between neuronal metabolism and synaptic density in participants across the continuum of AD‐related pathology.MethodParticipants were recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study. A subset of 13 participants (Table 1) were selected who had completed cognitive testing, structural MR imaging, and PET imaging with the following: [11C]PiB centiloid (CL) for amyloid +/‐ status, [18F]MK‐6240 SUVR for tau +/‐ status, [11C]UCB‐J DVR for regional synaptic density burden, and [18F]FDG SUVR for regional glucose metabolism. UCB‐J and FDG analysis used a whole cerebellum reference region; PiB and MK‐6240 analysis used cerebellar GM reference regions. Inter‐tracer (UCB‐J/FDG) correlations were performed in Freesurfer‐defined bilateral Braak‐associated ROIs (Medial Temporal Lobe [MTL]: entorhinal cortex, hippocampus, and amygdala; Ventral Temporal Lobe [VTL]: fusiform, lingual, and inferior temporal gyri), signature regions of hypometabolism in AD (posterior cingulate, parietal, and frontal cortices) and a region with only marginal hypometabolism in AD (occipital cortex). Associations were determined using Pearson correlations (r).ResultAll ROIs demonstrate a positive association between FDG SUVR and UCB‐J DVR, with r > 0.7 and p < 0.01 (Figure 1). The occipital, frontal, and posterior cingulate cortices demonstrate the strongest correlations (r = 0.84, 0.83, and 0.81, respectively).ConclusionIn cognitively impaired and unimpaired participants showing varying degrees of β‐amyloid and neurofibrillary tau burden, strong positive correlations are observed in regions associated with AD tau pathology and hypometabolism. Correlations are also observed in regions not typically associated with hypometabolism. This suggests that a relationship may exist between synaptic density and neuronal metabolism in the presence of AD neuropathology.
APOE genotype modifies microglial immunometabolism
Authors: Devanney Nicholas A , Lee Sangderk , Williams Holden C. , Allenger Elizabeth J. , Smith Cathryn T , Segovia Gabriella Morillo , Walsh Adeline E. , Friday Cassi , Golden Lesley R , Morganti Josh M. , Johnson Lance A 
Published: December 2023

AbstractBackgroundMetabolic dysfunction and neuroinflammation characterize Alzheimer’s disease (AD), but it is unclear if these two facets of the disease are linked. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD and is associated with increased neuroinflammation. Recent data from our lab and others show that E4 is also associated with increased aerobic glycolysis. These two findings may be intrinsically linked through the concept of ‘immunometabolism’ ‐ an emerging paradigm that implicates increased glycolysis as a core requirement during pro‐inflammatory activation, whereas increased oxidative phosphorylation is required for anti‐inflammatory responses.MethodPrimary microglia from mice expressing human APOE isoforms were stimulated with a combination of interferon‐γ and tumor necrosis factor‐α, two pro‐inflammatory cytokines implicated in AD. Metabolic responses were measured using the Agilent Seahorse platform and targeted metabolomics. In addition, we performed single‐cell RNA sequencing on brains from APOE targeted replacement mice at 3‐, 10‐, and 18 months of age. APOE targeted replacement mice were also crossed to the 5x Familial Alzheimer’s Disease model and brains were analyzed by spatial transcriptomics.ResultSeahorse revealed increased glycolysis and decreased mitochondrial respiration in E4 microglia. Targeted metabolomics revealed increased lactate and succinate in E4 microglia, metabolites known to accumulate in pro‐inflammatory macrophages. Aged E4 brains were found to harbor a metabolically distinct cluster of microglia that expressed a signature similar to the established ‘disease associated microglia’ (DAM) phenotype, even in the absence of neuropathology. SCENIC regulon analysis linked this cluster to the transcription network of HIF1a. Ongoing experiments targeting the HIF1a pathway seek to correct the E4‐associated increased aerobic glycolysis and excess pro‐inflammatory cytokine secretion.ConclusionOur findings reveal that inflammatory stimulation, age, and amyloid each induce a distinct metabolic response in E4 microglia. The accumulation of lactate and succinate and increased glycolysis in E4 microglia indicate altered metabolic preference conducive to pro‐inflammatory activation, whereas the decreased mitochondrial respiration may preclude effective anti‐inflammatory responses. We propose that this altered metabolism skews E4 microglia towards a phenotype that favors chronic neuroinflammation and neurodegeneration. Thus, reprogramming metabolism in E4 microglia may provide a novel therapeutic avenue for the treatment of AD.
Out‐of‐the box automated computation of cortical thickness of the medial perirhinal cortex does not replace segmentation by hand
Authors: Henzen Nicolas A. , Abdulkadir Ahmed , Reinhardt Julia , Blatow Maria , Kressig Reto W. , Krumm Sabine 
Published: December 2023

AbstractBackgroundCortical thickness of the medial perirhinal cortex (mPRC) is a promising marker of early, potentially pre‐clinical Alzheimer’s disease (AD) because atrophy of this region is causally linked to intracellular neurofibrillary tangles. Neurofibrillary pathology, a major neuropathological characteristic of AD, typically starts in the mPRC, also referred to as the transentorhinal cortex. From there it spreads to the entorhinal cortex and eventually to the hippocampus. To date, no tools exist that automatically compute the cortical thickness of the mPRC, most likely because of the novelty and complexity of the manual segmentation protocol and the large variability of the morphology of the mPRC. Herein, we aimed to develop an automated segmentation algorithm for the mPRC.MethodAn experienced rater (SK) manually segmented the mPRC from two data sets (train: n = 103; test: n = 44) using the FreeSurfer segmentation tools. The train data set (mean age = 76.4 ± 7.0 years; normal controls and patients with AD) was used to train the native FreeSurfer segmentation algorithm with the custom region as well as a voxel‐based deep convolutional neural network based on nnUNet with minimal adaptations to the training protocol. In a next step, the trained models were applied to the test data set (mean age = 69.2 ± 10.4 years; normal controls, AD, major depression, and mild cognitive impairment or dementia due to other etiologies than AD) and cortical thickness values were extracted. Finally, cortical thickness values of both segmentations were compared individually to the manual segmentation.ResultsIntraclass correlation coefficients (ICCs) between FreeSurfer and the manual segmentation reached .768 for the left hemisphere (lh) and .835 for the right hemisphere (rh). The deep learning method compared to the manual segmentation achieved ICCs of .840 for lh and .896 for rh.ConclusionThe deep learning based procedure outperformed the native FreeSurfer segmentation in this complicated segmentation task. Nevertheless, it did not reach inter‐human reliability (SK vs. unexperienced rater (NAH): lh = .953 and rh = .986). Next steps are customization of the deep learning algorithm and validation of clinical usefulness.
Immune regulatory roles for Kv1.3 channels in Microglia in Alzheimer’s Disease
Authors: Bowen Christine A , Lin Young Qingyang , Zeng Hollis , Nguyen Hai Minh , Xiao Hailian , Kumar Prateek , Duong Duc M. , Espinosa‐Garcia Claudia , Wulff Heike , Seyfried Nicholas T , Rangaraju Srikant 
Published: December 2023

AbstractBackgroundIn Alzheimer’s Disease (AD), a sub‐population of disease associated microglia present increased Kv1.3 channel abundance. Pharmacological blockade of Kv1.3 reduces Aβ pathology and dampens pro‐inflammatory function of microglia. To identify Kv1.3‐regulated neuroinflammatory mechanisms in microglia, we examined the interactome of Kv1.3 channels in vitro, and Kv1.3 deletion and inhibition in vivo.MethodsTurboID, a proximity‐dependent biotin ligase, was fused to the N‐term or C‐term of Kv1.3 and transduced in BV2 microglia. Kv1.3 and TurboID presence and activity were confirmed via qPCR, electrophysiology, flow cytometry, and western blot. Mass spectrometry(MS) of biotinylated proteins, under resting and lipopolysaccharide(LPS)‐treated conditions, identified Kv1.3 interactomes. Kcna3(Kv1.3)‐floxed mice were generated and crossed to CMV‐Cre mice for global Kv1.3 deletion. Three and six month old 5xFAD mice were treated with PAP1, a small molecule intracellular blockade of Kv1.3, for three months. At nine months of age behavioral tests were performed. Aβ pathology was evaluated using ELISA and Immunofluorescence. Brain nuclei were isolated for snRNAseq. CSF, plasma, and brain were processed for MS.ResultsProteomics of BV2‐Kv1.3‐TurboID microglia identified distinct N‐term (n = 991) and C‐term Kv1.3 (n = 849) interactors. Kv1.3 N‐term interacts with plasma membrane proteins (e.g. Cars1, Psma2) and mitochondrial trafficking proteins (Timm23). C‐term interactors were modified by LPS‐stimulation (C3, STAT1, Oasl1) (n = 36), and partly dependent on a PDZ‐binding motif (Snx3, ND3, n = 70). Predicted by MS, western blot confirmed mitochondrial Kv1.3 presence. In vivo global Kv1.3 deletion was verified by qPCR. 9month 5xFAD mice with the Kv1.3 blockade show a reduction in Aβ pathology and a rescue of fear conditioning. Brain cell type‐specific and tissue‐level effects of Kv1.3 blockade will be evaluated by snRNAseq and MS.ConclusionsWe identified N and C‐term domain‐specific and context‐dependent interactors of Kv1.3 channels in microglia, including several pro‐inflammatory C‐term interactors. We developed and validated a novel Kv1.3‐floxed line for global, and conditional, Kv1.3 deletion studies in mouse models of AD pathology. Kv1.3 blockers reduce Aβ pathology and correct behavioral deficits in 5xFAD mice. The transcriptomic and proteomic studies of brain and biofluids from this cohort will provide mechanistic insights and identify novel biomarkers of therapeutic efficacy of Kv1.3 blockers.
Relationships between AD‐related neuroanatomy and cognitive, physical, and social aging in vervet monkeys
Authors: Frye Brett M. , Negrey Jacob D. , Craft Suzanne , Register Thomas C. , Baxter Mark G. , Jorgensen Matthew J. , Kim Jeongchul , Barcus Richard A. , Whitlow Christopher T. , Shively Carol A. 
Published: December 2023

AbstractBackgroundIn humans, social integration wanes with age, a pattern hypothesized to stem from cognitive or physical decrements. Social isolation increases dementia risk. Nonhuman primates provide important translational opportunities to study brain‐body relationships that may promote healthy or pathological aging. Vervet monkeys (Chlorocebus sabaeus), like humans, have complex central nervous systems and naturally experience cognitive, functional, and neuroanatomical changes with age. These changes often recapitulate characteristics of early Alzheimer’s disease (AD), including Aβ accumulation in the brain, reduced CSF Aβ, and greater Aβ plaque burdens accompanied by reduced brain volumes.MethodWe studied 25 females, aged 8‐29 years (middle to very old‐aged), living in long term, stable, social groups. Using a cross‐sectional study design, we tested whether cognitive (executive function and working memory) or physical (gait speed) function mediated the effects of age on social behavior. We also used T1‐weighted structural MRI to test whether the cortical thickness of an AD‐signature region of interest (“meta‐ROI”) predicted social participation at one year follow‐up.ResultCognitive (executive function: b = ‐0.603; p = 0.038; working memory: b = ‐0.537; p<0.001) and physical (gait speed: (b = ‐1.005; p = 0.043) function were negatively associated with age. Time spent in affiliative behavior was inversely related to age (b = ‐0.723; p = 0.009), whereas time spent alone was higher for older‐aged monkeys (b = 0.723; p = 0.009). Time spent grooming others decreased with age (b = ‐0.217; p<0.001), but time receiving grooming did not (b = ‐0.057; p = 0.333). The number of social partners groomed diminished in aged subjects (b = ‐0.145; p<0.001). The relationships between age and sociality were mediated, in part, by cognitive function: higher degrees of executive function had a positive mediating effect on time spent in grooming interactions (b = 0.120; p = 0.047). Conversely, social participation was not mediated by physical performance. Finally, thinner cortices in the meta‐ROI predicted greater social isolation (t = ‐2.199; p = 0.038) and fewer numbers of social partners (z = ‐2.319; p = 0.020) at one year follow‐up.ConclusionThese results suggest that: 1) cognitive, physical, and social function of vervets decline with age like humans; 2) aging vervets are not socially excluded but decreasingly engage in social behavior; and 3) cognitive deficits stemming from cortical gray matter deficits may underlie the relationship between aging and social decline.
Sleep Disturbances predict cognitive decline in cognitively healthy adults
Authors: Mattos Meghan K , Zawar Ifrah , Manning Carol A , Quigg Mark S 
Published: December 2023

AbstractBackgroundSleep disturbances, including insomnia, poor sleep quality, and sleep fragmentation, are implicated in the development and progression of Alzheimer’s disease and related dementias in older adults. However, the effect of sleep disturbances on lifespan in those with cognitive impairment has not been studied independently from other neuropsychiatric symptoms such as disinhibition. The purpose of this study was to determine if sleep disturbances predict increased risk of earlier mortality across cognitive status (e.g., normal, mild cognitive impairment [MCI] and dementia) and risk of mortality independent from other neuropsychiatric symptoms known to predict dementia.MethodThe National Alzheimer’s Coordinating Center database was used to evaluate the mortality risk conferred by nighttime behaviors as determined by the neuropsychiatric inventory questionnaire (NPI‐Q). The effect of nighttime behaviors was used as a surrogate for sleep disturbances at the participant’s baseline assessment. Based on previous work, cognitive status was stratified by normal cognitive, MCI, and dementia using Montreal Cognitive Assessment scores. Covariates of age, sex, education, race, and other NPI‐Q items on mortality risk were analyzed using Cox regression.ResultThe sample was comprised of 31,288 participants, of whom 10,329 (33%) died during follow‐up and lasted a median [interquartile range] of 56.5 [30.2 – 88.8] months for deaths and 39.5 [23.1 – 75.1] months for survivors. One‐fifth of patients (n = 6509) experienced nighttime behaviors (e.g., nighttime awakenings). Worse cognitive status, older age, female sex, lower education, and increased neuropsychiatric burden increased mortality risk (ps≤.02). However, when explored independently, nighttime behaviors were found to predict earlier mortality (hazard ratio [HR]: 1.11 95% CI: [1.06,1.16], p<.001).ConclusionFindings expand on current evidence that the cross‐sectional prevalence of sleep disturbances increases with worsening cognition. Sleep disturbances predicted a higher risk of mortality while controlling for other variables. Potential mechanisms by which sleep disturbances may play a role in cognitive impairment or earlier mortality should be explored, including circadian rhythm disturbances and alteration in homeostatic and motivational processes.