bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomics identification of novel proteins dysregulated in Alzheimer’s Disease with potential as blood‐based biomarkers and related to Amyloid‐Beta Plaques
Authors: Montero‐Calle Ana , Coronel Raquel , de los Ríos Vivian , Fernández‐Aceñero María Jesús , Peláez‐García Alberto , Martínez‐Useros Javier , Mendes Marta L. , Liste Isabel , Barderas Rodrigo 
Published: January 2025

AbstractBackgroundDespite being the most common cause of dementia worldwide, the mechanisms underlying the progression of Alzheimer’s disease (AD) are not clear and effective treatments are still needed. Hence, further investigation regarding the pathogenesis of AD is required, which might allow for a better understanding of the disease, as well as for an early diagnosis of AD, thus improving the clinical management of AD patients. Here, to identify key proteins in AD pathogenesis, we performed two proteomics strategies, TMT (Tandem Mass Tags) 10‐plex quantitative proteomics and LFQ (Label Free Quantification).MethodFor the TMT analysis, proteins were extracted from frozen left prefrontal cortex brain tissue samples from AD at Braak IV‐VI, and from VD (vascular dementia) and FTD (frontotemporal dementia) patients, and healthy individuals as controls, trypsin digested, differentially labeled with the TMT reagents, and analyzed by tandem mass spectrometry coupled to liquid chromatography (LC‐MS/MS) using a Q‐Exactive mass spectrometer. For the LFQ analysis, a pull‐down with in vitro synthesized Abeta (Amyloid‐beta) fibers incubated with protein extracts from AD patients and healthy individuals was performed, and interacting proteins were analyzed on a Q‐Exactive. Proteomics data were analyzed with MaxQuant and the R program to identify dysregulated proteins.ResultAmong the 3281 proteins quantified by TMT, 15 and 154 proteins were found statistically significant ≥1.5‐fold upregulated and downregulated in AD patients in comparison to controls, respectively. After bioinformatics analysis, 10 candidate dysregulated proteins in AD were selected for further validation by orthogonal techniques to elucidate their role as tissue‐ or blood‐biomarkers, using tissue and plasma samples of AD patients and controls. Regarding the pull‐down, 332 proteins were identified as potential interactors of Abeta fibers, with 23 out of them selected for validation by WB and immunofluorescence.ConclusionThe dysregulation of selected targets in AD patients was confirmed at protein level in a different cohort of tissue samples. Importantly, two proteins showed potential as blood‐based diagnostic biomarkers of AD, and eighteen candidate proteins were validated as novel Abeta plaques interactors, highlighting a major role of these proteins in AD development and progression.
Machine learning‐based classification of aMCI and non‐aMCI using gait and MRI‐based characteristics
Authors: Kim Yeo Jin , Park Ingyu , Lee Sang‐Kyu , Choi Hui‐Chul , Ahn Moo‐Eob , Ryu Ohk‐Hyun , Jang Daehun , Lee Unjoo 
Published: January 2025

AbstractBackgroundIn patients with mild cognitive impairment (MCI), the presence or absence of memory deficits is associated with divergent clinical presentations, etiologies, and prognostic outcomes. These differences may also manifest in additional neurologic signs beyond cognitive impairments and are often reflected in distinct magnetic resonance imaging (MRI) profiles. Gait is one of the clinical characteristics that reflects brain function along with cognitive function. Therefore, we aim to distinguish between amnestic MCI (aMCI) and non‐aMCI (naMCI) using gait and MRI‐based biomarkers.MethodEighty patients diagnosed with MCI from three dementia centers in Gangwon‐do, Korea were recruited for this study. We defined MCI as having a Clinical Dementia Rating global score of 0.5, with a memory domain score at or above 0.5. All participants underwent the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) assessment for cognitive evaluation, gait assessment using GAITRite electronic walkway system and brain MRI. Based on CERAD, individuals with a verbal memory delayed recall score at or below ‐1.0 standard deviation from the norm were classified as aMCI, while those with scores higher than this threshold were categorized as naMCI. We trained a machine learning model using gait and MRI data parameters.ResultThe CNN resulted in the best classifier performance in separating aMCI from naMCI; its performance was maximized when only feature patterns that included GAIT set were used. (accuracy = 0.99 ± 0.04) The standard deviation of stride velocity and the standard deviation of stride length were the strongest predictors. Subsequently, machine learning analyses using the GAIT + WM data set (accuracy = 0.96±0.07) and the GAIT + GM dataset (0.95±0.08) demonstrated high accuracy.ConclusionMachine learning using GAIT data set achieved the highest accuracy in distinguishing between aMCI and naMCI.
Alterations in brain structure and functional connectivity associated with hearing loss and olfactory loss
Authors: Phillips Natalie , Best Paul T. , Grant Nicole , Kabir Ameera 
Published: January 2025

AbstractBackgroundSensory loss in hearing, vision, and olfaction are highly prevalent in older adults and are each associated with a higher risk of developing dementia. This study sought to identify the extent to which these sensory factors are associated with alterations in brain function and structure older adults with or at risk for dementia. We examined groups who range from relatively low risk (those with normal cognition and no cognitive complaints (NC)), to those with higher risk, namely individuals with subjective reports of cognitive decline (SCD) but normal cognition and those with mild cognitive impairment (MCI).MethodWe used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study (Release 7). Hearing loss was assessed with a pure‐tone screening protocol, vision was assessed with the MARS test for contrast sensitivity, and olfaction was assessed with the Brief Smell Identification Test (BSIT). We examined the frequency of sensory deficits in 128 NC (mean age = 69 years; mean education = 16 years), 135 participants with SCD (age = 70; education = 17), 241 with MCI (age = 72; education = 16), and 93 with Alzheimer’s disease (AD, age = 75; education = 15). Participants were matched on age and education, except for AD participants who were older.ResultsAs shown in Figure 1, normal sensory performance in all three modalities was observed in the minority of participants and decreased in prevalence across the dementia risk spectrum groups (e.g., NC: 29%; SCD: 29%; MCI: 11%; AD: 2%). Olfactory deficits (hyposmia or anosmia) were the most frequent (ranging from 45% in NC to 61% in AD), followed by hearing impairment, and then deficits in visual contrast sensitivity. Deficits in multiple sensory domains were highly prevalent, with 37% of participants with AD having deficits in two or more domains. Preliminary analyses indicate that hearing loss is associated with altered connectivity in the default mode network in MCI participants and olfactory loss is associated with reduced hippocampal volumes in SCD.ConclusionThese analyses indicate that sensory loss is highly frequent and co‐morbid in persons with or at risk for dementia. These findings have implications for cognition, brain function, functional activities, and care delivery for persons with or at risk for dementia.
Addressing the Unmet Hearing Care Needs of Persons Living with Cognitive Impairment: A Qualitative Study of End‐Users, Care Partners, and Experts
Authors: Nieman Carrie L , Blinka Marcela D , Hope Peter , Lee Paul , Tu Xueting , Wang Natalie , Yasar Sevil , Oh Esther S 
Published: January 2025

AbstractBackgroundHearing loss is highly prevalent and can have significant consequences for older adults aging with cognitive impairment. However, few older adults use hearing aids and disparities in care exist by race, ethnicity, and socioeconomic position.To understand the intersection of hearing loss and cognitive impairment with the ultimate goal of developing an affordable, accessible hearing care intervention responsive to the needs of end‐users, a series of semi‐structured interviews was conducted.MethodWe conducted 20 semi‐structured interviews with 10 participants with mild cognitive impairment (end‐users) and their 10 care partners and 9 experts. End‐users were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center. Experts were identified professionals with expertise in dementia, hearing, neuropsychiatric symptoms, healthcare delivery, intervention development, and program implementation and dissemination. We used a heterogeneous purposive sampling to recruit participants from diverse race/ethnicities, education, and income levels. Qualitative content analysis was used to identify themes related to the impact of hearing loss on work, relationships, family life, and neuropsychiatric symptoms along with considerations for the development of a hearing care intervention.ResultAmong end‐users and care partners, 30% self‐identified as African American, 45% as male, and 40% reported less than a college degree (Table 1). End‐users and care partners identified barriers to accessing hearing care, including the stigma associated with hearing loss, the cost of hearing aids, the lack of availability of hearing care, and the participants’ denial of hearing difficulties (Table 2). Suggested facilitators for improving access to hearing care include more affordable hearing aids and incorporating hearing screenings into routine medical care. The participants’ desire to improve communication and care partner support motivate accessing hearing care. Measures of hearing intervention success include strengthened social connections, reduced tension with care partners, and increased social activity. Experts emphasize the importance of education on hearing and dementia, the role of care partners, minimizing burden, and reliance on practical, affordable technology.ConclusionIn a diverse sample of persons living with cognitive impairment, their care partners, and experts, participants identified unique barriers, facilitators, motivators, and measures of success to guide the development of an affordable, accessible hearing care intervention.
Effect of hearing intervention on three‐year change in brain morphology
Authors: Pike James Russell , Huang Alison R , Deal Jennifer A. , Reed Nicholas S , Burgard Sheila , Chisolm Theresa , Couper David , Glynn Nancy W. , Gmelin Theresa , Goman Adele M , Gravens‐Mueller Lisa , Hayden Kathleen M. , Mitchell Christine , Pankow James , Sanchez Victoria A , Schrack Jennifer A , Albert Marilyn S. , Jack Clifford R. , Knopman David S. , Coresh Josef , Lin Frank R ,   ACHIEVE Collaborative Research Group
Published: January 2025

AbstractBackgroundPrior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.MethodThe ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.ResultAt baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).ConclusionHearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.
Emotional Distress Following Amyloid PET Disclosure: A Preliminary Analysis Across Cognitive Spectrum
Authors: Kim Jeong Eun , Ren Dianxu , Cohen Annie , Lopez Oscar L. , Lingler Jennifer H 
Published: January 2025

AbstractBackgroundGaining insight into the emotional consequences of disclosing amyloid Positron Emission Tomography (PET) results is essential for offering effective support to patients of varying cognitive status. This analysis aimed to examine variations in emotional distress levels following the disclosure of amyloid PET results among participants that are cognitively normal, with Mild Cognitive Impairment (MCI), or dementia.MethodThis investigation was a preliminary analysis of 55 participants, using 1‐month follow‐up call data of an ongoing brain imaging data repository study, obtaining baseline PET imaging on a subset of Alzheimer’s Disease Research Center (ADRC) participants. Multiple linear regression modelling was used to examine the relationship between emotional distress scores, measured by Impact of Genetic Testing questionnaire modified for amyloid PET disclosure, and diagnostic categories, while controlling for participants’ sex, age, level of education, and amyloid status. Additionally, pairwise comparisons were conducted to examine specific differences between diagnostic categories. Bonferroni correction was applied to adjust for multiple comparisons.ResultParticipants were predominantly White (94.5%), Non‐Hispanic (94.5%), highly educated (average of 16.6 years) individuals, with a mean age of 70.8. Of the 55 participants, 13 were cognitively normal, 17 with MCI, and 25 diagnosed with dementia. Approximately 54% were amyloid negative. During the 1‐month follow‐up call, participants exhibited a mean depression score (measured by Center for Epidemiological Studies Depression Scale) of 6.93 (SD = 7.57) and a mean anxiety score (measured by Spielberger State‐Trait Anxiety Inventory) of 28.55 (SD = 10.56). Participants’ diagnostic categories were marginally significantly associated with their emotional distress scores post disclosure (b = 4.945, SE = 2.577, p = 0.062). However, individual diagnostic categories revealed a positive direction in mean emotional distress scores: normal cognition (M = 7.320, SE = 4.306), MCI (M = 16.955, SE = 3.382), and dementia (M = 18.572, SE = 2.791).ConclusionThese preliminary findings suggest that the disclosure of amyloid PET results does not result in discernible differences in the level of emotional distress among cognitively symptomatic and asymptomatic individuals. This contributes to our understanding of the emotional impact of amyloid PET disclosures and may have implications for counseling and support strategies in the context of Alzheimer’s disease research and clinical settings. Further investigation with a larger sample size is recommended to validate these findings.
Mitochondrial replenishment as a treatment for Alzheimer’s Disease
Authors: Baudo Gherardo 
Published: January 2025

AbstractBackgroundFindings have demonstrated that mitochondrial dysfunction is vital to Alzheimer’s Disease (AD) pathogenesis and progression. This study explored an innovative treatment strategy involving transfer of polymer‐functionalized, healthy mitochondria to AD neurons. We hypothesized that this organelle transplantation approach would restore mitochondrial function and bioenergetics, preventing aberrant neuronal dynamics associated with AD.MethodNeuronal cells (SH‐SY5Y) were stimulated with amyloid‐β (Aβ1‐42). Mitochondria were functionalized with dextran‐triphenylphosphonium (Dex‐TPP/Mt) and administered to neurons. Internalization of Dex‐TPP/Mt was assessed, as was the effect of mitochondrial transfer on Aβ‐treated SH‐SY5Y cell ROS levels, mitochondrial membrane potential, mitochondrial dynamics, ATP levels, and apoptosis.ResultDex‐TPP/Mt underwent efficient internalization into Aβ‐treated SH‐SY5Y cells. The treatment reduced intracellular ROS levels and restored mitochondrial membrane potential. Mitochondrial quality control was also re‐established, as mitochondrial fusion and fission processes were balanced and mitophagy reduced. Dex‐TPP/Mt treated neurons also increased ATP levels. Notably, mitochondrial transfer modulated the Bax/Bcl‐2 ratio, inhibited caspase‐3 activation, and suppressed the pJNK pathway, highlighting reduced neuronal apoptosis that was confirmed by Annexin V assay.ConclusionMitochondrial transfer has potential as a therapeutic approach for AD. The treatment highlighted herein effectively mitigated the impact of Aβ on neuronal health by targeting mitochondrial dysfunction and oxidative stress. This opens several avenues for similar strategies aimed at addressing dysregulated bioenergetics and mitochondrial dynamics in AD.
Selective expression of HSP27 in cortex and hippocampus offers insights of TDP‐43 and APOE interaction
Authors: Abeer Muhammad I , Gitcho Michael A. 
Published: January 2025

AbstractBackgroundAggregation of transactive response DNA binding protein 43 (TDP‐43) is the major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, in up to 50% of Alzheimer’s disease (AD) cases TDP‐43 pathology was discovered and this pathology has been referred to as limbic‐predominant age‐related TDP43 encephalopathy (LATE). Several studies reported that TDP‐43 binds to heat shock protein family B (small) member 1 (HSPB1 or HSP27) but no functional evaluation of this interaction has been explored. Inducing expression of HSP27 has been shown to be protective of many other disease conditions and has been shown to reduce aggregation of amyloid in AD. In general, the goal is to utilize both primary neuronal cultures and mice that are selectively expressing pathogenic TDP‐43, HSP27, and apolipoprotein E (APOE) in the brain to characterize the effect of HSP27 overexpression on TDP‐43 and APOE. This will give us a better model to understand TDP‐43 proteinopathies. In the present study, we hypothesize that increased expression of HSP27 may reduce TDP‐43 aggregation and alter mitochondrial morphology.MethodA new transgenic mouse model was developed to selectively drive human HSP27 and pathological TDP‐43 with a defective nuclear localization signal (DNLS) in the hippocampus and neocortex using the Ca2+/calmodulin protein kinase (Camk2a) tetracycline inducible system. The following genotypes have been evaluated for immunohistochemistry, biochemistry (solubility fractionation), and Western blot: wild‐type, Camk2a/DNLS, Camk2a/HSP27 and Camk2a/HSP27/TDP43DNLS at 4 months of age.ResultPreliminary in vitro results show that cells overexpressing HSP27 reduce aggregation and protein levels of TDP43. However, mice overexpressing HSP27 in a TDP43DNLS background in the hippocampus and cortex does not show any reduction in the soluble fraction. Interestingly, increased expression of HSP27 in the hippocampus of Camk2a/HSP27 mice showed a significant reduction of endogenous APOE expression. Immunohistochemical and bioenergetic experiments are currently being carried out to evaluate the brain and mitochondrial morphology upon HSP27 overexpression.ConclusionOverall, our initial data suggests that modifying HSP27 expression modulates endogenous APOE level.
Cognitive Complaint, Mild Cognitive Impairment, and Mild Behavioral Impairment as Predictors of Dementia or Alzheimer’s Disease in a Population‐Based Sample: The Cache County Study
Authors: Herd Ryan C. , Mills Maddy , Hammond Alexandra G. , Gonzalez Hector L. , Drewel Mikaela , Rattinger Gail B. , Tschanz JoAnn T. 
Published: January 2025

AbstractBackgroundMild Cognitive Impairment (MCI) and Mild Behavioral Impairment (MBI) represent transitional states between normal aging and incipient dementia. We examined whether presence of cognitive complaint (CC), MCI, and MBI differentially predicted risk for all‐cause dementia or Alzheimer’s disease (AD) in a population‐based sample.MethodParticipants included 598 older adults [55% female, with mean (SD) age = 78.84 (7.51) years] without dementia at baseline of the Cache County Study on Memory in Aging. All completed a clinical assessment and were followed in subsequent waves until dementia diagnosis or non‐participation, for a maximum follow‐up time of 12 years. MCI classification was based on neuropsychological assessment with test scores falling 1.5 SD < mean on a single measure or 1.0 SD < mean on multiple measures per cognitive domain, according to aged‐based norms. CC was based on informant report of difficulties in memory, orientation, judgment, social functioning, home‐based activities, language, and recognition of others. MBI was based on the Neuropsychiatric Inventory (NPI), supplemented with informant interview. Participants were categorized as positive/negative for CC, MCI, or MBI only, or in combination; those negative on all three attributes served as the reference category. Separate Cox regression models examined CC‐MCI‐MBI status and time to all‐cause dementia/AD or right censoring, covarying age, sex, education, and APOE ε4 status.ResultOne hundred fifty‐six individuals developed dementia (118 AD). Compared to the reference category, MCI only [Hazard Ratio HR (95% CI) = 3.51 (1.49 – 8.22)], CC+MCI [HR (95%CI) = 5.24 (2.33 – 11.79), CC+MBI [HR (95%CI) = 5.29 (1.96 – 14.32)], MCI+MBI [HR (95%CI) = 4.31 (1.24 – 14.94), and CC+MCI+MBI [HR (95%CI) = 17.11 (7.58 – 38.65)] were associated with increased risk of dementia whereas MBI only or CC only was not. For AD, results were similar, except that MCI+MBI was not associated with increased risk (p = .165).ConclusionThe presence of MCI with or without cognitive complaint or in combination with MBI predicted future AD or all‐cause dementia. However, MBI was predictive only in combination with cognitive complaint/MCI. These results emphasize the importance of conducting both cognitive and behavioral assessments to buttress reports of cognitive concerns.