bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mild parkinsonian signs and incidence of Motoric Cognitive Risk syndrome
Authors: Leroy Victoire , Emmeline Ayers , Verghese Joe 
Published: January 2025

AbstractBackgroundMild parkinsonian signs (MPS) are prevalent in older adults and linked to an increased risk of dementia. However, their association with Motoric Cognitive Risk syndrome (MCR), a pre‐dementia syndrome characterized by slow gait speed and cognitive complaints, is unclear. This study aims to examine the association of MPS with incident MCR.MethodNon‐demented older adults without Parkinson’s disease were monitored annually (average follow‐up 30 months). We excluded participants with MCR at baseline and dementia incidence without previous MCR, as non‐cases. MPS were defined at baseline by the presence of bradykinesia, rigidity, or rest tremor rated by a study clinician using the Unified Parkinson’s Disease Rating Scale (UPDRS). MCR was diagnosed using established criteria at baseline and follow‐up. The association of baseline MPS and incident MCR was examined using survival analysis and reported as hazard ratio and 95% confidence intervals (CI).ResultOf the 580 participants, 227 (39.1%) had MPS and 44 (7.5%) had MCR at baseline. Of the 513 initially MCR‐free participants, 46 (8.9%) developed incident MCR. Incident MCR cases had a higher prevalence of MPS at baseline compared to participants who did not develop MCR (OR adjusted for age, geriatric depression scale (GDS) score, and stroke history = 3.8, 95% CI 1.8‐8.2), particularly bradykinesia (52.3% vs. 19.0%; p<0.001) and rigidity (54.5% vs. 28.1%; p<0.001). They were older (p<0.001), more disabled (p<0.001), and had more strokes (p = 0.005), and depressive symptoms (p<0.001) compared to individuals who did not develop MCR. Participants with MPS at baseline had a greater risk of developing incident MCR (HR adjusted for age, GDS score, and stroke history = 3.7, 95% CI 1.8‐7.7).ConclusionMPS predicted the onset of MCR, suggesting a significant role in the pathogenesis and in improving early assessment of risk for MCR.
Exploring the coding rare variants in Alzheimer’s disease
Authors: Cheng Po‐Liang , Lee Wan‐Ping 
Published: January 2025

AbstractBackgroundPeople leverage single‐variant association test to systematically evaluate common genetic variants (minor allele frequency 0.5% < [MAF) < 5%) for complex disease, such as Alzheimer’s disease (AD). Rare variants (MAF < 1%) could explain additional disease risk and are known to play an important role in the diseases. Unlike common variants, performing traditional single‐variant analysis on rare variants is often underpowered for general study sample sizes. A satisfied power for using single‐variants analysis on rare variants requires extremely large sample sizes that are often economically unaffordable. The alternative method to study the association between AD and rare variants was using aggregative testing that evaluate association for multiple variants in a biologically relevant region, such as a gene. However, the aggregative testing could only determine a set of variants instead of precisely determined the specific causal variant. Therefore, we try to use a new approach to identify coding AD causal variants.MethodWe first explored the case‐only coding rare variants in two independent datasets (ADSP with 16905 whole‐genome‐sequencing samples and ADGC with 38271 genotype samples that imputed by TOPMed). Then, we filtered variants that have at least two carriers in both datasets and CADD > 20. We further utilized STRING to build the protein‐protein interaction network for finding out the relation strength to known AD genes for those variants located in non‐conventional AD genes. Genes of the candidate rare variants were used to construct the protein‐protein interaction network with known AD genes. Non‐conventional AD genes that linked at least to five known AD genes, genes expressed in brain region, or neuron cells were selected and through literature searching to determine as potential novel AD genes.ResultThrough this approach, we identified seven coding rare variants in two known AD genes, SORL1 and CASP7, and in five novel AD genes, W LRP2, SPAG9, LEF1, PI4KA and USH2A. These potentially causal variants of AD could be further validated by biological functional assay in the future.ConclusionThe new approach could help us to explore rare variants and discovered potential novel genes that might contribute large impact in causing AD.
Central auditory abilities are associated with cognitive and structural neuroimaging markers of Alzheimer’s disease dementia
Authors: Lad Meher , Griffiths Timothy , Taylor John‐Paul 
Published: January 2025

AbstractBackgroundHearing loss is associated with cognitive and neuroimaging markers of Alzheimer’s disease dementia but it is unclear how specific measures relate to these after accounting for a range of hearing abilities.Method200 participants (155 cognitively normal, 25 mild cognitively impaired and 20 Alzheimer’s disease dementia) underwent auditory testing (peripheral and central abilities), cognitive testing and MR scanning (structural and diffusion‐weighted sequences) to evaluate the relationship between hearing, cognition and imaging brain measures.ResultCentral auditory measures such as speech‐in‐noise perception and auditory memory for longer durations were associated with cognitive impairment across the Alzheimer’s disease continuum and specific auditory measures were independently associated with morphometric and diffusion‐weighted brain measures.ConclusionAuditory cognition could serve as a unique marker of cognition in Alzheimer’s disease dementia and reflects imaging‐derived brain changes potentially related to neurodegeneration.
Immunotherapy targeting toxic Tau reduces and mitigates cognitive decline, and senescence in a human Tau mouse model
Authors: Al‐Shaebi Fadhl , Senapati Sudipta , Sciortino Alessia , Farag Marina , Samples Madison , Xavier Rhea , Kayed Rakez 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of tau protein in the brain, which forms neurofibrillary tangles and contributes to the gradual deterioration of brain function. As a consequence, cellular senescence occurs, leading to cognitive impairment and hastening the aging process. Immunotherapies targeting Aβ and other protein aggregates are also being developed in the meantime. This study looks at immunotherapy in a Mapt (hTau) mouse model. This could become a useful immunological treatment in the future by lowering inflammation and cellular senescence that come with getting older.MethodMapt (hTau) mice were inoculated in the hippocampus with 1 µg of brain‐derived Tau oligomers (BDTOs) from AD patients. After seven months, mice were injected in the tail vein with 120 µg of in‐house mouse monoclonal anti‐toxic tau antibodies (TTCM1‐2 and TOMA1‐4) or IgG isotype control. Mice were evaluated for cognitive and motor function before euthanasia, and brain neuropathology was investigated with immunohistochemistry, immunofluorescence, and western blot techniques.ResultTreatment with anti‐toxic tau antibodies reduced total tau levels and tau phosphorylation in the brain. Furthermore, immunotherapy reduced inflammation and cellular senescence markers.ConclusionThe observed decrease in tau aggregates following immunotherapy indicates that the mechanisms responsible for tau phosphorylation and/or aggregation may have been altered. Additionally, the decrease in senescence and inflammation markers suggests that immunotherapeutic strategies targeting tau are a promising approach in the management of tauopathies.
Meta‐analysis of NIH Alzheimer’s Disease‐Related Dementias (ADRD) programs responsive to the National Plan to Address Alzheimer’s Disease (AD)
Authors: McCartney Amber J , Astacio Herson , Shukla Arvind , Yin Xiling , Dodson Sara , Bryant Erin , Corriveau Roderick A 
Published: January 2025

AbstractBackgroundAD/ADRD diseases currently impact more than 6 million people in the US. Rare forms of AD/ADRD are caused directly and unambiguously by genetic mutations. However, most AD/ADRD burden is complex in etiology and thought to result from an interplay among multiple incompletely understood genetic, biochemical, lifestyle, environmental and psychosocial risk factors. Moreover, risk factors interact with other health factors to impact AD/ADRD outcomes. For example, while the most common dementia diagnosis is AD, research over the past decade revealed most people with a diagnosis of AD have multiple brain pathologies, other comorbidities, and many people diagnosed with clinical AD do not have AD pathology at all. This new knowledge highlights the importance of better understanding dementia syndromes, and the relationships among them, to increase chances of developing effective interventions. The NINDS partners with the NIA, the NIH lead for AD/ADRD, in the NIH response to the National Plan. NINDS leads ADRD including frontotemporal dementia (FTD), Lewy body dementias (LBD), vascular contributions to cognitive impairment and dementia (VCID) and multiple etiology dementias (MED). This project aims to evaluate NIH and the ADRD field’s responsiveness to ADRD research milestones from triennial NINDS ADRD Summits by mapping NIH‐funded research activities to ADRD milestones.MethodThe approach used text‐based analysis/mining of grant titles, abstracts, and specific aims to map awards and activities to ADRD milestones. Mappings were vetted by expert concurrence. The ongoing study includes new or competitively renewed NIH ADRD awards starting from fiscal year 2017. Findings help NIH to better understand the state of the field, identify research gaps and opportunities for future efforts, and enable public communication of research activities with an accurate, accessible, compact, and updatable data visualizations.ResultResults indicate the approach is feasible, and importantly the field and NIH have largely been responsive to the ADRD milestones in the National Plan to Address AD.ConclusionThe analysis points to several cross‐cutting ADRD research areas that may benefit from increased attention going forward, including health equity, the multiple etiology hypothesis of common dementias, emerging risk factors for common dementias (e.g. COVID‐19, TBI, and TDP‐43 proteinopathy), and clinical trials.
Diminished learning rates in mnemonic discrimination of scenes but not objects are associated with beta‐amyloid positivity
Authors: Polk Sarah E. , Gellersen Helena M. , Lottes Yannik , Glanz Wenzel , Berron David 
Published: January 2025

AbstractBackgroundThe advent of remote and unsupervised digital cognitive assessment facilitates the use of frequent assessments only days apart to examine learning rates. Learning rates have been shown to differentiate patients with Mild Cognitive Impairment (MCI) and preclinical Alzheimer’s disease (AD) from healthy individuals across a variety of cognitive measures. Here, we investigated whether impairments in learning rates in a mnemonic discrimination task were domain specific, as object and scene memory have been found to rely on anatomically distinct neural pathways that are differentially affected by AD.MethodsWe examined learning rates over two weeks in the Mnemonic Discrimination Task for Objects and Scenes (MDT‐OS) in N = 54 older adults (age = 67.1 ± 5.68) recruited through a memory clinic who were clinically cognitively unimpaired (CU, n = 44, nAβ– = 28, nAβ+ = 6) or had MCI (n = 10, nAβ– = 3, nAβ+ = 7). Five identical stimuli sets were completed at three‐day intervals on participants’ own smartphone or tablet.ResultsUsing linear mixed modeling, we found significant cognitive status‐by‐time interactions indicating that the MCI group showed reduced learning compared to the CU group in the Scene condition, though not the Object condition. However, a cognitive status‐by‐time‐by‐condition model indicated no significant effect of condition. We found no significant Aβ status‐by‐time interaction in either condition. However, an Aβ status‐by‐time‐by‐condition model revealed diminished learning in the Scene condition compared to the Object condition for the Aβ+ group but not the Aβ– group. In a sub‐group analysis including only CU individuals, this three‐way interaction effect remained significant.ConclusionThe current results suggest that individuals with MCI show diminished learning rates in mnemonic discrimination of scenes, compared to CU individuals. We identified ceiling effects in the Object condition, which may have contributed to a null finding. Additionally, we found that Aβ positivity was associated with reduced learning of scenes but not objects, both in the overall sample and in individuals with no clinical indication of cognitive impairment. In conclusion, learning rates in the MDT‐OS may be a sensitive marker of AD in individuals who do not yet meet the clinical threshold for cognitive impairment.
TDP‐43 proteinopathy induced transcriptional alterations in Alzheimer’s disease
Authors: Pevey Ryan S 
Published: January 2025

AbstractBackgroundTDP‐43 is an RNA binding protein that is a pathological hallmark of multiple neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). The frequency of observed TDP‐43 pathology is estimated at 97% in ALS, 45% in FTD and 40‐57% in AD and is characterized by a mislocalization of TDP‐43 from the nucleus to the cytoplasm. Indeed, TDP‐43 is the third most common proteinopathy in AD, behind only Amyloid beta and Tau. The normal function of TDP‐43 has been linked to multiple steps in RNA processing including transcription, splicing, RNA transport, stability, localization, and translation. Most studies aimed at understanding TDP‐43 pathology have been performed in the context of ALS and FTD, while little is known about the molecular mechanisms and consequences of TDP‐43 pathology in AD. We hypothesize that TDP‐43 dependent alterations in gene expression in neurons with TDP‐43 pathology are contributing to neuronal dysfunction and degeneration in AD and related dementias.MethodsTo test this hypothesis, we sorted neuronal nuclei with normal and depleted TDP‐43 levels from human post‐mortem AD and Mild Cognitive Impairment (MCI) patients as well as Non‐neurological Disease (ND) Controls.ResultsRNA sequencing results from these sorted nuclear isolates show substantial genome wide transcriptional alterations in gene expression as well as alternative splicing, and TDP‐43‐associated cryptic exon inclusion.ConclusionsThese results support the significant role of TDP‐43 pathology on the transcriptome of up to half of AD patients and the need for further exploration of a common but overlooked aspect of the most common progressive dementia in patients today.
Brief health literacy assessment as an enhancement to existing cognitive screening tests: an exploratory investigation
Authors: Vogeley Abigail , Curtis Laura M , Opsasnick Lauren , Batio Stephanie , Russell Andrea , Light Sophia W. , Yeh Fangyu , Yoshino‐Benavente Julia , Bonham Morgan , Lovett Rebecca , Wolf Michael S 
Published: January 2025

AbstractBackgroundMost cognitive screening tests used in primary care to identify adults with cognitive impairment, including Alzheimer’s disease and related dementias, have been limited in their diagnostic accuracy, especially in mild cases. Resultant false positives or false negatives (e.g., delayed diagnoses) have respective harms. While expressed concern of an individual’s real‐world self‐care abilities from a caregiver can improve confidence in a screening result, as many as half of patients with cognitive complaints may lack this informant. We explored whether the addition of an objective, brief, health literacy assessment could improve the accuracy of a longstanding, common cognitive screening tool.MethodData came from a longitudinal aging study of older adults from Chicago, IL. Cognitive function was assessed using Z‐scores generated from a comprehensive neurocognitive battery of 13 measured across 5 domains. Participants were determined to have an impairment if they scored ←1 on ≥2 tests within at least one domain. The Mini Mental Status Exam (MMSE) and the Newest Vital Sign (NVS), a common 3‐minute, 6‐item measure of health literacy, were administered. Receiver operating characteristic (ROC) curves assessed the specificity and sensitivity of adjusted MMSE models (cut‐off score ≤26) with and without the NVS to detect cognitive impairment. Areas under the curve (AUCs) were compared using the DeLong test.ResultParticipants (N = 389) were on average 71 years old (SD 5.2); most participants were female (72%) and non‐Hispanic White (56%). Most (86%) had 2+ chronic conditions (M 3.4 (SD 1.8)), and 28% had at least a mild cognitive impairment based on our comprehensive neurocognitive battery. ROC analyses indicated that cognitive impairment detection by the MMSE alone (AUC = 0.79, 95% CI [0.73‐0.84]) was significantly improved (Z = ‐3.68, 95% CI [0.03,0.11], p‐value = <0.001) with inclusion of the NVS (AUC = 0.86, 95% CI [0.82‐0.90]).ConclusionOur findings demonstrate the potential benefit of integrating a brief assessment of real‐world self‐care task performance and health literacy, such as the NVS, with routine cognitive screening tests to improve accurate identification of cognitive impairment in primary care. Improving the accuracy of common screening tools may help facilitate earlier detection, diagnosis, and subsequent care.
Elevated brain miR298 is associated with a reduced risk of Alzheimer’s disease
Authors: Lahiri Debomoy K. , Wang Ruizhi , Maloney Bryan , Ghetti Bernardino , Saykin Andrew J. , Kumar Subodh , White Fletcher A , Greig Nigel H , Sambamurti Kumar , Counts Scott E. 
Published: January 2025

AbstractBackgroundNon‐coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA‐induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule‐associated protein tau and amyloid‐β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression.MethodLevels of miR298 from non‐cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT‐PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic‐ or its antagomiR‐expressing human neuronal and astrocyte cultures.ResultLevels of miR298 varied in postmortem temporal lobe between AD patients and age‐matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose‐associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures.ConclusionThese studies suggest that miR298 regulates a coordinated network of AD‐related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late‐onset cases, we will profile miR298 in brain tissue samples from early‐onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau‐overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.
Subjective memory complaints and neuropathologic changes at age 90 and older: The 90+ Study
Authors: Melikyan Zarui A. , Kawas Claudia H. , Paganini‐Hill Annlia , Al‐Darsani Zeinah , Jiang Luohua , Bukhari Syed A. , Montine Thomas J. , Corrada María M. M. 
Published: January 2025

AbstractBackgroundSubjective Memory Complaints (SMC) are defined as the perception of one’s own memory. In several studies SMC are associated with Alzheimer’s disease (AD) neuropathologic changes, and only one study has analyzed and found an association of SMC with other neurodegenerative, but not vascular, neuropathologic changes. Yet, the evidence on the association of SMC with non‐AD neuropathologic changes is insufficient. We aim to examine the association of SMC with neurodegenerative and vascular neuropathologic changes in individuals age 90 and older (oldest‐old) without dementia at death.MethodThe participants of The 90+ Study, a longitudinal study of aging and cognition, who had neuropathologic examination, SMC evaluation, and had no dementia at consensus case conference were included in the analysis. SMC was evaluated with a question from the Geriatric Depression Questionnaire (GDS) “Do you feel you have more problems with memory than most?”, consensus case conference diagnosis was normal cognition or Cognitive Impairment No Dementia (CIND). SMC was dichotomized as reported ever vs. never during the study follow‐up, and neuropathologic changes were dichotomized as present (see Table 2) vs. absent. We estimated odds ratio [OR] and 95% confidence interval [CI] for presence of each neuropathologic change in those with normal cognition and CIND using logistic regression adjusted for demographics, GDS minus the SMC item averaged across all visits, and MMSE averaged across all visits.ResultIn 238 participants mean age at autopsy was 98 years, 121 (51%) had normal cognition, 67 (28%) have ever reported SMC (Table 1). Those with normal cognition and SMC had higher odds of AD neuropathologic change (OR = 2.9; CI: 1.5‐7.9; p = 0.04), Lewy Body Disease (LBD) (OR = 3.6; CI: 1.8‐11.8; p = 0.04), and atherosclerosis (OR = 3.1; CI: 1.2‐8.1; p = 0.02). There were no significant findings in those with CIND (Figure, Table 2).ConclusionIn the oldest‐old with normal cognition SMC are associated with higher odds of neurodegenerative (AD and LBD) and vascular (atherosclerosis) neuropathologic changes. It is possible that those with normal cognition complain more selectively with respect to neuropathologic changes, compared to those with CIND.