bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post COVID 19 Pandemic –Changing landscape of Dementia Profile A Study from a tertiary care center in India
Authors: Kushwaha Suman , Panda Ashwin Kumar , Singh Mridula , Anthony Aldrin , Maheshwari Siddharth , Kumar Rashi , Dhamija Rajinder 
Published: January 2025

AbstractBackgroundSARS CoV‐2, neurotrophic virus in response to neuroinflammation causing varying cognitive deficits in post pandemic period. New onset rapidly progressive cognitive decline and deterioration in degenerative dementia has been seen in clinics in recent times. The paradigm shift of presentation of dementia needs detailed evaluation to facilitate further management.MethodDuration of study‐ 2 years. RetrospectiveAll the patients admitted with cognitive impairment were evaluated: Detailed history, Cognitive testing, biochemical and hematological parameters. Neuroimaging in all patients & CSF in selected cases. Accordingly categorized into subtypes. History of COVID 19 was confirmed by Clinically, hospitalization and investigations.ResultTotal Cases – 53. Age Range 50 ‐75 yr. Dementia Subtypes Patients, Alzheimer’s disease –14, Frontotemporal ‐10, Rapidly progressive dementia ‐15, Vascular – 8 and Parkinson’s dementia‐ 6.History of respiratory symptoms were present in 28 patients while COVID test was positive in 12 patients. Hospitalization for COVID ‐19 in 10 patients. The degenerative dementias have rapid progression of symptoms. The incidence of RPD has increased. Treatable cause of RPD were investgated 12 patient had immune mediated dementia and has partial response on immunomodulation. Seven patients have succumbed.ConclusionCOVID‐19 has significant effect on cognitive decline. Neuroinflammation is key factor causing degeneration. We need to know how this is resulting in neurodegenerative processes and cognitive functioning. There is need to further explore post pandemic dementia in systematic studies for new onset cognitive decline for facilitating the therapeutic strategies.
Language impairment associated with prognosis in progressive supranuclear palsy
Authors: Cordero Indira Ruth Garcia , Hadian Mohsen , Bayram Ece , Rodriguez‐Porcel Federico , Stephen Christopher , Pantelyat Alex , Iyer Jay , Xie Tao , Boxer Adam L , Gunzler Douglas , Dale Marian , McFarland Nikolaus , Kang Kyurim , Swan Matthew , Wills Anne‐Marie , Lang Anthony E , Tartaglia Maria Carmela 
Published: January 2025

AbstractBackgroundLanguage impairment is common in progressive supranuclear palsy (PSP) and is often overlooked due to the severity of the motor symptoms. We investigated whether language can be used to predict PSP prognosis.MethodsOne hundred‐forty‐six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV‐8E12) clinical trial were evaluated at baseline and week 32 using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the PSP rating scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL). Percentage of change was calculated for each measure. Using correlations, we evaluated relationships between all RBANS‐subscores (language, attention, memory and visuoconstructional), the PSPRS and SEADL scores at baseline; p‐values were FDR corrected. Linear regression analyses were performed between the RBANS‐language, RBANS‐delayed‐memory and RBANS‐executive at baseline and the percentage of change over time. Grey matter volumes were extracted from three regions of interest based on language (bilateral temporal poles and inferior frontal gyri), executive (bilateral dorsolateral and superior frontal gyri and frontal pole) and memory (bilateral hippocampus, inferior, middle and superior temporal gyri) areas.ResultsMean age of PSP patients: 68.8 years (49‐86 years), 57 (39%) females. The RBANS language, executive and delayed memory scores at baseline were positively correlated with each other and with visuoconstructional and immediate memory score (all p<0.05). Only the RBANS‐language score at baseline predicted percentage of change in PSPRS (B = ‐0.63, p = 0.003). The percentage of change in the RBANS‐language score was predicted by the RBANS‐language at baseline (B = ‐0.59, p<0.001). Lower age at baseline was associated with a worsening in language score over time (B = 0.51, p = 0.009). Language grey matter volume was associated with the change in RBANS‐language score (B = 0.01, p = 0.02).Conclusionslanguage impairment at baseline, in contrast to memory and executive functions, was predictive of functional decline as measured by PSPRS. Atrophy in language areas at baseline predicted language decline. Language impairment may be an independent prognostic factor in PSP.*Based on research using data from AbbVie that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.
Association between Hippocampal Volume and Cognition in the Oldest‐Old Individuals from Colombia
Authors: Kaplan Elizabeth , Zuluaga Yesica , Vasquez Daniel , Hincapie Liliana , Aguillon David Fernando , Madrigal Lucia , Baena Ana Y , Vila‐Castelar Clara , Alvarez Sergio , Ochoa‐Escudero Martin , Giraldo‐Chica Margarita M. , Gomez Liliana A Ramirez , Langella Stephanie , Arboleda‐Velasquez Joseph F , Lopera Francisco , Quiroz Yakeel T. 
Published: January 2025

AbstractBackgroundLife expectancy is on the rise, accompanied by an increased prevalence of cognitive impairment and Alzheimer’s disease. Despite this global trend, our understanding of the neural mechanisms underlying cognitive changes in the oldest‐old (>80 years old) population remains limited. Unraveling these mechanisms may provide valuable insights and therapeutic interventions for individuals grappling with cognitive impairments in older age. Increased hippocampal volume has been associated with better cognitive function and its sparing in late life has been linked to better cognitive and functional outcomes. In this study, we examined hippocampal volume and cognitive performance in a group of the oldest‐old individuals from Colombia.Methods13 participants (9 women, 4 men), with an average age of 94.8 (6.24) years were included in this study. Cognitive performance was measured using the Mini‐Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning Total. Functional impairment was assessed using the Functional Assessment Scale Test (FAST). Structural MRI scans were conducted at the Hospital Pablo Tobon Uribe in Colombia and processed with FreeSurfer (v7.2). Right and left hippocampal volumes were averaged. Linear regression models were used to investigate the relationship between hippocampal volume and cognitive performance.Results7 participants were cognitively‐unimpaired (FAST = 1), 3 endorsed subjective complaints (FAST = 2), and 3 met criteria for dementia (FAST ≥3). Participants had a mean hippocampal volume of 2,990 (459 mm³), mean MMSE score of 21.2 (6.15), and mean Memory Score of 10.5 (4.52). Regression models revealed higher hippocampal volume was significantly associated with better memory scores after adjusting for FAST impairment, age, sex, and intracranial volume (p = 0.012). The relationship between higher hippocampal volume and MMSE scores, controlling for the same variables, approached significance (p = 0.06).ConclusionsOur preliminary findings suggest a positive association between hippocampal volume, a marker of neurodegeneration, and cognitive performance in a cohort of the oldest‐old individuals from Colombia. This study is ongoing and future research, incorporating a larger sample size and additional biomarkers, is needed to validate these results, as well as to further our understanding of the relationship between neural structure in late life and cognition.
APOE genotype‐dependent effects of enhanced BMP signaling on astrocytes and co‐cultured neurons
Authors: Linden Anne K , Affaneh Amira , Kessler John A , Yu Peng Chian‐ 
Published: January 2025

AbstractBackgroundApolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD), and aging is the greatest overall risk factor for AD. Many cellular and molecular changes occur within the brain throughout aging, one of which being the increased bone morphogenetic protein 4 (BMP4) signaling. As APOE and BMPs are known to interact in non‐neuronal organs, we hypothesized that enhanced BMP signaling in the brain may interact with APOE in a genotype‐dependent manner to initiate or exacerbate neuropathological cascades relevant to AD.MethodE4 patient‐derived IPSC, along with CRISPR‐corrected isogenic APOE3 (E3) controls, were virally induced into astrocytes with SOX9 and NFIB overexpression, or neurons with NGN2 overexpression, using previously published protocols. After maturation, astrocytes and neurons cultured alone or in co‐culture, were treated for 72 hours BMP4 or vehicle prior to collection to observe changes.ResultIn the presence of BMP4, E4 astrocytes accumulated larger amounts of lipids in the cytoplasm compared to E3 astrocytes. This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4. Further, single cell transcriptomic analysis of astrocyte‐neuron co‐cultures revealed that BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co‐cultured neurons. These BMP4 induced changes coincide with enhanced phosphorylation of tau and reduced oxidative phosphorylation capacity in neurons cocultured with E4 astrocytes compared to E3 astrocytes.ConclusionIncreased BMP signaling alters the physiology of astrocytes in an APOE‐dependent manner, with E4 astrocytes exhibiting more abnormalities in lipid metabolism than E3 astrocytes. Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4. E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency. This suggests that enhanced BMP4 signaling in the aging brain may be one of the contributing factors to development of AD.
The klotho F/C AD risk haplotype drives distinct phenotypes in a novel mouse model
Authors: Sasner Michael , Pandey Ravi S , Kotredes Kevin P , Garceau Dylan , Weber Channing , Agoro Rafiou , Preuss Christoph , Carter Gregory W 
Published: January 2025

AbstractBackgroundApolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for Alzheimer’s disease (AD), but APOE4 carriers do not always develop AD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klothoharbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against AD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models.MethodMouse klotho differs at the key amino acid position p.C370S rendering the native mouse haplotype as “KL‐F/S”, matching neither of the observed human haplotypes. We have replaced this with either the homozygous protective KL‐V/S or common KL‐F/C haplotypes using CRISPR/Cas9. We have tested the effects of these klotho haplotypes on klotho expression in serum, brain, and kidney relative to B6 controls and to the amyloidogenic AppSAA AD model, which exhibit significant amyloid neuropathology. We have also run RNA‐seq on whole brain homogenates at 12 months of age.ResultSecreted p‐KL was decreased in KL‐F/C mice harboring the novel mouse risk haplotype relative to age matched B6 controls and to KL‐V/S mice. In contrast, KL‐V/S mice showed no significant differences in soluble p‐KL serum levels when compared to B6 controls. Secreted p‐KL levels in KL‐V/S mice were significantly elevated when compared to the APPSAA mice, whereas young KL‐F/C mice showed similar levels to the aged APPSAA model. Transcriptional analysis indicated that the KL‐V/S haplotype was anti‐correlated with AMP‐AD human modules, while the KL‐F/C risk haplotype was significantly correlated to AD signatures in modules enriched for neuronal system, cell cycle, myelination, and cellular stress response pathways.ConclusionThese data suggest the native mouse klotho allele may act similarly to the protective KL‐V/S haplotype, while the KL‐F/C haplotype leads to lower secreted klotho and potentially greater disease risk. These models are therefore suitable for experiments to elucidate how klotho variants protect from AD pathologies, and will enable detailed studies of how this protection is specific to the APOE4 genotype.
Transcriptome Signatures for Cognitive Resilience Among Individuals with Pathologically Confirmed Alzheimer Disease
Authors: Li Donghe , Han Xudong , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R 
Published: January 2025

AbstractBackgroundThe molecular mechanisms underlying individuals with neuropathologically confirmed Alzheimer disease (AD) but who were cognitively healthy prior to death (i.e., cognitively resilient) remain largely unknown.MethodWe evaluated brain‐derived RNA sequencing data from 213 individuals with cognitive resilient and 383 symptomatic AD cases. This data included newly generated sequences from Boston University Alzheimer’s Disease Research Center (BUADRC) participants, and existing data from the Framingham Heart Study (FHS), Religious Orders Study, Rush Memory and Aging Project (ROSMAP), and the Mount Sinai Brain Bank (MSBB). Differential gene expression analyses between cognitive resilient and symptomatic AD were conducted in each dataset and then the results were combined by meta‐analysis. Differentially expressed genes (DEGs) at the transcriptome‐wide significance (TWS) level (P<10‐6) in meta‐analysis and nominally significant (P<0.05) in at least two datasets were included in subsequent analyses of pathways and associations with cognitive and neuropathological traits.ResultWe identified 42 TWS genes, including 17 that were meta‐analysis P<5 × 10‐8. The two most significantly DEGs in meta‐analysis, ADAMTS2 (Log2 fold change [Log2FC] = 0.45, P = 2.25 × 10‐14) and SCGN (Log2FC = 0.57, P = 1.84 × 10‐11), were both up‐regulated in symptomatic AD brains. Significant pathways involving alpha‐amino acid catabolic process and chemical synaptic transmission modulation were identified. These genes exhibited distinct patterns of association with domain‐specific cognitive tests, which the most significant association was found with SMPX expression for memory (beta = ‐0.08, P = 0.002). Regarding neuropathological traits, IL2RG expression was the most significant association with pTau181 (beta = ‐3.56, P = 0.002). Of the two most significant DEGs, ADMTS expression was associated with memory (beta = ‐0.013, P = 0.002) and pTau231 (beta = 0.008, P = 0.005), while SCGN expression was associated with language (beta = ‐0.1, P = 0.025) and executive function (beta = ‐0.1, P = 0.02).ConclusionWe identified multiple DEGs for cognitive resilience, several of which were also associated with measures of cognitive performance prior to death and AD‐related neuropathological traits at autopsy, thus providing important insights into resilience mechanisms and strategies for delaying clinical symptoms of AD. Notably, ADAMTS2 was the top‐ranked DEG in a study conducted in brains from African American AD cases and controls (see Logue et al. abstract for this meeting).
Propagation of distinct tau strains in neuronal systems with physiological tau expression
Authors: Hromadkova Lenka , Urquhart Kiley , Kim Chae , Haldiman Tracy , Safar Jiri 
Published: January 2025

AbstractBackgroundPathological tau forms from Alzheimer’s disease (AD) brains act as seeds, replicating in cells and forming tau aggregates in a template‐like manner. The exploration of this prion‐like pathogenic mechanism has predominantly occurred in transgenic mice and cell systems that overexpress tau protein and its truncated forms with pro‐aggregation mutations. However, these systems do not entirely capture the propagation kinetics and template conformational changes of various tau seeds. Our investigation focuses on tau propagation in cell systems with normal tau levels, emphasizing molecular conformation variability among tau strains, considering them as distinct populations in individual AD cases (Hromadkova et al., Cell Biosci., 2023).MethodWe employed three types of cell systems: mouse primary neurons, differentiated SH‐SY5Y, and iPSCs‐derived neurons. We optimized culture conditions and timing for inoculation with AD‐tau isolates. The amount and conformational state of AD‐tau were characterized using conformational stability assay (CSA) and conformation‐dependent immunoassay (CDI). Subsequently, tau aggregates newly formed in neurons exposed to AD‐tau were subjected to immunostaining and cell lysis. We analyzed the results using confocal microscopy, immunoblot techniques, and CDI.ResultIn all three systems, tau protein showed the tendency to aggregate when exposed to AD‐tau inoculates. During the early stages of inoculation, we noted the formation of tau aggregates with conformational properties resembling those found in the original AD‐tau isolates. Extended inoculation revealed increased aggregation, different from original AD‐tau, suggesting favorable propagation of highly seed‐competent tau entities in long‐term cultures.ConclusionOur findings indicate that different tau strains manifest as dynamic entities, exhibiting variability not only in molecular conformations and structural arrangements but also in the kinetics of inter‐neuronal propagation. This diversity might contribute to the observed heterogeneity in AD phenotypes. The presence of different tau strains among AD patients introduces an added layer of complexity to disease progression and outcomes. Consequently, it may be worthwhile to consider more personalized therapeutic interventions tailored to individual patients.
Genetic Analysis of an Amyloid PET‐Negative Autopsy‐Confirmed Alzheimer’s Pedigree
Authors: Talozzi Lia , Peña‐Tauber Andrés , Jensen Tanner D. , Wilson Edward N. , Young Christina B. , Stewart Ilaria , Cobos Inma , Vallejo Kristen , Hefti Marco M , Guen Yann Le , Williams Kennedy , Vossler Hillary , Gorzynski John , Andreasson Katrin I. , Mormino Elizabeth , Ashley Euan , Greicius Michael D 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta‐amyloid and tau biomarkers can now add in‐vivo support to the AD diagnosis. Rarely, a patient with AD confirmed at autopsy may have a negative amyloid PET. Here we describe a pedigree in whom the index case was amyloid PET‐negative. We performed genetic sequencing of two affected siblings to identify a set of candidate single nucleotide variants (SNVs) and structural variants (SVs) associated with disease and rare in healthy older controls from several large genetic databases.MethodWe performed long‐read sequencing (LRS) to comprehensively evaluate both SNVs and SVs. The index case, an APOE3/E4 male, developed memory trouble at 68 that progressed to probable AD at 72. Notably (Fig. 1) his amyloid‐PET scan, which was confirmed to be of high technical quality, was negative. His tau PET scan was positive and his plasma Abeta42/40 was in the expected range for Stanford AD patients. His family history is extensive and suggestive of an autosomal dominant pattern of late‐onset AD (Fig. 2). The patient’s sister was diagnosed with AD at 62. We filtered their shared heterozygous SNVs keeping those with a minor allele frequency < 0.01 in gnomAD and that were not present in any ADSP healthy controls (HC) over 70y.o. (N = 19771;62.1%females;81±6.4y.o). Shared SVs were kept as candidates if they were not seen in any Stanford LRS HC (N = 95;59%females;72±1.5y.o.)ResultNeuropathological analysis revealed that both siblings met the A3B3C3 criteria for AD and had cerebral amyloid angiopathy. Among rare mutations on genes expressed in the brain (Table 1), a novel missense in ADNP (Activity‐Dependent‐Neuroprotector‐Homeobox), and a 267bp deletion on TET1 (Tet‐Methylcytosine‐Dioxygenase) were identified. The 3426bp insertion on ATP8A2 (ATPase‐Phospholipid‐Transporting‐8A2) was the longest, rare insertion found. Additionally, a large duplication (∼20Kbp) and inversion (∼160Kbp) were observed.ConclusionThis study highlights an unusual AD pedigree and emphasizes the potential utility of LRS in identifying causal SNVs and SVs. In future work we plan to perform additional amyloid stains to understand why the index case PET was amyloid‐negative. We are also assessing additional family members to improve our ability to identify a causal mutation.
The Relationship of Neuropsychiatric Symptoms and ADRD Pathologies
Authors: Bacci Julia R. , Rudolph Marc D. , Mielke Michelle M. , Craft Suzanne , Bateman James R. , Lockhart Samuel N. 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS) in the Alzheimer’s Disease (AD) clinical spectrum are common, yet the pathological underpinnings are unclear. Prior research has been inconsistent, attributed in part to concomitant co‐pathologies. Additionally, prior modeling approaches have disregarded the distributional properties of right‐skewed NPS data and utilized predominantly racially homogenous cohorts. Thus, we examined the relationship between NPS and markers of vascular injury and neurodegeneration using generalized linear models (GLM) in a diverse community‐based sample. Of additional interest was whether these relationships differed by cognitive status or race.MethodsWe evaluated cross‐sectional relationships of brain white matter hyperintensity volume (WMHv) and plasma neurofilament light chain (pNfL) to NPS (NPI‐Q total severity scores) in 588 Wake Forest ADRC Clinical Core study participants. Analyses included participants with consensus diagnoses of cognitively unimpaired (CU; N = 348) and mild cognitive impairment (MCI; N = 240). WMHv and pNfL were log‐transformed prior to model entry. GLMs included age, sex, education, race, and cognitive status as covariates and pathologies as predictor variables. Secondary models included aforementioned covariates and pathology by (a) cognitive status and (b) race interaction terms to investigate how these associations differed.ResultsWMHv was not significantly associated with NPS (N = 561; β = 0.203; p = 0.053); further, we did not observe an interaction between cognitive status and WMHv (N = 561; β = ‐0.055; p = 0.800). However, a significant race by WMHv interaction on NPI‐Q was demonstrated (N = 561; β = ‐0.414; p = 0.016). In White participants, elevated WMHv was significantly related to elevated NPS (N = 434; β = 0.325; p = 0.006); whereas in Black/African American participants elevated WMHv was significantly related to lower NPS (N = 119; β = ‐0.239; p = 0.049). pNfL was not significantly associated with NPS (N = 506; β = 0.149; p = 0.576). A significant pNfL by cognitive status interaction on NPI‐Q was found (N = 506; β = ‐1.055; p = 0.029; Figure 2), where elevated pNfL was related to elevated NPS in MCI participants (N = 198; β = 1.656; p = 0.004) but not CU participants (N = 308; β = ‐0.316; p = 0.260). However, we did not observe an interaction between race and pNfL (N = 506; β = 0.185; p = 0.678).ConclusionConsistent with previous work we demonstrate associations of pNfL and WMHv with NPS. Future analyses with this cohort will examine additional biomarkers, including amyloid‐beta and tau measured in CSF, plasma, and PET.