bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering mechanisms of hyperexcitability in tauopathies with functional genomics
Authors: Boggess Steven C , Gandhi Vaidehi , Tsai Ming‐Chi , Chou Yu‐Ying , Hanson Jesse E. , Kampmann Martin 
Published: January 2025

AbstractBackgroundPatients with Alzheimer’s Disease and related dementias associated with the accumulation of pathological tau (tauopathies) in neurons have an increased incidence of epileptic episodes and sub‐clinical epileptiform activity. This neuronal hyperexcitability represents some of the earliest changes in patient brains, is associated with more severe symptoms, and presents an opportunity for early therapeutic intervention. Despite these provocative observations, the molecular details of how tau and neuronal excitability are connected in tauopathies remain unknown. Thus, identification of how pathological tau influences neuronal activity will reveal novel neuronal biology, further elucidate the in vivo function of tau, and possibly reveal new therapeutic strategies and targets. We are developing methods for identifying modifiers of neuronal hyperexcitability in tauopathies through functional genomics.MethodsThe calcium integrator CaMPARI2 was incorporated in iPSCs that also constitutively express catalytically dead Cas9 (dCas9) fused to a KRAB transcriptional repressor to inhibit expression of a gene targeted by a sgRNA (CRISPRi). We demonstrated that photoconversion of CaMPARI2 is dependent on neuronal activity, and that it reports the observed differences between neurons carrying a disease‐causing mutation in tau and a wild‐type isogenic control. iPSCs are differentiated into neurons by overexpression of NGN2 and activity was recorded via CaMPARI2 photoconversion after 3 weeks of maturation. We performed CRISPRi screening on more that 3000 genes, including genes associated with neurodegenerative disease. FACS was used to sort these neurons into two populations: one consisting of the highly active (high CaMPARI2 ratio) neurons and one consisting of sparsely active (low CaMPARI2 ratio) neurons. Frequency of each sgRNA was identified by next‐generation sequencing.ResultWe have identified genetic modifiers that affect neuronal excitability specifically in WT or tau‐mutant neurons, but not the other. Validation of hits by whole‐cell electrophysiology recordings indicates that the CaMPARI screen can detect a diversity of mechanisms that impact neuronal excitability. Gene Ontology enrichments implicate mitophagy and metabolism as potential drivers of changes to neuronal excitability.ConclusionFunctional genomics screens are being developed to identify modifiers of excitability in disease and healthy neurons. Further screening and validation experiments will reveal mechanisms that lead to hyperexcitability in tauopathies and potential targets for therapeutic intervention.
Age at Diagnosis of Cataract and Subsequent Risk of Dementia
Authors: Geng Chaofan 
Published: January 2025

AbstractBackgroundEpidemiological evidence regarding the association between cataract onset age and risk of incident dementia remains unexplored. To examine whether age at cataract diagnosis is associated with risk of incident dementia and its subtypes.MethodsThis prospective, population‐based cohort study utilized data from the UK Biobank that collected baseline information between 2006 and 2010. A total of 442,376 participants who were diagnosed with dementia at baseline, had missing covariate data, or had dementia before the onset of cataracts during a median follow‐up of 12.6 years were excluded from the analysis. Cox regression models and propensity score matching was ultimately used to analyze the associations between cataracts and their age of onset with subsequent all‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD).ResultsUpon comparison with subjects unaffected by cataract, patients afflicted with cataract exhibited a significantly elevated risk of all‐cause dementia ((hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.62‐1.98), AD (HR:1.79, 95% CI: 1.92‐2.48) and VD (HR: 1.78, 95% CI: 1.54‐2.04). After propensity score matching, compared with individuals without cataract, individuals with cataract diagnosed at younger than 60 years had the highest HR for developing VD (adjusted HR = 3.73, 95%CI: 1.25‐11.12, p‐value = 0.018).ConclusionIn this prospective cohort study, an earlier onset of cataracts was found to be associated with an increased risk of subsequent VD, highlighting the importance of monitoring cataract patients, particularly those diagnosed at age less than 60 years, for the occurrence of VD, providing new ideas for the clinical prevention and intervention of VD.
Circulating microRNAs related to cognitive performance in the general population
Authors: Melas Konstantinos , Talevi Valentina , Krüger Dennis Manfred , Pena Tonatiuh , Aziz N. Ahmad , Fischer André , Breteler Monique M.B. 
Published: January 2025

AbstractBackgroundMicroRNAs have been linked to dementia. However, understanding their relation to cognition in the general population is required to determine their potential use for the detection and prevention of age‐associated cognitive decline and preclinical dementia. Therefore, we examined the association of circulating microRNAs with cognitive performance in a population‐based cohort and the possible underlying mechanisms.MethodWe used data from 2869 participants (55.6% women, mean age: 55.01 years, age range: 30 to 95 years) of the Rhineland Study, a prospective population‐based study in Bonn, Germany. Circulating microRNA and gene expression were measured through RNA‐Seq and microRNAs were clustered using weighted gene co‐expression network analysis. Cognitive domain scores were derived from a neuropsychological test battery. Brain imaging measures were obtained using Freesurfer on 3T T1‐weighted MR images. We employed multivariable linear regression to evaluate the association of cluster and individual microRNA expression levels with cognitive domain scores, imaging measures, and target gene expression, adjusting for multiple testing with the false discovery rate (fdr) method.ResultOne microRNA cluster, represented by miR‐134‐5p, miR‐409‐3p, miR‐370‐3p, and miR‐493‐3p, was significantly associated with executive function (standardized β: ‐0.045, fdr‐adjusted p‐value: 0.043). Another cluster, represented by hub microRNAs miR‐215‐5p and miR‐192‐5p, was associated with episodic verbal memory at suggestive significance (standardized β: ‐0.040, fdr‐adjusted p‐value: 0.097). When examining individual microRNAs, miR‐92b‐3p, miR‐1976, miR‐4677‐5p, and miR‐10401‐3p were significantly associated with executive function and global cognition. Importantly, miR‐215‐5p, miR‐192‐5p, miR‐92b‐3p, miR‐1976, and miR‐10401‐3p were also associated with cortical thickness, predominantly in the temporal and frontal regions. Functional enrichment analysis of microRNA target genes uncovered involvement of pathways related to brain and dendrite development, axon guidance and synapse assembly.ConclusionWe identified microRNA clusters and individual microRNAs that were related to different cognitive functions. Some of these microRNAs were also related to cortical thickness, suggesting that part of their relation with cognition is mediated through alterations of brain structure. The identified microRNAs regulated genes related to brain homeostasis and development. Our results contribute to a better understanding of brain epigenetics and provide potential molecular targets for the detection, prevention or treatment of cognitive dysfunction.
Unlocking Blood Drivers of Neurodegeneration: Mechanisms and therapies
Authors: Akassoglou Katerina 
Published: January 2025

AbstractBackgroundCerebrovascular alterations and innate immune activation are key features of Alzheimer’s disease (AD). However, the mechanisms that link blood‐brain barrier disruption to neurodegeneration are poorly understood and well‐defined druggable targets at the neurovascular interface are limited.MethodBy developing a multiomic and genetic loss‐of‐function pipeline, we reported the transcriptomic and global phosphoproteomic landscape of blood‐induced microglia activation and the causal role for fibrin in induction of neurodegenerative genes and oxidative stress pathways in innate immune cells1. Volume imaging in cleared mouse and human AD brains combined with repetitive in vivo two‐photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. We developed a first‐in‐class fibrin‐targeting immunotherapy to selectively inhibit fibrin‐induced inflammation without interfering with its beneficial coagulation effects2.ResultWe identified the blood coagulation factor fibrinogen as necessary and sufficient for the induction of pathogenic neuroinflammation in neurologic diseases3. Fibrinogen induces spine elimination and promotes cognitive deficits in AD mouse models mediated by oxidative stress induction in microglia4. Fibrin‐targeting immunotherapy entered the CNS, bound to fibrin, and inhibited amyloid‐driven neurotoxicity and neurotoxic inflammatory gene programs in AD mice2.ConclusionThus, fibrinogen links cerebrovascular damage with immune‐mediated neurodegeneration and fibrin therapeutics may have important therapeutic implications inhibiting vascular‐driven neurodegeneration in AD and related conditions.References1. Mendiola et al. Nat Immunol 2023, 24:1173‐11872. Ryu et al. Nat Immunol 2018, 19:1212‐12233. Petersen et al., Nat Rev Neurosci. 2018, 19:283‐3014. Merlini et al. Neuron 2019, 101:1099‐1108
Systemic Mechanisms of Brain Aging and Rejuvenation
Authors: Villeda Saul 
Published: January 2025

AbstractBackgroundAging drives cellular and cognitive impairments in the adult brain. It is imperative to gain mechanistic insight into what drives aging phenotypes in the brain in order to maintain, and even restore, functional integrity in the elderly.MethodWe, and others, have shown that systemic interventions ‐ such as heterochronic parabiosis (in which a young and old circulatory system are joined) and administration of young blood or exercise induced blood factors ‐ can reverse age‐related impairments in regenerative, synaptic and inflammatory processes, as well as rescue cognitive faculties in the aged brain.ResultRejuvenating systemic intervention studies have revealed an age‐dependent bi‐directionality in the influence of the systemic environment indicating pro‐youthful trophic factors in young blood elicit rejuvenation while pro‐aging immune factors in old blood drive aging.ConclusionIt has been proposed that introducing pro‐youthful trophic factors or mitigating the effect of pro‐aging immune factors may provide effective strategies to rejuvenate aging phenotypes in the brain. Despite this potential, much is unknown as to the systemic and molecular mechanisms regulating the effects of blood‐borne factors. I will discuss work from my research group that begins to provide insight into the beneficial effects of targeting individual systemic immune factors and the downstream molecular drivers promoting rejuvenation in the aging brain.
Association between anxiety, stress, and cognition in middle‐aged adults: Exploratory factor analysis across multiple anxiety and stress measures
Authors: Chan Ivana , Lim Yen Ying , Maruff Paul 
Published: January 2025

AbstractBackgroundAnxiety and stress have been identified as potential risk factors of cognitive impairment, but research examining this association in midlife has been limited.MethodThe current study examined the associations between anxiety and stress symptoms, and cognition in middle‐aged cognitively unimpaired adults (n = 2,463) enrolled in the Healthy Brain Project. Exploratory factor analysis was conducted on items in the Anxiety Subscale of the Hospital Anxiety and Depression Scale, Anxiety and Stress Subscales of the Depression, Anxiety and Stress Scale, and Perceived Stress Scale. Cognition was measured using the Cogstate Brief Battery (CBB).ResultThe solution that resulted in the best fit to the data comprised five factors which explained for 48% of the variance: Over‐Reactivity, Panic, Low‐Control, Tension and Intolerance. Panic‐related symptoms were significantly associated with both poorer attention and memory. Having clinically meaningful anxiety symptoms, or both anxiety and stress symptoms, was associated with poorer memory.ConclusionAnxiety and stress symptoms may be linked to a heightened risk of developing cognitive impairment. Specifically, panic‐related symptoms may play a significant role in the relationship between anxiety symptoms and cognition. Limitations include: 1) cross‐sectional nature of the study limited ability to ascertain direction of causality; 2) individuals with major psychiatric conditions were excluded from the study, thus limiting external validity of the current findings; 3) HBP sample has a higher proportion of individuals with a family history of dementia compared to the general population, hence the sample presents with an increased risk of developing dementia and generalizability of our findings may be limited.
Reducing contamination from off‐target binding in the meninges in PI‐2620 tau PET scans
Authors: Hand Maxwell W , Tennant Victoria R , Lee Noelle , Tubi Meral A , Toga Arthur W. , O'Bryant Sid E. , Christian Bradley T. , Braskie Meredith N 
Published: January 2025

AbstractBackgroundPositron emission tomography (PET) tau tracer PI‐2620 frequently shows off‐target meningeal binding (Figure 1). Of standard regions of interest, only lateral parietal (LP) is contaminated by this. We compare the standardized uptake value ratio (SUVR) in the LP before and after eroding the LP mask to remove meningeal contamination.MethodWe evaluated 1191 older adults from the Health & Aging Brain Study‐Health Disparities with available [18F]‐PI‐2620‐PET scans (Table 1). We created: 1) a FreeSurfer‐derived LP mask 2) an eroded LP mask, and 3) in a subset of 90 participants (30 participants from each cognitive group) an LP border mask capturing meningeal signal (Figure 2).To create the eroded LP mask, we eroded a full brain mask (FSL erode kernel sphere 3) and multiplied it by the Freesurfer‐derived LP mask. To create the LP border mask we dilated each participant’s LP mask (kernel box 6), subtracted the brain mask, and thresholded at 0. We used linear regression to examine relationships between: 1) original and eroded LP SUVR and 2) LP border tau‐binding and SUVR change (original LP SUVR minus eroded LP SUVR). We also related eroded and non‐eroded LP signal to 1) medial temporal SUVR, which is not strongly affected by meningeal signal and 2) age.ResultThe eroded LP SUVRs and original LP SUVRs were highly correlated (β = 0.93; p<0.01). Age was associated with LP SUVR after (β = 0.15; p<0.01), but not before (β = 0.026; p = 0.37), LP mask erosion. Higher medial temporal lobe SUVR was associated with higher LP SUVR both before and after (both p<0.01) erosion of the LP mask. In the 90 participants with LP border masks, higher LP border signal was associated with greater LP SUVR change after erosion (β = 0.048, p<0.01).ConclusionSUVR contamination in the LP due to off‐target PI‐2620 binding was reduced using mask erosion. Greater change in SUVR was associated with higher initial contamination (indicated by more off‐target signal contiguous to the LP region). Mask erosion also strengthened the relationship between LP SUVR and age, suggesting that removing contamination from the meninges helped highlight true tau signal.
Studying the mechanistic links between microtubule disruption and tauopathy protein pathogenesis
Authors: Zeng Wen , He Zhuohao 
Published: January 2025

AbstractBackgroundPathological tau plays critical roles in many neurodegenerative diseases (NDD), including Alzheimer’s disease (AD). However, the mechanisms underlying the initial tau pathogenesis are largely unknown. Extensive tau pathology has been observed in the brains with chronic traumatic encephalopathy (CTE), suggesting repeated traumatic brain injury (rTBI) correlates with tau pathogenesis. However, the mechanistic links are missing.MethodWe developed a rTBI mouse model, combined with our recently developed seeding models, to investigate whether and how rTBI is correlate with initial tau pathogenesis. Moreover, we utilized cryo‐electron microscopy (Cryo‐EM) and chemistry synthesis approaches to examine the co‐factors that are involved in tau fibrilization.ResultWe found rTBI induced tau pathogenesis and spreading, and the microtubule disruption is involved in such process. Pharmacologically disrupting microtubule induced tau pathogenesis, which could be rescued by microtubule stabilizer. Further study showed microtubule disruption induced Golgi apparatus (GA) fragmentation, which would be also observed in tauopathy brain tissues. Moreover, GA contents could directly induce the tau fibrilization. When inoculated into WT mouse brains, these fibrils transformed endogenous physiological tau into pathological status, mirroring the tau extracted from human patient brains. Subsequent Cryo‐EM structures showed the tau fibrils recapitulated certain pathological tau harbored similar folds as the tau fibrils extracted from human AD and chronic traumatic encephalopathy (CTE) brains.ConclusionOur studies suggest microtubule disruption induces GA fragmentation, resulting in the leakage of GA contents, that could trigger tau fibrilization and pathogenesis. Our results suggest keeping microtubule and GA integrity as novel intervention strategies for the treatment of tauopathy diseases.
Associations Between Speech‐based Biomarkers of Cognition and Traditional Neuropsychological Assessments in a Preclinical AD Cohort
Authors: Alexopoulou Zampeta‐Sofia , Köhler Stefanie , Tröger Johannes , Mallick Elisa , Linz Nicklas , Priller Josef , Schneider Anja , Fließbach Klaus , Falkenburger Björn , Wiltfang Jens , Zerr Inga , Jessen Frank , Klockgether Thomas , Düzel Emrah , Spottke Annika , Wagner Michael , Laske Christoph , Manera Valeria , Teipel Stefan , König Alexandra 
Published: January 2025

AbstractBackgroundSpeech and language impairments are associated with cognitive decline in neurodegenerative dementias, particularly Alzheimer’s Disease (AD), where subtle speech changes may precede clinical dementia onset. As clinical trials prioritize early identification for disease‐modifying treatments, digital biomarkers for timely screening become imperative. Digital speech‐based biomarkers can be employed for screening populations at the earliest AD stages. An automated phone‐based screening battery has been created, encompassing speech‐related neurocognitive tests (Semantic Verbal Fluency and Verbal Learning Test). This allows the extraction of speech‐based biomarkers alongside classical cognitive scores. This study aims to validate digital speech biomarkers in early‐stage AD by comparing them to traditional evaluation methods.MethodWithin the PROSPECT‐AD project, speech and gold‐standard clinical data were obtained from the German DELCODE and DESCRIBE cohorts. We used data from N = 14 healthy controls (HC), N = 75 participants presenting with Subjective Cognitive Decline (SCD) and N = 18 participants presenting with amnestic Mild Cognitive Impairment (aMCI). Spearman rank correlations were computed between speech biomarkers and gold‐standard clinical measures. Kruskal‐Wallis test assessed group differences and regression analysis adjusted for age, sex and education, associated domain‐specific speech biomarkers and cognitive assessment scores.ResultThere was a significant difference in the speech biomarker for cognition composite score (ki:e SB‐C) between diagnostic groups (x2(2) = 18.06, p <0.001). Significant correlations were found between ki:e SB‐C and all global anchor scores including MMSE (r = 0.48, d = 0.97, p <0.001), CDR‐SoB (r = ‐0.49, d = ‐0.98, p <0.001) and PACC5 (r = 0.56, d = 1.12, p <0.001) (Figure 1). All domain‐specific biomarker composite scores (memory, executive function, processing speed) significantly correlated with CDR, with strongest correlations found with the memory biomarker. All correlations remained significant when controlling for age, sex and education. Finally, based on the regression analysis results, domain‐specific biomarkers were significantly associated with respective domain‐specific anchors (Clock Drawing, TMT‐A/B, Digits Span, Figure Drawing, ADAS‐Cog, Verbal Fluency) (Table 1).ConclusionFindings support prior research, emphasizing speech biomarkers as a promising tool for remote early‐stage AD screening, with potential implications for scalable screening in research trials and healthcare.
Timed “ Up and Go” test in single and dual‐task conditions in older people with and without cognitive impairment according to Verbal Fluency Screening
Authors: Baccani Beatriz S. E. , Borges Sheila de Melo 
Published: January 2025

AbstractBackgroundMotor performance is related to executive function, especially in dual tasks conditions. Thus, the aim of this study was to compare the results of Timed “Up and Go” test with and without dual task in older people with and without cognitive impairment according to verbal fluency test.MethodA cross‐sectional study was carried out in 291 elderly people attended by the Basic Health Unit of the city of Santos, São Paulo, Brazil. These elderly patients were divided in two groups, according to the presence of cognitive impairment (SG; n = 106) and the group without cognitive impairment (CG; n = 185) using Verbal Fluency (VF) test – animals category. The Timed “up and go” (TUG) test was evaluated under three experimental conditions: TUG‐simple (TUG alone); TUG‐cognitive (TUG with animal fluency task); and, TUG‐manual (TUG while carrying a full cup of water). The Mann‐Whitney test was used to compare TUG test between the groups (SG and CG) and ANCOVA for adjustment of the variable (age). The numerical data was presented with mean [minimum‐maximum] between groups.ResultThe results showed a significant difference between groups on the development of TUG simple (SG = 11.17[6.63‐33.26] seconds, and CG = 9.79[5.0‐17.25] seconds ‐ p<0.001), TUG‐cognitive (SG = 13.29[6.07‐60.02] seconds, and CG = 11.76[4.15‐28.88] seconds ‐ p<0.001); and, TUG‐manual (SG = 12.29[7,13‐38,70] seconds, and CG = 10.5[4.75‐19.85] seconds ‐p<0.001) and this values remained significant after ANCOVA for adjustment of age (p<0.001).ConclusionOlder adults with cognitive impairment evaluated by VF test presented worse motor performance in both, with and without dual‐task conditions as compared to older person without cognitive impairment.