bluuebunny/crossref_metadata_2025_split huggingface dataset:
KLOTHO KL‐VS genotype modifies the relationship between cardiorespiratory fitness and CSF biomarkers of neurodegeneration, synaptic dysfunction, and inflammation
Authors: Jarchow Mackenzie , Driscoll Ira , Breidenbach Brianne M. , Cook Noah R. , Gallagher Catherine L. , Johnson Sterling C. , Asthana Sanjay , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Cook Dane B. , Dubal Dena B. , Okonkwo Ozioma C 
Published: January 2025

AbstractBackgroundLess adequate cardiorespiratory fitness (CRF) is associated with several aspects of Alzheimer’s disease (AD) pathology, including neuroinflammation, neurodegeneration and synaptic dysfunction, all of which are known contributors to the clinical outcome – progressive cognitive decline [1]. AD‐associated biomolecular changes also seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL‐VSHET) [2]. While KL‐VSHET and CRF both appear to mitigate aspects of AD pathology, they have been exclusively studied in isolation. Here we investigate whether the relationships between CRF (VO2 max) and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, synaptic dysfunction, and inflammation differ for KL‐VSHET compared to non‐carriers (KL‐VSNC).MethodThe cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=132; MeanAGE=62.7) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center. Covariate‐adjusted (age, sex, parental AD history, APOE, and age difference between CSF sampling and exercise test) linear models examined the relationship between VO2 max and CSF biomarkers of neurodegeneration [α‐synuclein (α‐syn), neurofilament light polypeptide (NfL), total tau (tTau)], synaptic dysfunction [neurogranin (Ng)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), chitinase‐3‐like protein 1 (YKL‐40), interleukin 6 (IL‐6), S100 calcium‐binding protein B (S100B)] as a function of KLOTHO KL‐VS.ResultThe interaction between VO2 max and KL‐VSHET was significant for tTau (P=0.05), Ng (P=0.02), sTREM2 (P=0.02), and YKL‐40 (P=0.03) (Table 1; Figure 1), such that KL‐VSHET who were more fit had significantly lower levels of tTau, Ng, sTREM2, and YKL‐40 but not α‐syn, NfL, GFAP, IL‐6, or S100B (all Ps>0.63).ConclusionWe report a synergistic relationship between KL‐VSHET and CRF with regard to neurodegeneration (tTau), synaptic dysfunction (Ng) and inflammation (sTREM2 and YKL‐40), suggesting a protective role for both KL‐VSHET and better cardiovascular fitness against unfavorable AD‐related changes. Their potentially shared biological mechanisms will require future investigations.References[1] Huuha, A.M., et al., Can exercise training teach us how to treat Alzheimer's disease? Ageing Res Rev, 2022. 75: p. 101559.[2] Driscoll, I., et al., AD‐associated CSF biomolecular changes are attenuated in KL‐VS heterozygotes. Alzheimers Dement (Amst), 2022. 14(1): p. e12383.
Higher cardiorespiratory fitness is associated with higher cerebral myelination in normative aging
Authors: Faulkner Mary E , Gong Zhaoyuan , Bilgel Murat , Laporte John P , Guo Alex , Bae Jonghyun , Elango Palchamy , Bergeron Christopher M , Bouhrara Mustapha 
Published: January 2025

AbstractBackgroundAge‐related white matter (WM) deterioration has been associated with several neurodegenerative diseases, including Alzheimer’s disease. Studies suggest that cardiorespiratory fitness (CRF) is important in preserving WM structure and function. However, clinical investigations of the relationship between myelin integrity and CRF are lacking. In this study, we evaluated the association between CRF, assessed by the maximum rate of oxygen consumption (VO2max), and cerebral myelin content, defined by myelin water fraction (MWF), throughout the adult lifespan. Understanding the mechanisms of WM degeneration is crucial for developing targeted interventions to maintain cognitive health into late life.MethodAfter excluding subjects with cognitive impairments or unexploitable MRI data, a total of 110 cognitively unimpaired participants, ranging in age from 22 to 94 years, were drawn from the BLSA and GESTALT studies. Each participant underwent our BMC‐mcDESPOT MRI protocol for whole brain MWF mapping. VO2max was assessed using graded maximal treadmill test as per our established protocol. Fourteen WM ROIs were defined from the MNI structural atlas. For each ROI, a linear regression model adjusted for relevant covariates (Table 1) was used to determine whether 1) VO2max is significantly correlated with MWF, and 2) the strength of the correlation between VO2max and MWF depends on age (age×VO2max interaction). Continuous variables were z‐scored.ResultHigher VO2max was significantly associated with higher MWF (Figure 1). This association was strongest in brain regions susceptible to early degeneration (Table 1), including the frontal lobes (β=0.28, p=0.011) and white matter tracts, such as the internal capsule (β=0.27, p=0.025) and corona radiata (β=0.27, p=0.016). Further, the interaction between age and VO2max exhibited i) a steeper positive slope in the older age group, suggesting that the effect of VO2max on MWF is stronger at older ages, and ii) a negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with more rapid demyelination with advancing age (Figure 2 & Table 1).ConclusionThese original findings provide the first evidence that high CRF is important for the preservation of myelin integrity and slowing of age‐related neurodegeneration, laying the groundwork for further investigations including longitudinal and interventional studies.
A disease modification drug screening platform targeting neuronal hyperexcitability and seizures in Alzheimer’s disease‐associated mouse models
Authors: Knox Kevin M , Lehmann Leanne M , Sanz Aaron Del Pozo , Robinson‐Cooper Larissa , Davidson Stephanie , Barker‐Haliski Melissa 
Published: January 2025

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) associated with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants increases risk of seizures. Targeting epileptiform activity with antiseizure medicine (ASM) administration to AD patients may beneficially attenuate cognitive decline (Vossel et al, JAMA Neurology 2021). However, whether mechanistically distinct ASMs differentially suppress seizures in discrete EOAD models is understudied (Lehmann et al, Neurochem Res 2021). To fill this gap, we validated a moderate‐throughput drug screening program consisting of well‐established ASM discovery tests applied in three discrete EOAD‐associated models: PSEN2 knockout (KO), PSEN2‐N141I (Volga German variant), and APPswe/PS1dE9 mice. Critically, PSEN2‐N141I model does not demonstrate accumulated amyloid beta (Ab) whereas APP/PS1 mice show increased Ab expression by ∼6 months‐old. We hypothesized EOAD‐associated models would differentially influence focal seizure threshold, susceptibility to evoked focal seizures, and ASM sensitivity with advanced age.MethodPSEN2 KO, PSEN2‐N141I, APP/PS1, and wild‐type (WT) mice were tested beginning at 2‐months‐old and up to 14‐months‐old in acute and chronic seizure screens: minimal clonic and 6 Hz focal seizure threshold, 6 Hz electroconvulsive test, corneal kindling, and kainic acid‐induced status epilepticus (KA‐SE), consistent with our published methods for ASM discovery (Barker‐Haliski et al, Neurochem Res 2017; Knox et al, Epilepsia 2021). Mice were assessed in two seizure threshold tests every 2 months until 12‐months‐old. Mechanistically distinct ASMs (diazepam, valproic acid, lamotrigine, and levetiracetam) profiled genotype‐specific pharmacosensitivity in the seizure assays (6 Hz, corneal kindling, and KA‐SE).ResultFunctional connectivity differences appeared as notable blunting of age‐related increases in 6 Hz seizure threshold of APP/PS1 mice by as early as 4‐months‐old (APP/PS1 median convulsant current: 24.6 mA [22.2‐26.9] versus WT: 31.7 [27.8‐36.9]). Chronic kindled seizure susceptibility varied by genotype, with ASM‐specific differences in seizure control between EOAD models. Specifically, kindled seizures of aged APP/PS1 mice were more sensitive to valproic acid and levetiracetam, whereas valproic acid and lamotrigine were more potent in aged PSEN2‐N141I mice.ConclusionEOAD‐associated risk genes do not equally influence age‐related seizure susceptibility or impact ASM efficacy; seizures in AD may require precision medicine interventions. Further ASM profiling focused on attenuating neuronal hyperexcitability may uncover novel disease‐modifying strategies for AD.
Pattern‐separation induced neural activations in midlife women at risk for AD
Authors: Zhuang Xiaowei , Yang Zhengshi , Cordes Dietmar , Caldwell Jessica ZK 
Published: January 2025

AbstractBackgroundSex‐specific functional‐brain changes during memory tasks have been reported along the Alzheimer’s disease (AD) continuum. However, mid‐life risk factor effects on memory‐related neural activation remain less clear in women with increased AD risk. Here we examined brain activations during a modified pattern‐separation task and their associations with verbal memory scores in midlife women at risk for AD due to family history.MethodMRI data were acquired from 12 middle‐aged at‐risk women on a 3‐Tesla Siemens Skyra scanner (34 to 57 years old, mean‐age=50.83). Three task‐functional MRI (fMRI) runs were collected (TR=1.485s, 2mm isotropic, 524 time‐frames) during a modified pattern‐separation task with explicit encoding and recognition phases (detailed in Figure 1).After preprocessing, a general linear model (GLM) was employed on time‐frames during the recognition phase across three sessions concatenated. Five conditions were modeled, including new‐objects correctly identified as new (Foils), same‐objects correctly identified as same (Hits), similar‐objects correctly identified as similar (LureCR) or falsely identified as same (LureFA), and all other trials. Whole‐brain voxel‐wise analyses were conducted to examine differential activations for lure discrimination (LureCR‐LureFA). The association between significant neural activations and participants' age, task performance, and verbal memory scores (RAVLT) were tested.ResultsRobust neural activations were observed during Hits, LureCR and LureFA conditions (Figure 2(A)).Significant lure‐discriminative activity (LureCR‐LureFA) was observed in a cluster peaked at left inferior‐parietal, spanning across left‐angular, left‐middle‐temporal, and left‐supramarginal regions (red circle in Figure 2(B)). Neural activations in the left medial temporal region were positively correlated with age (correlation=0.61, p=0.04, Figure 2(C)), and positively correlated with task performance (partial‐correlation=0.83, adjusting for age, p=0.03, Figure 2(C)). A trend‐level negative association was observed between neural activations in the left inferior parietal region and RAVLT‐immediate scores (Figure 2(D)).ConclusionIn 12 at‐risk women, we observed robust lure‐discriminative activations in the left temporal and inferior parietal regions for during an object pattern‐separation task. Greater neural activation in these regions was evident in participants with higher task accuracies, but older and worse RAVLT performances, potentially indicating a compensatory neural mechanism to achieve high accuracies in a pattern‐separation task in midlife women 10 or 20 years prior to a potential AD onset.
A novel amyloid MRI imaging based on analysis of texture features representing Aß aggregation
Authors: Tatewaki Yasuko , Yamagata Hitoshi , Thyreau Benjamin , Yoneda Tetsuya , Nakase Taizen , Asato Momoka , Nagasaka Tatsuo , Kaneko Naoki , Hinman Jason , Taki Yasuyuki 
Published: January 2025

AbstractBackgroundThe importance of detecting amyloid β (Aβ) in the early stages of Alzheimer's disease has markedly increased following the approval of Lecanemab, a disease‐modifying drug. MRI is a non‐invasive and less expensive rather than amyloid PET as gold standard for Aβ biomarker, but its clinical ability to detect Aβ has not been demonstrated. MRI phase information reflects paramagnetic substance including iron associated with Aβ aggregation. We have developed a novel approach utilizing multi‐gradient echo (GRE) to perform texture analysis of the phase information, enabling visualization of Aβ. The primary aim of this study is to evaluate the diagnostic capabilities of this "Amyloid MRI" technique.MethodThe consecutive 48 participants (mean age: 72±10, mean MMSE: 25±4) who visited our memory clinic, and underwent both MRI and amyloid PET were enrolled. Amyloid PET images were visually interpreted as Aβ positive (n=30) or negative (n=18), and standardized uptake value ratio (SUVr) maps were generated. Multi‐GRE images were acquired with a 3‐Tesla MRI. We generated a phase slope map, i.e. a first‐order linear estimate of the phase change in time, and segmented four anatomical regions‐of‐interest (ROI) for cortex‐based analysis. Statistical analysis of texture features (mean, SD and entropy) derived from the phase slope map over each ROI was performed. We investigated the correlation between the mean value of regional SUVr and that of texture parameters of the phase slope map, and determined the optimal cut‐off of a linear classifier by ROC analysis based on the diagnosis of amyloid PET.ResultThe correlation coefficients between the mean value of SUVr and the texture features of the phase slope map in parietal, PCCpre, frontal and temporal were 0.57 (p<0.0001), 0.56 (p<0.0001), 0.48 (p<0.0006) and 0.22 (p<0.22), respectively. The optimal cut‐off values for diagnosing Aβ positive or negative showed a sensitivity of 83% (73‐93%), specificity of 89% (74‐103%) and accuracy of 85%(75‐96%).ConclusionThe texture features of the phase slope map could reflect the spatial aggregation pattern of Aβ. Our method highlighted the potential to visualize Aβ using MRI.
Diagnostic challengein late onset CADASIL with atypical presentation‐case report
Authors: Romero Aury Stella Carrasquilla , Holguin Sergio Andres Taborda 
Published: January 2025

AbstractBackgroundThis study examines an exceptional case of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a hereditary cerebrovascular disease caused by a mutation in the notch3 gene. In contrast to typical cases manifesting before the age of 50 with migraines, this report highlights an atypical presentation in a 70‐year‐old woman with no history of migraines nor cognitive impairment.MethodThe patient, with a history of type 2 diabetes, hypothyroidism, and dyslipidemia, was initially treated for cognitive impairment and behavioral changes under suspicion of autoimmune encephalitis. During outpatient follow‐up, the notch3 mutation was documented (Variant c.421c>T; p.Arg141Cys heterozygous NOTCH3 probably pathogenic Code 404841 GP) and confirmed through brain magnetic resonance imaging (MRI) consistent with CADASIL. The clinical examination included neuropsychological assessments and detailed genetic testing.ResultThe patient experienced rapid cognitive deterioration and behavioral changes, with temporary improvements following immunosuppressive treatments. However, complications arose, including pulmonary thromboembolism. Brain MRI revealed hyperintensity in the white matter of frontal and temporal lobes. Genetic analysis identified a probably pathogenic heterozygous variant in the notch3 geneConclusionThis case underscores the importance of considering CADASIL in atypical presentations, especially in older patients. Confirmation of the diagnosis through MRI and genetic analysis emphasizes the significance of these diagnostic tools. While proven therapies for improving the disease are lacking, the study highlights the relevance of comprehensive care and specialized follow‐up in CADASIL cases. It concludes with the need for further research in older adult populations to better understand the prevalence and evolution of the pathology in this demographic.
A trial of the iron‐chelator deferiprone in Alzheimer’s disease
Authors: Ayton Scott , Bush Ashley I. ,   3D trial investigators
Published: January 2025

AbstractBackgroundIron is vital for metabolism but can act as a catalyst for oxidative damage. Elevated brain iron, determined from biomarkers of iron (CSF ferritin and quantitative susceptibility mapping MRI) and from post‐mortem measurement of brain iron, has been associated with accelerated cognitive decline in multiple Alzheimer’s disease (AD) clinical, cohorts. These findings supported the hypothesis that treatment with the brain‐permeable iron chelator deferiprone may be associated clinical benefit in AD.MethodsA multicentre, phase II, double‐blind, randomized, placebo controlled clinical trial of deferiprone (15 mg/kg administered orally twice a day) was conducted in people with amyloid‐confirmed MCI and mild AD (MMSE≥20) over 12 months. The primary outcome was cognition, assessed at baseline, 6 months, 12 months using neuropsychological test battery of memory (3), executive function (3) and attention (2). Secondary outcomes included adverse events (safety analysis), change in brain iron burden measured by quantitative susceptibility mapping MRI (target engagement), and brain volume changes (secondary efficacy measure).Results81 participants were recruited and randomized in a 2:1 ratio (53 drug:28 placebo). Baseline characteristics were equivalent between arms. 54 participants completed the study (withdrawals = 7 placebo and 20 deferiprone arm). Quantitative susceptibility mapping of the hippocampus at baseline and 12 months confirmed a significant (β[95%CI]:‐6.7 [‐11.0,‐2.5]; P = 0.004) lowering of brain iron in the deferiprone arm (mean change:‐3.71 ppb, 95% CI:‐7.24, ‐0.18) compared to placebo, whose iron levels increased during this timeframe (+3.03 ppb, 95%CI: 0.27, 5.80). Participants in the Deferiprone arm showed large statistically significant cognitive decline (β[95%CI]:‐0.295 [‐0.456, ‐0.135], P<0.001, Cohen’s d: ‐0.704) compared to placebo (deferiprone mean change, [95%CI]:‐0.86, [‐1.12, ‐0.61]; placebo mean change, [95%CI]:‐0.27, [‐0.55, 0.00]).ConclusionDeferiprone (30 mg/kg/day) treatment markedly accelerated cognitive decline in people with amyloid‐confirmed MCI and mild AD. These findings highlight the importance of iron for cognition in AD, and provoke new questions. It is possible that iron elevation in AD is protective, or represents iron being sequestered inappropriately (e.g. deposited in pathology) leading to functional iron deficiency; or the chosen dose of deferiprone was too high for this condition.
Plasma Biomarkers for Accelerated Cognitive Decline: A Tool for Targeted Clinical Trial Recruitment
Authors: Anastasi Federica , Escalante Armand González , Segura‐Retana Pol , Ortiz‐Romero Paula , López‐Martos David , Sánchez‐Benavides Gonzalo , Minguillon Carolina , del Campo Marta , Suarez‐Calvet Marc 
Published: January 2025

AbstractBackgroundDetecting Alzheimer's disease (AD) biological hallmarks before clinical symptoms emerge is now possible with available blood‐based biomarkers. However, the rate of cognitive decline varies among individuals at risk of AD, and accurate prognostic blood‐based biomarkers are lacking. Our goal is to identify plasma proteins predictive of fast cognitive decline in asymptomatic individuals at risk of AD.MethodWe studied 93 cognitively unimpaired individuals from the ALFA+ cohort with two longitudinal cognitive assessments (3‐year follow‐up, Preclinical Alzheimer Cognitive Composite, PACC). PACC‐changes were calculated as the change in PACC scores between two visits divided by the time elapsed. Adjustments for demographic variables associated with PACC‐change (age and education years) were made by residualizing. Two groups were defined based on residual median values, namely the slow‐ and the fast‐cognitive decliners groups. Protein levels in plasma were measured using Proximity Extension Assay (PEA) technology (Olink).ResultIn a preliminary analysis, non‐parametric univariate analysis of baseline proteomics data identified 74 significantly different proteins between slow‐ and fast‐cognitive decliners. Specifically, 29 proteins were upregulated in fast decliners, and 45 in slow decliners, with the latter enriched in REACTOME Pathways of Cytokine Signalling and Immune System. Synaptic proteins were among the most significantly deregulated.ConclusionPlasma protein signatures at baseline differ between individuals with fast and slow rates of cognitive decline. Early identification of those with rapid disease progression is crucial for efficient clinical trial recruitment. Faster cognitive decline can shorten testing periods, enhancing trial efficiency and expediting the assessment of potential interventions.
Discriminating between native and phosphorylated tau proteins using fluid‐lipid bilayer‐coated nanopores
Authors: Awasthi Saurabh , Mayer Michael 
Published: January 2025

AbstractBackgroundTau protein phosphorylation and aggregation are the pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. Multiple phosphorylation sites in Tau protein at serine (S), threonine (T), and tyrosine result in high heterogeneity and enhanced aggregation kinetics.MethodHere, we used nanopores coated with a fluid lipid bilayer to characterize native and hyperphosphorylated Tau proteins on a single‐molecule level.ResultSingle‐molecule level analysis determines the size, shape, net charge, and dipole moment of individual tau protein monomers. The approach makes it possible to differentiate native and hyperphosphorylated Tau proteins based on their net charge. Moreover, single‐particle size analysis revealed the spontaneous formation of low‐n oligomers such as dimer, trimer, tetramer and pentamers; no other molecules were needed to initiate aggregation to these oligomers.ConclusionThe nanopore‐based approach enables discrimination of native and hyperphosphorylated Tau proteins based on their net charge. Furthermore, single‐particle size approximation is helpful for detecting early‐stage aggregation of Tau and characterization of various oligomer species.