bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Transport Mapping Derived Tracer Velocity for Alzheimer’s Disease
Authors: Zhou Liangdong , Wang Yi , Chiang Gloria , de Leon Mony J. , Li Yi 
Published: December 2023

AbstractBackgroundThe Alzheimer’s disease (AD), featured with extracellular beta‐amyloid plaque and intracellular tau tangles, are considered caused by the brain clearance function deficits. One anatomical representation of the fluid stasis is the enlargement of the perivascular space. Our hypothesis is that the fluid stasis will reduce the fluid velocity, and the reduced fluid velocity will drive the PET tracer slower than normal. We used the velocity map from our proposed quantitative transport mapping (QTM, L. Zhou MRM 2020.) to evaluate the PET tracer velocity in Alzheimer’s disease.MethodFifty‐seven subjects (age: 69.7±9.1, Female/male = 37/20, NL/MCI = 45/12) went through both 11C‐PIB and 18F‐MK‐6240 PET scan for Aβ and tau deposit measurements, and MRI scan for ROI parcellation. PIB SUVR, MK vCSF‐Slope (Y. Li Fluids Barriers CNS 2022), MK QTM are processed for the following analysis. Specifically, vCSF‐Slope was computed as the tracer turnover rate in lateral ventricle using the dynamic MK data between 10 to 30min, normalized by the whole brain AUC in 1 to 4min. QTM velocity was processed using the dynamic MK data between 40 to 55min using mass conservation equation. Regression model for predicting Aβ using QTM was conducted by controlling for age and sex. The relationship between QTM and vCSF was evaluated. The use of QTM to distinguish subjects groups are tested.ResultOur preliminary results showed that quantitative transport mapping(QTM) based on fluid mechanics is significantly associate the ventricular CSF clearance(vCSF) measured by dynamic PET data and brain amyloid(PiB PET). The regression model shows that cerebral cortex (GM) QTM velocity (p<0.01, t = ‐2.76) and age (p<0.05, t = 2.55) are significantly associated with the GM PIB SUVR as shown in Figure 1. This indicates that high Aβ deposit is associated with lower QTM velocity, i.e., clearance deficits. Figure 2 shows that in GM QTM velocity is correlated with the vCSF‐Slope (p<0.05, r = 0.37). Figure 3 shows that QTM velocity in both GM and lateral ventricle are able to distinguish normal and MCI/AD groups.ConclusionThe tracer velocity in the brain tissue measured by QTM is associated with ventricular CSF turnover rate and brain amyloid burden.
Acknowledgement: This study is supported by NIA grant AG057848
Blood‐based quantification of Aβ oligomers indicates impaired clearance from brain in ApoE ε4 positive subjects
Authors: Willbold Dieter , Blömeke Lara , Rehn Fabian , Pils Marlene , Kraemer‐Schulien Victoria , Kutzsche Janine , Bujnicki Tuyen , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Bürger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Wagner Michael , Peters Oliver , Bannach Oliver 
Published: December 2023

AbstractBackgroundQuantification of Aβ oligomers in plasma may be useful not only for early diagnosis of Alzheimer’s disease (AD), but particularly to improve our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology due to very low concentrations and possible interferences of matrix components. Owing to their central role in AD pathology, oligomers are an attractive therapeutic target to ultimately halt disease progression or even to cure AD.MethodIn the present study, we developed and validated the surface‐based intensity‐distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. sFIDA is single particle sensitive and completely insensitive to Aβ monomers.ResultThe blood‐based sFIDA assay delivered a sensitivity of 1.8 fM, an inter‐ and intra‐assay variation below 20% for silica‐nanoparticles (SiNaPs) as calibration standard, and no interference with matrix components. Quantification of Aβ oligomers in 366 plasma samples from the DELCODE cohort, revealed decreased oligomer concentrations in subjective cognitive decline and AD patients compared to healthy controls. Correlation analysis between CSF and plasma oligomer concentrations suggest an impaired clearance of Aβ oligomers depending on ApoE ε4 status.ConclusionsFIDA is able to quantitate Aβ oligomers in plasma samples down to the low fM range. Aβ oligomers in plasma may reveal clearance mechanisms from the brain into blood, and how they are impaired during disease progression.
Concurrent MR‐PET investigation of memory consolidation and dopaminergic modulation in ageing
Authors: Yi Yeo‐Jin , Garcia‐Garcia Berta , Johansson Jarkko , Betts Matthew , Speck Oliver , Kreißl Michael C. , Düzel Emrah , Hämmerer Dorothea 
Published: December 2023

AbstractBackgroundThe dopaminergic system plays a crucial role in modulating learning and memory and undergoes age‐related changes that contribute to neurological disorders (Volkow et al., 1998; Pan et al., 2019) and reduced cognitive maintenance in ageing (Nyberg et al., 2016). Advanced imaging techniques can assess dopaminergic function in vivo in humans. In our study, we used dynamic concurrent magnetic resonance‐positron emission tomography (MR‐PET) which allows to infer dopamine release concurrent to functional MR imaging to investigate the relationship between dopaminergic neuromodulation in memory and healthy ageing. These measurements provide valuable insights into the critical role of the dopaminergic system in sustaining cognitive function during ageing and may help us elucidate the consequences of neuromodulatory decline in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s dementia.Method27 healthy adults over 65 underwent two dynamic MR‐PET imaging sessions with [18F]fallypride to measure D2/3 receptor occupancy and changes in nondisplaceable binding potential (∆BPND) in the striatum and extrastriatal regions. MRI scans were acquired concurrently, along with functional scans during a reward‐based memory task. Transient endogenous dopamine release was captured using a linear parametric neurotransmitter PET model.Result∆BPND of active PET (high dopamine condition) session was negatively correlated with the T‐static values in the bilateral hippocampus activation clusters in the reward versus neutral scene stimuli contrast (rho = ‐.41, p<.05), while the correlation was nonsignificant in passive PET (low dopamine condition) session.ConclusionWe used concurrent MR‐PET imaging to investigate the role of endogenous dopamine release and hemodynamic activity in memory consolidation. Higher endogenous dopamine release in the hippocampus during memory encoding was associated with greater functional activation in response to reward‐associated stimuli. Future analyses will examine links between brain health indicators and individual differences in memory consolidation and cognitive function. These findings may have implications for improving memory function in ageing and neurodegenerative diseases.
Human CSF pharmacoproteomics establishes in vivo‐relevant BACE1 substrates as pharmacodynamic biomarkers for chronic BACE inhibition in clinical trials
Authors: Lichtenthaler Stefan F , Giesbertz Pieter , Graf Ana , Kennedy Matthew E. , Horiguchi Naotaka , Müller Stephan A. 
Published: December 2023

AbstractBackgroundBACE1 is a major drug target for Alzheimer’s disease, but several late‐stage clinical trials with BACE‐inhibitors were associated with adverse events, most notably worsening in measures of cognitive function. Inhibition of BACE1‐dependent processing of a set of CNS membrane proteins is possibly responsible for these adverse findings. It is however unknown, which physiological BACE1 substrates are affected in humans at clinically relevant doses of a BACE inhibitor. To identify such substrates, we carried out a quantitative proteomic analysis of cerebrospinal fluid (CSF) from a subset of participants of phase 2 clinical trials with umibecestat or atabecestat or of a phase 3 clinical trial with verubecestat.MethodPre‐ and post‐dose CSF samples were quantitatively analyzed by nanoLC‐MS/MS. Selected proteins were further validated by ELISA. Changes in BACE1 substrate abundance were correlated with changes in Ab, sAPPb and with occurence of cognitive worsening.ResultMore than 1,000 CSF proteins were relatively quantified between the BACE inhibitor‐treated groups versus placebo. The cleaved extracellular domains of several BACE1 substrates with established neuronal or synaptic functions displayed a dose‐dependent reduction. This included SEZ6, SEZ6L, CACHD1, CHL1, L1 and the APP family members APLP1 and APLP2. While some substrates, e.g. SEZ6, were reduced to similar degree as Ab and sAPPb, the reduction for other substrates was less than 50%, presumably because they are cleaved by additional proteases other than BACE1. BACE inhibition significantly and dose‐dependently increased CSF abundance of only a single quantified protein, the myelin‐associated glycoprotein. Similar protein changes upon BACE inhibition or BACE1 deletion were seen in CSF of mice and of non‐human primates and indicate that BACE1 substrates are evolutionarily conserved.ConclusionBACE inhibitors in clinical trials block cleavage of multiple BACE1 substrates in a dose‐dependent manner. A reduction of the inhibitor dose to less than 50% BACE1 inhibition may be an appropriate strategy to avoid side effects in future clinical trials with BACE inhibitors. Our analysis also demonstrates that proteomics enables pharmacodynamic studies of multiple CSF proteins in single measurements, which are suitable for precision medicine approaches in future clinical trials with BACE inhibitors.
Performance of optimized prototype LUMIPULSE G immunoassays for plasma pTau181 and pTau217
Authors: Lambrechts Charlotte , Van Loo Maxime , Vanbrabant Jeroen , Dekeyser Filip , Bayoumy Sherif , Verberk Inge M.W. , Zwan Marissa D. , van der Flier Wiesje M. , Rubel Carrie E. , Czerkowicz Julie , Fraser Kyle , Graham Danielle , Inaoka Daigo , Aoyagi Katsumi , Teunissen Charlotte E. , Stoops Erik 
Published: December 2023

AbstractBackgroundThere is a need for automated random access plasma phosphorylated Tau (pTau) methods that reflect AD pathology with consistent performance. LUMIPULSE (LP) assays could offer a solution. Initial prototype pTau181 and pTau217 LP assays showed lower clinical performance versus Quanterix Homebrew assays (Poster #79533 – P4‐06). This new study presents optimized pTau181 and pTau217 LP assays, showing data on their analytical and clinical performance compared to the initial prototype method (Ref) and an in‐house pTau181 Quanterix Homebrew assay.MethodPlasma pTau181 and pTau217 LP assays were developed using recombinant pTau181 mAb RD‐070, resp. pTau217 mAb RD‐085, combined with an ALP‐Fab conjugate from recombinant N‐terminal Tau mAb RD‐073. In the optimized automated protocol, an assay specific diluent (ASD) is added (20%) to the sample to increase signal specificity. Analytical and clinical performance of the reference versus ASD‐treated prototypes to distinguish AD from controls was evaluated using 40 CSF‐confirmed AD‐dementia and 40 age‐matched healthy volunteer plasma samples.ResultAnalytical performance: Both optimized pTau181 and pTau217 LP tests demonstrated high precision comparable to their reference assays (inter‐run %CV on 3 neat plasma samples < 7.4). LLOQ was not affected by ASD‐treatment. Clinical performance: pTau181 LP assays demonstrated comparable AUC and median fold change with (AUC 0.828, fold change 1.9) and without ASD (AUC 0.823, fold change 1.5) while the SIMOA assay demonstrated a higher AUC (0.866) and fold change (2.9). For pTau217, the performance improved from an initial AUC of 0.918 to 0.935, and a fold change of 3.72 instead of initially 2.76. (Figure 1). All assays correlated strongly (p<0.00001) (Table 1); highest correlations among them were observed with the pTau217 ASD‐treated assay.ConclusionUsing an assay specific diluent resulted in improved clinical performance for the pTau217 prototype LUMIPULSE assay, in line with other published pTau217 assays. We did not achieve improved performance of the pTau181 LP assay with the ASD addition. Most important to emphasize, a performant pTau217 assay prototype is under development on an fully automated, scalable platform. Next steps include verification of performance in additional well‐characterized AD cohorts and characterization of lot consistency and robustness of the pTau181 and pTau217 N‐terminal LUMIPULSE assays.
The effect of oral galactose on oxidative stress in the brain of a transgenic mice model of Alzheimer’s disease
Authors: Barilar Jelena Osmanović , Kovac Diana , Knezovic Ana , Perhoc Ana Babic , Salkovic‐Petrisic Melita 
Published: December 2023

AbstractBackgroundChanges in the brain energy metabolism and oxidative stress can be found before development of Aβ plaques in Alzheimer’s disease (AD) and galactose showed potential therapeutic effect in Tg2576 mice AD model. We aimed to investigate changes in the hippocampal (HPC) energy status and oxidative stress before and after galactose treatment in this model.MethodAdult male B6; SJL‐Tg(APPSWE)2576Kha transgenic (TG) mice (Tg2576) and wild types (WT) aged 5 (5M) and 10 (10M) months were used. Oral galactose therapy was given to half of WT (WT+G) and half of TG (TG+G) group for 2 months (200mg/kg/day), while another half of each group received water ad libitum. Protein expression of insulin receptor substrate (total and phosphorylated; IRS, pIRS), AMP‐activated protein kinase (AMPK, p‐AMPK) was measured by western blot. Corticosterone levels were measured by ELISA, and spectrophotometry were used to measure the parameters of oxidative stress (MnSOD; TBARS). Data were analyzed by Kruskal‐Wallis and Mann‐Whitney U‐test (p<0.05).ResultThe levels of corticosterone were decreased in 5M TG mice (p = 0.0055; n = 8) and galactose (5M TG+G) increased it to the levels of control. Galactose decreased MnSOD (p = 0.0329;n = 5) in 10M TG mice. The decrement in p/t IRS ratio (p = 0.043; n = 5) was seen only in 10M TG mice, and galactose (10M TG+G) reversed it to the levels of control. Increased AMPAK levels were found in 5M TG+G (p = 6,5e‐04; n = 5) and 5M WT+G (p = 8,6e‐05; n = 5) groups, while pAMPK was increased only in 5M TG (p = 0.013; n = 5), and decreased in 5M TG+G group after galactose treatment (p = 0.034: n = 5).ConclusionGalactose increased the corticosterone and AMPK levels in young TG mice, while in older TG mice oral galactose had the effect on the level of MnSOD and p/t IRS ratio. The potential therapeutic impact of oral galactose in Tg2576 mice seems to be connected to maintaining of oxidative stress and energy balance and depends on the animal age and AD stage at which the treatment was initiated. Supported by HRZZ IP‐2018‐01‐8938 and the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”, GA KK01.1.1.01.0007 funded by the European Union)
Effects of a 24‐week resistance exercise program on psychological distress in cognitively normal older adults. Preliminary results of The AGUEDA Randomized Control Trial
Authors: Bellon Dario , Rodriguez‐Ayllon Maria , Solis‐Urra Patricio , Coca‐Pulido Andrea , Mora‐Gonzalez Jose , Toval Angel , Fernández‐Ortega Javier , Bakker Esmée A , Ortega Francisco B , Esteban‐Cornejo Irene 
Published: December 2023

AbstractBackgroundThe World Health Organization (WHO) estimates that, by 2050, the world’s population over the age of 65 will reach 71 million, and in turn, there is a clear trend of increasing numbers of older adults with some form of mental illness. Indeed, over 21% of older people are affected by mental disorders (e.g., depression or anxiety). Favorably, exercise is known to be an effective alternative for the prevention and treatment of mental health disorders, however, most of this evidence has focused on aerobic training, whereas the effects of resistance training remain unexplored. Thus, the aim of this study is to examine the effects of a 24‐week resistance exercise program on psychological distress in cognitively normal older adults.MethodsThe study included 81 cognitively normal older adults with valid baseline and follow‐up data who were randomly assigned to either a 24‐weeks resistance exercise program (n = 43) or a wait‐list control group (n = 38) as part of the AGUEDA trial (NCT05186090). The exercise program included 3 sessions/week, 60 min each. Psychological distress indicators (i.e., depression‐anxiety symptoms, stress and loneliness) were assessed using a set of valid and reliable self‐reported questionnaires. The effects of the intervention were examined using analysis of covariance (ANCOVA), where post‐exercise outcome values were the dependent variables, group (exercise vs control) the fixed factor, and baseline outcome data the covariates. The intervention effects were presented as z‐scores of changes.ResultsThe AGUEDA exercise program had a no effect on anxiety symptoms (z‐score = 0.106), 95% confidence interval (CI): ‐0.514 to 0.126, p = 0.232), stress (z‐score = 0.036), 95% CI: ‐0.313 to 0.449, p = 0.723) and loneliness (z‐score = 0.026), 95% CI: ‐0.315 to 0.432, p = 0.723). There was a borderline, with a small, nonsignificant effect on depressive symptoms (z‐score = ‐0.106), 95% CI: ‐0.752 to 0.051, p = 0.086).ConclusionThe 24‐weeks exercise intervention had no effect on most of the psychological distress indicators. However, we observed a borderline, small, nonsignificant effect in depressive symptoms. Therefore, future interventions with a larger sample size or longer intervention are needed to confirm these findings.
Periodontitis and future cognitive decline
Authors: McGuinness Bernadette , Passmore Anthony Peter , Holmes Clive , Teeling Jessica , Linden Gerry , Farsi Dominic , McEvoy Claire T , McKay Gareth J , Abadelkareem Rana , Patterson Christopher , McAlinden Michael 
Published: December 2023

AbstractBackgroundPeriodontitis (gum disease) is a is a chronic inflammatory disorder. Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Aggregatibacter actinomyecetemcomitans (Aa), and Treponema denticola (Td) are the most common periodontal pathogens. Evidence of a longitudinal association between periodontitis and dementia is currently lacking. We therefore proposed that prior periodontitis in 60‐70 year old men increases the longitudinal risk of cognitive decline.MethodPRIME‐COG is a nested in PRIME (Prospective Epidemiological Study of Myocardial Infarction), a cohort study of men in Northern Ireland (NI). Between 2001 and 2003, 1400 men underwent a periodontal examination, had inflammatory markers measured in blood, exposure to periodontopathogens identified within dental plaques, and a cognitive assessment. 874 men had a comprehensive cognitive assessment fifteen to twenty years later from which a consensus diagnosis of normal cognition, mild cognitive impairment (MCI) or dementia was made by experienced clinical researchers. Logistic regression models were performed to assess the association between periodontitis and future cognitive endpoints. In addition, serum IgG levels to Pg, Tf, Aa and Td and a panel of pro‐inflammatory cytokines were determined at baseline and follow‐up visits.ResultWe did not identify any significant associations between periodontitis and dementia and/or MCI or cognitive decline in the extended follow up period. No differences in IgG serum titres to pathogens in baseline and follow‐up visits were seen for patients diagnosed with dementia or MCI, whereas levels were significantly decreased in the normal cognition group. Serum levels of IL‐6 at baseline were significantly higher in patients with MCI and dementia compared to those with normal cognition among men aged 76 years plus (p = 0.002); and 81 years plus (p = 0.02) respectively. IL‐8 levels were significantly different in patients with MCI aged 81+ years compared to those with normal cognition at baseline (p = 0.014) and follow‐up (p = 0.012).ConclusionWithin a cohort of older men residing in the NI, periodontitis was not associated with later onset of dementia or MCI following an extended follow up. Maintenance of high IgG levels over the years might indicate ongoing persistent infection associated with dampened immune response. This could contribute to increased risk of dementia/MCI.
Dissecting the shared genetic basis of Alzheimer’s disease and hippocampal volumes
Authors: Jiang Chenyang , van der Lee Sven J , van der Flier Wiesje M. , Tijms Betty M. , Reus Lianne M. 
Published: December 2023

AbstractBackgroundHippocampal atrophy is an important pathophysiological event in Alzheimer’s disease (AD) etiopathology. Still the mechanistic link between these volumetric abnormalities and AD remains poorly understood. In this study, we estimated polygenic overlap with mixed effect directions between AD and bilateral hippocampal volumes, and identified commonly shared genetic variants between two traits, involved in several synaptic and immunomodulatory genes.MethodFor this study we used GWAS summary statistics on AD (1,11,326 cases and 6,77,663 controls) (Bellenguezet et al., 2022) and hippocampal volumes (33,224 populations controls) (Smith et al., 2021). First, we applied Bivariate causal mixture model (MiXeR version1.3, Frei et al., 2021) to quantify the polygenic overlap between AD and bilateral hippocampal volumes. For each AD‐volume pair, MiXeR estimated the shared polygenic architecture between two traits, irrespective of the direction of individual variants effects.To explore the MiXeR estimated shared genetic basis at individual variant level, we used the conjunctional false discovery rate (conjFDR) analysis (Andreassen et al., 2013) on the association of AD with bilateral hippocampal volumes, and vice versa. The conjFDR analysis is built on an empirical Bayesian statistical framework. Four regions (MHC, 8p23.1, MAPT, APOE) with complex LD patterns were excluded from the analyses because complex correlations in regions with intricate LD might bias the estimation.ResultMiXeR univariate analysis estimated the number of AD risk variants to be around 343 genetic variants, and the number of variants for bilateral hippocampal volumes between 901 and 942 variants. MiXeR bivariate analysis estimated that the number of shared variants between AD and bilateral hippocampal volumes was around 75 and 96 variants (see Figure 1). At conjFDR < 0.05, we identified 10 common loci shared by AD and left hippocampal volume,6 lead SNPs had consistent effect directions, while 4 loci have opposite effect directions according to their Z value. 8 common loci shared by AD and right hippocampal volume, 5 lead SNPs have consistent effect directions, 3 have opposite effect directions. (see Figure 2 and Table 1)ConclusionThis study provides evidence of a shared genetic architecture between AD and bilateral hippocampal volumes. The identification of common loci helps to understand the role of hippocampus in AD pathology.