bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stable Isotope Labelling Kinetics tracing of Neurofilament Light in stem cell‐derived neurons and humans
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Coulton John , Zetterberg Henrik , Elbert Donald L , Bateman Randall J. , Mills Kevin , Wray Selina , Paterson Ross W. 
Published: December 2023

AbstractBackgroundNeurofilament light (NfL) is a neuronal cytoskeletal protein that is released into the extracellular environment from degenerated axons. As such, NfL levels in cerebrospinal fluid (CSF) and serum have been proposed as a promising biomarker of neurodegeneration, yet the metabolism of NfL in human neurons is unknown. Kinetic protein labelling can provide protein half‐lives and rates of production and clearance in vitro and in vivo.MethodUsing a stable isotope tracer (13C6‐leucine), we labelled two lines of pluripotent stem cell‐derived neurons and human study participants with primary tauopathies (n = 9). We collected neuronal lysates and conditioned media every three days during the labelling (“pulse”) and post‐labelling (“chase”) phases. CSF samples were collected across five visits, scheduled around 4, 14, 20, 60 and 120 days post‐labelling. We measured the ratio of labelled to unlabelled NfL using targeted mass spectrometry workflows to quantitate the rates of protein labelling (fractional synthesis rate) and label loss (fractional clearance rate), together providing the protein turnover rate.ResultThe average half‐life of NfL in cell lysates was four days (± 1.06 SD, n = 3 independent biological replicates). The turnover of extracellular NfL in neuronal conditioned media was slower than that found in neuronal lysates, suggesting that NfL is a rather stable protein in the extracellular milieu in vitro. In contrast, analysis of CSF from the in vivo tauopathy cohort detected low labelling of NfL (0.04 – 0.36%) by 120 days (n = 5), indicating that in vivo turnover is exceptionally slower than in vitro and that extended CSF collection and analysis >120 days post‐labelling is crucial to capture NfL production and clearance in vivo. To this end, additional analysis of healthy controls and patients with Alzheimer’s disease (control and AD cohorts; n = 24), which include CSF collection up to 219 ‐ 444 days post‐labelling, is ongoing.ConclusionTracking of both intracellular and extracellular NfL in neurons derived from healthy control individuals, as well as cells with mutations implicated in neurodegenerative diseases, are expected to shed light into the dynamics of NfL turnover in both physiological and pathological conditions. This will be critical for interpreting NfL in response to disease‐modifying therapies.
Pooled Modeling of Disease Progression in Two BACE1 Inhibitor Verubecestat Trials in Prodromal to Moderate Alzheimer’s Disease
Authors: Kleijn Huub Jan , Stone Julie A , Hu Henry , Crockett Theresa Y , Xu Ming , Robey Seth , Egan Michael F. 
Published: December 2023

AbstractBackgroundThe BACE inhibitor verubecestat (MK‐8931) at doses of 12 and 40 mg demonstrated cognitive and functional decline relative to placebo in a Phase 3 trial of prodromal AD (APECS, NCT01953601) and no effect on progression in a Phase 3 trial of mild‐to‐moderate AD (EPOCH, NCT01739348). Disease progression modeling was used to investigate the temporal pattern of the cognitive and functional drug effects and to explore covariate, dose‐ or exposure‐dependency in the pooled data from both trials. The key objective was to determine whether the rate of progression was slowed by BACEi but obscured by an early detrimental drug effect.MethodDisease progression models for the clinical efficacy outcomes (ADAS‐cog11, CDR‐SB) were developed using similar methodology to an established ADAS‐cog disease progression model (Ref). Parameters describing placebo response were first estimated. Akaike Information Criteria (AIC) were then used to select among potential drug effects (effects on progression rate and/or early detrimental offset) and to test for dependencies on dose, drug exposure, and patient characteristics. A simulation exercise confirmed that a true 25% or 50% reduction in the progression rate with treatment could be reliably identified in the setting of the early detrimental effect.ResultResults were generally concordant across ADAS‐cog11 and CDR‐SB. An early symptomatic (detrimental offset) response was identified with verubecestat; no effect on rate of disease progression was supported. The magnitude of the drug effect offset was estimated 1.8 for ADAS‐cog11 and 0.33 for CDR‐SB. Covariates were generally concordant across measures with disease severity at baseline identified for both progression rate and detrimental offsetting. Additionally, age, weight, geographic region, and education effects were identified on progression. Threshold analysis of the detrimental offsetting effect suggested that the effect was present in less severe disease but absent in the most advanced AD patients (ADAS‐cog11 baseline>24 and CDR‐SB baseline > = 12).ConclusionNo dose or AUC dependency on the detrimental offsetting effect of verubecestat was found, indicating that the maximum effect is achieved at 12 and 40 mg doses. There was no evidence supporting a slowed rate of disease progression by BACEi after accounting for the early detrimental drug effect.
Blood brain barrier damage in a mouse model of frontotemporal dementia
Authors: Orsini Franca , Micotti Edoardo , Martucci Annacarla , Pascente Rosaria , Bosica Marco , Forloni Gianluigi , Fioriti Luana 
Published: December 2023

AbstractBackgroundClinical evidence supports a major contribution of vascular insufficiency to the development of tauopathies. Interestingly, observations in patients with Fronto‐Temporal Demetia (FTD) highlighted microvascular changes predominantly within the areas affected by neuronal pathology. Further, data in animal model demonstrated that Tau‐P301L induces neurovascular dysfunctions independent of neurodegeneration, suggesting that cells of the Blood Brain Barrier (BBB) may represent a novel therapeutic target. However, the molecular mechanisms of vascular insufficiency in FTD remain elusive.MethodTo establish the pathological relationship between BBB alteration and FTD progression, we used JNPL3 mice, which express human Tau‐P301L mutation, and wild‐type (WT) controls. We assessed their memory at 5, 10 and 15 months using the Radial‐Arm‐WaterMaze (RAWM) and Y‐maze and their white matter integrity by MRI. We assessed Tau pathological changes (hyperphosphorylation and aggregation) and vascular alterations by WB and RT‐PCR. In addition, to determine the causal link between Tau and BBB damage we assessed viability of brain microvascular endothelial cells (BMECs) exposed toTau oligomers (oP301L) in vitro.ResultCompared to WT, white matter integrity is significantly compromised as early at 5 months in JNPL3 mice, when modest alterations in cognition also appear, while more pronounced memory deficits occur at 10 months. pTau‐(199/202) and IgG extravasation increase over time starting at 5 months and Claudin5 (CLND5), the most enriched tight‐junction protein in BMECs, is reduced in JNPL3 at 15 months. In addition, the mRNA for ICAM‐1(Intercellular Adhesion Molecule‐1) is upregulated already at 5 months in JNPL3 mice, indicating that BMECs acquired a proinflammatory phenotype. Further, oP301L reduced significantly BMECs viability in vitro after 24h.ConclusionOur data demonstrate that endothelial alteration occur at early stages of disease in JNPL3 mice. Based on these we hypothesize that: 1) Tau deposition in blood vessel might be an early event that precedes neuronal loss; 2) cognitive deficits arise from the toxic effects of oTau both on neurons and endothelial cells, thus suggesting that targeting both cells might be more effective to slow down disease’s progression.
Performance testing of a novel GFAP ELISA for CSF and blood based matrices
Authors: Demeyer Leentje , Vanhooren Melanie , Sluijs Jacqueline , Hol Elly , Stoops Erik 
Published: December 2023

AbstractBackgroundGlial Fibrillary Acidic Protein (GFAP) and its isoforms are intermediate filament cytoskeletal proteins expressed in astrocytes. Reactive astrogliosis, hallmarked by an increase in GFAP expression, is part of the pathogenesis of Alzheimer’s disease (AD). A reliable and globally available method for measurement of GFAP in CSF and plasma is required as a pharmacodynamic biomarker of astrocyte reactivity in AD drug development programs. Here we describe the specificity and performance of a monoclonal antibody (mAb) based colorimetric ELISA for measurement of GFAP in human CSF and plasma while comparing with existing benchmarked measuring methods.MethodA prototype colorimetric ELISA was designed using a 96‐well microplate with capture mAb ADx RD‐089 paired with the biotinylated detection mAb ADx RD‐090. High specificity for GFAP was verified by testing recombinantly expressed intermediate filaments like vimentin, nestin, and synemin up to a concentration of 10,000 pg/mL. A method comparison study was performed using a set of 15 CSF and 13 plasma samples (commercially sourced, no clinical typing). Finally the prototype ELISA was compared to a commercially available QTX Simoa GFAP assay (Cat# 102336).ResultThe assay design is a 3‐step sequential incubation (2‐1‐0.5 hrs) procedure while shaking with a respective 20‐ and 4‐fold dilution of CSF and EDTA plasma. The assay calibration ranges between 25 and 5,000 pg/mL and GFAP levels of the CSF and plasma samples tested were above LLOQ and within the measuring range. Furthermore, reproducibility was between 2.0 – 13.6% for CSF, and between 5.4 – 11.4% for EDTA plasma. An appropriate parallelism was obtained with back‐calculated concentrations between 80‐120% across the measuring range. Finally, the assays’ GFAP levels correlated well with QTX Simoa for both CSF Pearson r = 0.98 (0.94 – 0.99) and plasma Pearson r = 0.97 (0.90 ‐ 0.99).ConclusionThis colorimetric ELISA prototype assay enables the quantification of GFAP in both CSF and plasma. Alternatively it is a new accessible immunoassay method to support clinical trials where reactive astrogliosis needs to be assessed.
Differential expression of 5mC epigenomic regulators in Alzheimer’s disease
Authors: PerezGrovas‐Saltijeral Adriana , Rajamani Anto Praveen Rajkumar , Knight Helen Miranda 
Published: December 2023

AbstractBackgroundEpigenetic processes are molecular mechanisms that contribute to the pathogenesis of neurodegenerative diseases. 5‐methylcytosine (5mC) and the oxidised state, 5‐formilcytosine (5fC), are known transcriptional regulators moderated by sets of writer, reader, and eraser effector proteins. We propose that gene expression variation in DNA effector proteins may contribute to Alzheimer’s Disease (AD) neuropathology. We also aimed to characterize the distribution of 5fC modifications across brain regions and within cellular compartments to better understand the role of 5mC/5fC modifications in AD.MethodsRNA sequencing data for 17 effector proteins obtained from the Aging, Dementia and Traumatic Brain Injury Study was analysed to assess variation in abundance of 5mC writers, readers, and erasers. Gene expression data were compared across four brain regions in 51 AD and 56 healthy control samples, and between Braak and CERAD neuropathological scales. In addition, we examined the presence and distribution of 5fC by immunofluorescence (IF) across four brain regions in sections from healthy individuals.ResultsTranscripts of DNA methylation writers DNMT1, DNMT3A and DNMT3B were found increased in the AD cohort across 3 brain regions, whilst the reader UHRF1 mRNA was decreased in the same assessment. GADD45B and AICDA, DNA methylation erasers, showed changes in mRNA abundance across Braak and CERAD neuropathological load groupings. IF analysis indicated 5fC modification to be highly abundant in dentate gyrus and within the cytoplasm of hippocampal mossy cells and of neurons in cortical layer III. Within neuronal cells, we observed 5fC partially colocalizing with mitochondria especially within hippocampal neurons.ConclusionOur findings indicate that changes in 5mC/5hmC/5fC effector protein expression are associated with AD and its neuropathology. The characterisation of 5fC localisation in human brain indicates high abundance within the cytoplasm of hippocampal cells suggesting that 5fC may be involved in pre‐ and post‐transcriptional control of memory processing pathways and, when disrupted, may lead to neurodegenerative disease.
References: Sanchez‐Mut JV, et al. Transl Psychiatry. 2016; Miller JA, et al. Elife. 2017; Bachman, M., et al. Nat Chem Biol. 2015; Zhang Y, Zhou C. DNA Repair (Amst). 2019; Aging, Dementia and TBI Study (2017) Available from Allen Brain Atlas
The theory of the multiple reserves: The cognitive, physical, psychological and social factors that determine the quality of aging
Authors: Friedland Robert Paul 
Published: December 2023

AbstractBackgroundIn the 1980s the finding that education was linked to lower risk of Alzheimer’s disease (AD) led to the concept of cognitive reserve (CR). Extensive evidence of the protective role of cognitive activities in school, as well as at home and at work has supported the concept of CR. However, AD is clearly a multifactorial condition and there are other important lifestyle factors linked to AD risk.MethodThe literature was searched to find factors other than CR that are protective against the development of AD.ResultThe theory of the multiple reserves presents the physical, psychological and social factors that must be considered. Physical reserve includes the health of all the bodies' systems, including the microbiome. Psychological reserve considers emotional stability and ability to maintain healthy mental functions in response to stress. Social reserve considers interpersonal networks and support systems and the ability to be connected to others and society.ConclusionThe multiple reserve concept helps to demonstrate the opportunities for reducing AD risk through development of the four reserves. Cognitive activities throughout life should be enhanced, and ways to elevate the other reserve factors should be developed, Persons should be encouraged to enhance all of the four reserve factors to reduce their risk of the disease, as well as reduce the rate of progression. Furthermore, public policy should be designed to augment all four of the reserves all each stage of life.
Physical Activity in Community‐Dwelling Older Persons With Mild Traumatic Brain Injury
Authors: Agrawal Sonal , Kim Namhee , Leurgans Sue E. , Dams‐O'Connor Kristen , Bennett David A. A , Buchman Aron S , Schneider Julie A 
Published: December 2023

AbstractBackgroundTo examine the association between traumatic brain injury (TBI) and physical activity in older adults.MethodWe conducted a cross‐sectional analysis of 944 older persons (mean age = 85, SD = 7.48 years; 77% female) at their last available physical activity measure from the Rush Memory and Aging Project. Physical activity was measured 24 hours per day for 7‐10 days with wrist‐worn actigraphy (Actical; Philips Respironics, Bend, OR). We analyzed two separate outcomes from actigraphy: total daily activity and intensity of daily activity. To account for positive skewness, we applied a logarithmic transformation. TBI status was assessed by self‐report. We classified the participants as 1) TBI with loss of consciousness (LOC), 2) TBI without LOC, or 3) no TBI exposure (reference group). Multiple linear regression analyses, adjusted for age, education, and sex, were used to examine TBI with LOC and TBI with no LOC as separate predictors in a single model for each actigraphy outcome.ResultA history of TBI was reported in 351 (37%) participants, of whom 89 (9%) had at least one TBI with LOC and 262 (28%) had TBIs that did not result in LOC. Individuals with TBI with LOC had less total daily physical activity, with their total daily physical activity being about 19% (95%CI = 3.4%, 32.5%) lower than the reference group. The intensity of daily physical activity in those with TBI with LOC was 10% (95%CI = 0.7%, 18.2%) lower than the reference group. These associations remained after controlling depression, BMI, vascular risk factors, vascular diseases, and motor ability. Those with TBI without LOC did not differ from the reference group in daily physical activity and intensity of daily physical activity. We analyzed a subset of the 944 consisting of 710 deceased individuals who had undergone pathologic examination from postmortem brain tissue. Even after accounting for brain pathologies of Alzheimer’s disease, Lewy bodies, and cerebral infarcts, TBI with LOC remained associated with daily physical activity (p = 0.002).ConclusionOur result suggests that people with a history TBI with LOC may be associated with lower daily physical activity levels independent of the accumulation of diverse brain pathologies.
Association of tau burden with sleep disordered breathing in adults with Down syndrome
Authors: Smith Anna C. , Hartley Sigan , Plante David T. , Johnson Aubrey S. , Guzmán Diana S. , Okafor Amarachukwu , Rossano Samantha , Tudorascu Dana , Brickman Adam M. , Christian Bradley T. , Okonkwo Ozioma , Ances Beau , Cohen Annie , Handen Benjamin L. , Lao Patrick J. 
Published: December 2023

AbstractBackgroundAdults with Down syndrome (DS) overproduce the amyloid precursor protein and nearly all evidence clinical symptoms of Alzheimer’s Disease (AD) dementia in later life. Sleep disordered breathing, and specifically, obstructive sleep apnea (OSA), is common in adults with DS. OSA has been associated with risk of AD in adults without DS, and sleep disturbances may have a bidirectional relationship with AD pathology. We hypothesized that greater tau burden is associated with subsequent sleep disordered breathing in a time‐lagged design.MethodsEighty young adults with DS (37±8 yrs, 49% women, 94% cognitively‐stable/6% MCI‐DS) from the ABC‐DS study underwent tau PET ([18F]‐AV1451, Braak stage SUVRs) and were assessed 4±0.7 years after PET using WatchPAT home sleep testing. Sleep variables included oxygen desaturation index (ODI) and apnea‐hypopnea index (AHI). General linear models assessed tau burden on later sleep impairments. Models were run in the whole group and the cognitively‐stable group alone, with and without age adjustment. Analyses were run using overall sleep measures and those in REM and non‐REM (NREM) sleep separately.ResultsIn unadjusted models, greater tau in early, middle, and late Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. In the cognitively‐stable group alone, greater tau in early and middle, but not late, Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. Adjusting for age, greater tau in late Braak stages was associated with ODI in the whole group and the cognitively‐stable group alone. Associations for overall sleep measures were driven by NREM measures (Table 1).ConclusionIn adults with DS with a high prevalence of OSA, tau burden was associated with subsequent intermittent nocturnal hypoxemia as measured by the ODI during NREM sleep. These findings align with those in adults without DS, linking AD pathology, disturbed sleep, witnessed apneas, and nocturnal hypoxemia. Both longitudinal and randomized studies are required to clarify cause‐effect relationships, including the presence of mediating and/or moderating variables such as reduction in sleep depth or continuity.
Apolipoprotein E4 affects locus coeruleus functional connectivity in preclinical Alzheimer’s disease
Authors: Um Yoo Hyun , Wang Shengmin , Kang Dong Woo , Lim Hyun Kook 
Published: December 2023

AbstractBackgroundRecent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status.MethodsA total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model.ResultThe LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum.ConclusionThe aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.
Neuronal pentraxin‐2 by Simoa ‐ a potential synaptic biomarker in Alzheimer’s disease
Authors: Nilsson Johanna , Sauer Mathias , Grötschel Lana , Stomrud Erik , Janelidze Shorena , Blennow Kaj , Zetterberg Henrik , Brinkmalm Ann , Hansson Oskar , Ashton Nicholas J. 
Published: December 2023

AbstractBackgroundSynaptic dysfunction and degeneration are believed to be among the earliest and most reliable indicators of cognitive impairment in neurodegenerative disorders, including Alzheimer’s disease (AD). Discovering and verifying novel biomarkers that can quantify synaptic degeneration and serve as prognostic indicators would be valuable to track cognitive decline in clinical and drug trial settings. By using mass spectrometry, we have studied a panel of 17 synaptic proteins as potential biomarkers for AD and a broad range of neurodegenerative disorders. Of these proteins, neuronal pentraxin‐2 (NPTX2) has shown great promise as a synaptic biomarker, showing a decrease in symptomatic disease. Therefore, we aimed to develop a Single molecule array (Simoa) for NXPT2, a method more suited for routine clinical assessment than mass spectrometry‐based workflows.MethodWe developed an in‐house NPTX2 Simoa assay on the HD‐X platform (Quanterix) with paramagnetic beads coupled with a rabbit monoclonal capture antibody (EPR24020‐38, Abcam) and biotinylated rabbit monoclonal detector antibody (EPR15618, Abcam), both specifically targeting NPTX2. Full‐length recombinant NPTX2 (7816‐NP‐050, Biotechne) was used as the calibrator. Using the assay, we analyzed 55 healthy controls (78.0 (6.5 SD) years) and 54 AD patients (73.5 (7.0 SD) years) using 2 uL cerebrospinal fluid (CSF) in the BioFINDER pilot study. Group comparisons were performed using the Wilcoxon rank sum test and linear models adjusted for age and sex were used to assess associations of NPTX2 protein levels with cognitive function (mini mental status exam (MMSE)) and with neuroimaging, e.g., Aβ‐PET, tau‐PET (temporal ROI, Braak I‐IV) as well as cortical thickness in an AD signature composed of temporal regions in the AD group.ResultCSF NPTX2 concentration was found to be lower in AD compared with controls (p = 0.017, Figure). Lower NPTX2 concentration was associated with greater tau PET SUVR (β(SD) = ‐0.25(0.079), p‐value = 0.0027) and cortical thickness atrophy (β(SD) = 0.075(0.024), p‐value = 0.0034)) but not with amyloid‐β PET SUVR. Lower NPTX2 concentration was also associated with lower MMSE score (β(SD) = 2.62 (0.75), p‐value = 0.0010).ConclusionWe have successfully developed a Simoa assay of a novel CSF biomarker, NPTX2. This semi‐automated method allows for large‐scale evaluation of NPTX2, a leading candidate for synaptic degeneration in neurodegenerative disorders.