bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Tau Protein Aggregation Using Small Molecule Inhibitors and Immunotherapies
Authors: Martic Sanela 
Published: December 2022

AbstractBackgroundTau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Small molecules and immunotherapies have been tested targeting tauopathies. Understanding of the inhibitor mode‐of‐action is needed in order to develop effective drugs against neurodegeneration.MethodThe full length tau protein (2N4R, 441) was used in vitro with aggregation inducers: heparin and arachidonic acid. We have used small molecule inhibitors based of dopamine receptor agonist as inhibitors of tau aggregation in vitro. The inhibition of tau aggregation was also conducted in vitro using anti‐tau antibodies. The biophysical methods including electron microscopy and fluorescence spectroscopy were used to measure inhibitor efficiency.ResultThe anti‐tau antibodies which target epitope in R1‐R4 repeat domain were most effective in inhibition aggregation. The small molecules containing catechol groups were effective aggregation inhibitors and were in micromolar range, which was similar to the efficacy of methylene blue.ConclusionThe tau aggregation was inhibited in vitro using dual approach, with small and large molecules, indicating that both strategies are viable against tauopathies. Future work will require design of multifunctional inhibitors to improve selectivity and potency.
A simple, automated, speech‐based and AI‐enhanced screener for mild cognitive impairment and amyloid beta positivity
Authors: Fristed Emil , Skirrow Caroline , Meszaros Marton , Lenain Raphael , Meepegama Udeepa , Papp Kathryn V. , Ropacki Michael T. , Weston Jack 
Published: December 2022

AbstractBackgroundVocal and linguistic changes in Alzheimer’s dementia have been documented. The current study assesses whether a fully automated speech‐based artificial intelligence (AI) system can detect early clinical impairment and amyloid positivity, which characterise the earliest stages of Alzheimer’s disease (AD).MethodTwo studies were completed in the UK and USA: AMYPRED‐UK (NCT04828122) and AMYPRED‐US (NCT04928976). 200 participants with established amyloid beta (Aβ) and clinical diagnostic status (97 Aβ+, 103 Aβ‐ from prior PET scan or CSF tests; 94 cognitively unimpaired (CU), 106 with mild cognitive impairment (MCI) or mild AD) were recruited and completed automated assessments with the Automatic Story Recall Task (ASRT) either in‐clinic or via telemedicine appointment. The AI text‐pair evaluation model ParaBLEU produced vector‐based representations of the abstract, generalized patterns that differed between the original story text and transcribed retellings. These were fed into logistic regression models trained with tournament leave‐pair‐out cross‐validation analysis to predict Aβ status and MCI/mild AD. Potential benefits of screening using the ASRT system were examined via simulation, including: (1) identifying MCI in primary care, and (2) reducing the number of PET scans required in clinical research studies and trials.ResultUsing an average of only 6.56 minutes of speech per participant, the ASRT system predicted Aβ positivity in the full sample (area under the receiver operating characteristic curve (AUC) = 0.77) and in diagnostic subsamples (MCI/mild AD: AUC = 0.82; CU: AUC = 0.71), as well as MCI/mild AD (AUC = 0.83) in the full sample. Simulation indicated that screening with the ASRT system could: (1) increase correct (+8.5%) and reduce incorrect referrals (‐59.1%) compared with the Mini‐Mental State Exam; and (2) enrich samples for Aβ positivity prior to PET scan (‐35.3% and ‐35.5% fewer scans required in MCI and CU individuals, respectively).ConclusionWith the first disease‐modifying treatment for AD now available, there is an urgent need for improved screening to identify individuals at risk for AD dementia. The ASRT system is a brief, effective, automated, speech‐based cognitive assessment offering scalable screening for MCI/mild AD and amyloid beta biomarker positivity.
Glial activation may mediate Alzheimer’s disease progression
Authors: Rossano Samantha M , Johnson Aubrey S. , Lao Patrick J. , Klein Julia , Tomljanovic Zeljko , Stern Yaakov , Brickman Adam M. , Lee Seonjoo , Kreisl William Charles 
Published: December 2022

AbstractBackgroundGlial activation may precede regional tau progression through Braak stages in Alzheimer’s Disease (AD)[1]. However, the role of glial activity in the temporal progression of AD is not well characterized.MethodNineteen controls and 22 patients with clinical diagnosis of MCI or AD underwent [18F]florbetaben, [18F]MK‐6240, and [11C]PBR28 PET to measure β‐amyloid, tau, and TSPO (a glial biomarker). Standard uptake value ratios and corrected gray matter volume (%GM) were calculated from prefrontal, temporal, and parietal regions to create composite AD‐centric measures for β‐amyloid, TSPO, and neurodegeneration. Braak‐specific gray matter volumes were used to measure tau and neurodegeneration in early (I/II), middle (III/IV) and late (V/VI) Braak regions. Tau and TSPO were measured with (‐PVC) and without partial volume correction. Correlation analyses were performed between TSPO and β‐amyloid, tau, and MMSE scores. Mediation analyses explored the effect of TSPO in the steps along a proposed model for AD progression (Fig 1).ResultGreater TSPO‐PVC was associated with greater β‐amyloid (std.β=0.38, p=0.015), and with greater tau‐PVC in middle (std.β=0.45, p=0.004) and late Braak regions (std.β=0.50, p=0.002, Fig 2), even after controlling for %GM. Greater TSPO‐PVC was associated with lower MMSE score (std.β=‐0.53, p=0.006). Similar results were observed for uncorrected PET data. TSPO‐PVC mediated the relationship between tau‐PVC in early Braak regions and tau‐PVC in middle Braak regions (indirect effect=0.118, p=0.017) and the relationship between tau‐PVC in middle Braak regions and neurodegeneration in middle Braak regions (indirect effect=‐0.255, p=0.027). TSPO‐PVC mediated the relationship between neurodegeneration and impaired MMSE performance for early (indirect effect=0.233, p=0.021) and middle Braak regions (indirect effect=0.204, p=0.029), and between neurodegeneration and impaired Trails B performance for early (indirect effect=0.283, p=0.009) and middle Braak regions (indirect effect=0.228, p=0.017).ConclusionTSPO is related to β‐amyloid burden, tau pathology in middle and late Braak regions, and cognitive impairment in a manner independent of neurodegeneration. Our results suggest that glial activity impacts the progression of tau pathology from early to middle Braak regions and influences the relationship between neurodegeneration and cognitive impairment in these same regions.Reference: 1. Pascoal, T.A., et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med 27, 1592–1599(2021).
Understanding reactive astrogliosis in degenerative proteinopathies through the lens of postmortem brain imaging techniques
Authors: Kumar Amit , Fontana Igor C. , Nordberg Agneta K 
Published: December 2022

AbstractBackgroundThe discovery and validation of biomarkers beyond amyloid‐β and tau is now considered as a research priority in the Alzheimer’s disease (AD) field. In this context, astrocytes ‘key homeostatic cells’ in the central nervous system (CNS) are potential targets thanks to their swift response in AD pathology. Astrocytes tend to changes in brain physiology after CNS injury/insults via a specific defence response called reactive astrogliosis. The role of astrocytes in AD pathology is still under examination, however recent studies have openly suggested that reactive astrogliosis is an early event which may precede other hallmarks of the disease. In our recent work, we have speculated, based on clinical/translational in vivo and in vitro brain imaging studies, that there are two waves, ‘first (early) and second (late)’, of reactive astrogliosis in AD pathology with a distinct, close‐knit relationship with other pathological markers. Reactive astrogliosis also seems to play a critical role in other proteinopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) and SMBT‐1 (both targeting MAO‐B) as well as 11C‐BU99008 (detect imidazoline2 binding sites), which we believe is of utmost relevance to shed more light on the role of reactive astrogliosis, including astrocytic heterogeneity and improve our understanding of the underlying mechanism in these proteinopathies.MethodWe used a mixed battery of specialized in vitro radioligand binding assays (saturation and competition studies in brain tissues) and large frozen human brain section autoradiography in AD, PSP, CBD and control brains.ResultIn our studies, we demonstrated that BU99008 could visualize reactive astrogliosis and target multiple binding sites in AD brain. We observed that BU99008 and DED varied in their binding behavior in AD and control brains, suggesting that they might be targeting a specific state/or a different sub‐population of astrocytes.ConclusionPostmortem brain imaging techniques are valuable tools for validation (pre‐clinical) of novel PET‐tracers. Our ongoing studies in PSP and CBD brains as well as with SMBT‐1 will provide deeper insight into the role of reactive astrogliosis in these deadly diseases.
An Epigenome‐wide association study of psychosis in Alzheimer's disease dorsolateral prefrontal cortex
Authors: Weymouth Luke Stephen , Kouhsar Morteza P , Creese Byron , Bergh Sverre , Wedatilake Yehani , Torkamani Ali , Smith Adam R. , Selbaek Geir , Sweet Robert , Ballard Clive G , Mill Jonathan , Kofler Julia , Pishva Ehsan , Lunnon Katie 
Published: December 2022

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving etiology. In this study we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 192 post‐mortem brain samples.MethodBrain samples with corresponding in life neuropsychiatric assessments were obtained from the University of Pittsburgh Alzheimer’s disease Research Center (PITT‐ADRC). AD pathology was assessed and classified using CERAD neuritic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. The presence or absence of delusions and hallucinations was scored on the CERAD Behavioral Rating Scale. DNA was extracted, bisulfite treated and then profiled on the Illumina Methylation EPIC Array.ResultAfter data processing and quality control we used linear regression models to compare 152 AD+P samples to 40 AD samples without psychosis (AD‐P). A regional analysis of spatially correlated p‐values highlighted four differentially methylated regions (DMRs) associated with psychosis, which are being replicated in other data sets and validated for cell specificity using fluorescence activated nuclei sorting (FANS).ConclusionThe development of effective therapies for AD+P is an urgent priority. To address this we have collated a well powered study cohort to interrogate the epigenetic basis of AD+P, finding significant methylomic variation. This variation provides an insight into potential mechanisms and biomarkers which will help to identify drug targets and enable better treatment with existing medications.
Endothelial mitochondrial dysfunction during Cerebral Amyloid Angiopathy and Hyperhomocysteinemia
Authors: Parodi‐Rullan Rebecca M , Fossati Silvia 
Published: December 2022

AbstractBackgroundHyperhomocysteinemia (HHcy), or high levels of homocysteine, is considered a risk factor for vascular disease. Cardiovascular (CV) risk factors, such as HHcy, may lead to exacerbation of cerebral amyloid angiopathy (CAA) due to their detrimental effects on cerebrovascular function. Cerebrovascular function is regulated, in part, by endothelial cells (EC), the most important cellular component of the blood‐brain barrier (BBB). Dysfunctional ECs may lead to deficits in vascular perfusion, clearance, and may eventually result in neuroinflammation, microhemorrhages, and neurodegeneration. EC mitochondria serve as sensors of cellular damage and mediate downstream pathways such as cell death and inflammation. In ECs, mitochondrial dysfunction may lie as the point of convergence of CV risk factors and amyloid β (Aβ)‐induced neurovascular dysfunction. Understanding the mitochondrial deficits elicited by CV risk factors, Aβ, or their combination, may open roads to new therapeutics aimed at preserving mitochondrial function. Indeed, we have previously shown that carbonic anhydrase inhibitors (CAi) reduce amyloid‐induced cell death and mitochondrial dysfunction. Here, we aim to understand the changes occurring in EC mitochondria during Aβ‐ and mixed (Aβ+HHcy)‐ vascular pathologies. In addition, we will assess the therapeutic potential of CAi in such pathologies.MethodHuman brain microvascular ECs were challenged with Aβ, Hcy, or the combination in the presence or absence of CAi. EC barrier properties and changes in mitochondrial function were assessed.ResultThe presence of Aβ or Hcy independently increased BBB permeability, and, when both present, Hcy worsened Aβ‐induced barrier permeability; these effects were prevented by CAi. Preliminary data suggests that the mitochondrial ATP production is impaired in the presence of Aβ40‐E22Q (Dutch mutant) but not in the presence of Hcy. These results may be a reflection of the observed deficits in mitochondrial oxygen consumption rate (OCR).ConclusionThe EC barrier is negatively affected by the presence of Aβ, and Hcy aggravates Aβ‐induced BBB permeability. The presence of Aβ40‐E22Q affects mitochondrial OCR and ATP production, indicative of changes in cellular metabolism and mitochondrial dysfunction. These results suggest a central role of the mitochondria as a mediator of vascular dysfunction in the presence of Aβ.
GFAP expression levels are associated with brain glucose metabolism in a rat model of Alzheimer’s disease
Authors: Machado Luiza Santos , da Rocha Andreia Silva , Soares Carolina , de Souza Débora Guerini , Ramos Vanessa G. , Bellaver Bruna , Ferreira Pamela C.L. , Zimmer Eduardo R. 
Published: December 2022

AbstractBackgroundGlial Fibrillary Acidic Protein (GFAP) is an intermediate filament expressed almost exclusively in astrocytes, and it is usually overexpressed in reactive astrocytes. We have previously shown that astrocytes play a critical role in brain energy metabolism and are significant contributors to the [18F]FDG‐PET signal. The cortex is majorly composed of glial cells, whereas the cerebellum is predominantly composed of neurons. In light of this, whether GFAP levels in the brain tissue are associated with [18F]FDG‐PET signal remains unknown. Thus, we aimed to investigate the associations between cortical and cerebellar GFAP levels with brain glucose metabolism in a rat model of Alzheimer’s disease.MethodsBrain metabolism of ten‐month‐old TgF344‐AD (n=8) and wild‐type (WT,n=6) rats was assessed with [18F]FDG‐PET. Then, GFAP RNA levels were quantified in the frontal cortex (CXF), temporoparietal cortex (CXTP), and cerebellum (CB) using qRT‐PCR. The [18F]FDG‐PET standardized uptake ratio (SUVr) was calculated using pons as the reference region. T‐tests were used to assess the differences between groups in GFAP RNA expression levels and regional brain [18F]FDG‐PET. Comparisons were conducted using t‐statistical analyses at voxel level (RMINC). Differences were considered statistically significant at p<0.05 (t>2).ResultsNo differences between groups were found in the whole brain FDG metabolism or regions of interest (CXF, CXTP, and CB;t(13)<2). At the voxel level, we identified small cortical hypermetabolic clusters in the TgF344‐AD rats (t(13)=5.55, local maxima). The GFAP RNA was increased in the CXTP of TgF344‐AD rats (p=0.001). No significant differences were found between groups in GFAP RNA levels in other brain regions evaluated. Interestingly, we found positive correlations between [18F]FDG‐PET metabolism and the GFAP RNA expression in the CXTP (local maxima, t(13)=8.33;Fig.1a) and CXF (local maxima, t(13)=4.82;Fig.1b). By contrast, [18F]FDG metabolism did not associate with GFAP RNA expression levels in the CB (t(13)<2;Fig.1c).ConclusionGFAP RNA levels were increased in the CXTP of TgF344‐AD rats, which may indicate early astrocyte reactivity. GFAP RNA expression was associated with [18F]FDG metabolism only in cortical regions, suggesting that astrocytes may have major roles in cortical glucose uptake, but not in cerebellum.
Validation and utility of plasma neurofilament light as a biomarker for vascular cognitive impairment
Authors: Kautz Tiffany F , Mathews Julia J , Parent Danielle , Sudduth Tiffany L , Liu Qianqian , Wiedner Crystal , Wang Chen‐Pin , Mbangdadji Djass , Bis Joshua C , Sagare Abhay P , Beiser Alexa S , Pottanat George , Aparicio Hugo J , Thompson Jeffery F , Erickson Kelsey , Jin Lee‐Way , Gonzales Mitzi M , Ghosh Saptaparni , DeCarli Charles S. , Wang Danny JJ , Wilcock Donna M , Rosenberg Gary A , Lu Hanzhang , Kramer Joel H. , Launer Lenore J. , Fornage Myriam , Mosley Thomas H , Maillard Pauline , Gudnason Vilmundur , Singh Herpreet , Helmer Karl G , Schwab Kristin , Greenberg Steven M , Tracy Russell P. , Kivisäkk Pia , Seshadri Sudha , Satizabal Claudia L 
Published: December 2022

AbstractBackgroundNeurofilament light chain (NfL) is a broad marker of neuroaxonal injury that is elevated in the CSF in those with vascular cognitive impairment and dementia (VCID). Blood and CSF levels highly correlate, making it an attractive peripheral marker for VCID pathology. As part of the MarkVCID consortium, we sought to evaluate the instrumental validity of plasma NfL using the Quanterix Simoa platform and assess its validity for risk stratification in clinical trials of VCID.MethodPlasma NfL was measured using HD‐X and HD‐1 Simoa instruments. For instrumental validation, we used samples from the MarkVCID consortium to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL with general cognitive function (GCF) as the primary outcome. In secondary analyses we assessed associations with white matter hyperintensities (WMH), an established small vessel disease marker. Models were adjusted for potential confounders. The clinical validation included established cohorts from the CHARGE consortium (i.e., CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Additional analyses are underway in MarkVCID sites.ResultWe found low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in blood samples drawn within 30 days (ICC=0.968). There was high consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.06; ‐0.17]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in CHARGE cohorts and the UCD ADRC (P<0.01).ConclusionOur results suggest plasma NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH across independent samples, providing evidence that plasma NfL can be a useful biomarker for stratification in VCID trials.
Blood‐based biomarkers for neurodegeneration in non‐Hispanic Black and White older adults: Results from the Einstein Aging Study (EAS)
Authors: Engeland Christopher G , Katz Mindy J. , Qin Jiyue , Wang Cuiling , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Graham‐Engeland Jennifer E , Pavlovic Jelena , Derby Carol A. , Lipton Richard B. 
Published: December 2022

AbstractBackgroundWith recent technological advancements, neurodegenerative biomarkers (NDBMs) in blood plasma now produce results comparable to those obtained in cerebrospinal fluid, supporting the possibility of less invasive and costly determination of risk status for Alzheimer’s disease (AD). However, most research with these novel biomarkers has been in predominately non‐Hispanic (NH) White samples. Hence, little is known about distributions of these biomarkers among NH Blacks despite their elevated risk for AD.MethodBlood plasma samples were obtained from 254 older participants in the EAS who were free of dementia (mean age [SD]=77.6[4.9] years; range 70‐93 years; 66.1% female; 46.5% NH Black, 53.5% NH White; 27.2% mild cognitive impairment (MCI) as defined by Jak/Bondi criteria). AD biomarkers [β‐amyloid (Aβ40, Aβ42), pTau181], along with biomarkers of generalized neuronal damage and astrocyte activation [neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), respectively] were quantified in blood using Single molecule array (Simoa) assays on HD‐X Analyzers (Quanterix, Billerica, MA). Comparisons of NDBMs between groups were conducted using Wilcoxon rank sum test in unadjusted analyses, and linear regression models adjusting for covariates including age, gender, education, diabetes history, myocardial infarction, and hypertension.ResultWe observed lower overall levels of NDBMs in NH Blacks vs. NH Whites regardless of MCI status (Aβ40, Aβ42, and NfL (ps<0.05) see Table 1). Among NH Whites, those with MCI had higher Aβ40, Aβ42, and NfL (ps<0.05) compared to cognitively normal individuals; no significant differences by MCI status were observed among NH Blacks (not shown). The above race differences in Aβ40, Aβ42, and NfL remained evident across the full sample in linear regression analyses (adjusted for MCI status and covariates). When stratified by MCI status, race differences remained evident for NfL (regardless of MCI status); for Aβ40, race differences were evident among individuals with MCI only (see Table 2). Although individual analytes differed, the Aβ42/Aβ40 ratio did not differ by race.ConclusionNH Blacks exhibited lower overall levels of NDBMs compared to NH Whites, and associations between NDBMs and MCI were in the expected directions only among NH Whites. These race differences suggest that future work is needed to develop generalizable norms for blood‐based NDBMs.