bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virtual brain network modeling in AD: from pathophysiology towards treatment
Authors: de Haan Willem 
Published: December 2023

AbstractBackgroundWhile much is known about the pathology and clinical symptoms of AD, their mutual relationship to impaired brain function during the AD disease course is incompletely understood. For deriving a coherent, integrated multi‐scale disease mechanism, computational neurophysiology is a promising candidate. Virtual models of neurons, neuronal circuits and large‐scale networks are being used at different scales and for different purposes. Ranging from biologically plausible neural mass models to more abstract models of complex system behaviour or pathology spreading patterns, their diversity and versatility can help to address issues that are hard to tackle experimentally.MethodIn this presentation I will review several recent developments that illustrate how virtual models can help to translate local neuronal activity to brain‐wide network level data, probe the effects of AD pathology on brain network behaviour, and predict neurophysiological outcomes of different types of treatment. More specifically, I will show how amyloid‐induced hyperexcitability is compatible with large‐scale oscillatory slowing in AD, and how we can simulate counteracting activity‐targeting interventions such as non‐invasive brain stimulation using virtual models.ResultAD‐like adaptations in neuronal excitability in neural mass model parameters led to the combination of high absolute power and large‐scale oscillatory slowing in nearly all tested scenarios. In contrast, the hypoexcitable neural mass scenarios did not produce AD‐like oscillatory changes. Furthermore, simulating various counteracting tDCS‐induced excitability changes led to highly variable ‘virtual treatment’ outcomes, supporting the idea that electrode location choice can play a substantial role in tDCS treatment success, and generating specific predictions to be falsified in patient studies.ConclusionVirtual models of altered brain activity can help to understand AD pathophysiology and facilitate treatment development.
Positron emission tomography (PET) imaging of neuroinflammation in healthy and Alzheimer disease participants using TSPO tracers
Authors: Fuh Jong‐Ling , Lin Yung‐Shuan , Yeh Skye Hsin‐Hsien , Lee Wei‐Ju , Chang Wen‐Yi , Chang Chi‐Wei , Yang Bang‐Hung , Peng Nan‐Jing , Huang Wen‐Sheng 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. In addition to the widely recognized accumulation of amyloid and tau protein being the core pathology of AD, neuroinflammation is another cause of brain dysfunction and structural change. Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. With the development of TSPO positron emission tomography (PET) tracer, we were able to evaluate neuroinflammation non‐invasively in a clinical cohort of AD spectrum.MethodCognitively impaired patients (including AD and mild cognitive impairment (MCI)) and cognitively normal controls (CN) were recruited from single dementia clinic. [18F]FEPPA, the second‐generation PET ligand specifically binds TSPO was synthesized fully automated. Structural brain MRI and functional PET imaging were performed simultaneously with a PET/MR scanner (SIGNA, GE Company, USA). Kinetic analyses were performed using PMOD 4.2 modeling software. Total distribution volume (VT) in each ROI, including frontal, temporal, inferiolateral parietal, occipital, hippocampus and cerebellum, were derived from a two‐tissue compartment model (2‐TCM). In addition, APOE and rs6971 polymorphism genotyping were conducted in all subjects. Mann‐Whitney U Tet, Kruskal‐Wallis Test and linear correlation were performed.ResultA total of 39 participants (23 males and 16 females) participated, including 13 cognitively normal, 9 with MCI and 17 with Alzheimer’s disease. The rs6971 genotype had no significant effect on [18F]FEPPA binding to TSPO. The amount of TSPO expression was independent of age, gender, and APOE ε4 carrier status. The VT of each ROI did not differ significantly between cognitive groups. VT of frontal, temporal, inferiolateral parietal and occipital lobe were all negatively correlated with MMSE, Boston Naming Test and Trial Making A performance. However, such association was not observed between VT of hippocampus and cognitive tests.ConclusionAlthough there was no difference between TSPO expression in each ROI among cognitive groups, we still observed that higher TSPO expression in the cortex was associated with worse performance in certain cognitive tests. This implied that the increase in neuroinflammation was related to the decline of cognitive performance regardless of cognitive diagnosis.
The role of the biofilm of Porphyromonas gingivalis in driving amyloid beta secretion and aggregation
Authors: Dumoulin David , Fulop Tamas , Beauregard Pascale B. 
Published: December 2023

AbstractBackgroundOver the past five years, the hypothesis linking periodontitis to Alzheimer’s disease (AD) has gained significant traction even though little is known about the underlying mechanisms driving this association. Periodontitis is caused by the dysbiosis of the dental biofilm, an extra‐cellular matrix produced by bacteria, which is mostly caused by the Gram‐negative bacterium Porphyromonas gingivalis. P. gingivalis has been found to infect the brain of AD patients and drive amyloid beta (Aβ) production while biofilm components can be identified interwoven with Aβ plaques1,2. We therefore hypothesize that P. gingivalis drives Aβ production in neural cells which co‐aggregates with bacterial biofilm to expedite plaque formation and downstream neuroinflammation.MethodTo assess if the biofilm of co‐aggregation of Aβ and the matrix was then analyzed by fluorescence microscopy, atomic force microscopy (AFM) and thioflavin T (ThT) fluorescence assays. To examine whether P. gingivalis stimulates Aβ production, we infected BE(2)‐M17 human neuroblastomas at a mean of infection of 1:100 before collecting cells and supernatant proteins to observe the cell response through protein and transcription assays.ResultsWhen co‐cultured, P. gingivalis and Aβ1‐42 co‐aggregated in plaque‐like structures, Interestingly, colocalization analysis revealed that Aβ1‐42 particularly associate with the extracellular component of biofilm (Figure 1). ThT assays and AFM imaging demonstrated faster aggregation of Aβ1‐42 when co‐incubated with fragments of P. gingivalis biofilm for 8 h, which suggests a significant cross‐seeding phenomenon between the two components (Figure 2). Furthermore, infection of human neuroblastomas resulted in a significant increase in Aβ production that could be detected by western blot, thus offering a workable model to study the link between AD and periodontitis (Figure 3).ConclusionOur project offers significant insights into the relationship between periodontitis and AD, allowing us to understand how P. gingivalis triggers Aβ production and how its biofilm drives plaque aggregation. This research greatly contributes to a better understanding of external AD risk factors and how to mediate their impacts on neurodegeneration.
1Dominy et al. Science Advances (2019)
2Mirzaei et al. Microbial Pathogenesis (2020)
Visual rating scales of atrophy to differentiate Frontotemporal dementia from Primary psychiatric disorder: results from DIPPA study
Authors: Fumagalli Giorgio G , Sorrentino Federica , de Boer Sterre C.M. , Riedl Lina , Landin‐Romero Ramon , Matis Sophie , Southwood Dean , Chatterton Zac , Diehl‐Schmid Janine , Halliday Glenda M , Ducharme Simon , Piguet Olivier , Pijnenburg Yolande A.L. , Galimberti Daniela 
Published: December 2023

AbstractBackgroundAdult‐onset behavioral changes and altered executive functioning are frequently caused by behavioural variant of Frontotemporal dementia (bvFTD) or primary psychiatric disorders (PPD) which overlap in terms of clinical presentations but differ in terms of treatment and prognosis. The multi‐centre study DIPPA‐FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late‐onset PPD. Although atrophy on neuroimaging seems to be an appropriate discriminator between neurodegenerative and non‐neurodegenerative conditions, the sensitivity of frontotemporal atrophy for bvFTD is relatively low, whereas decreased brain volumes may be found in conditions like schizophrenia. The aim of the study is to identify a discriminative pattern of brain atrophy between bvFTD and PPD in a clinically applicable way.MethodThe DIPPA FTD consortium retrospectively collected patients with late onset behavioral disturbances after the age of 45 years, across 5 centers (Milan, Amsterdam, Munich, Sydney, Montreal). The subjects had been classified either as bvFTD or PPD according to current clinical criteria and the majority had clinical follow‐up. Among the patients collected in the project, only those with T1 MRI available were selected. A protocol of 9 visual rating scales of atrophy (orbitofrontal, anterior cingulate, anterior temporal, fronto‐insula, medial temporal, parietal, medial ventricular and axial ventricular) was applied by a rater blind for clinical and demographic infomation. The rater was asked to classify the subjects as bvFTD or PPD. A composite score of frontal, temporal and ventricular rating scales was also calculated.ResultThe MRIs of 323 subjects (211 bvFTD and 112 PPD) were analysed. Groupwise bvFTD cases showed significantly higher scores of atrophy for all the scales used. The rater accurately predicted 72% of the cases (Sens 0.70, Spec 0.76) while the composite score reached an accuracy of 76% (Sens 0.77 Spec 0.74). ROC curve analysis showed that fronto‐insula was the single most useful scale in the differentiation between bvFTD and PPD (AUC 0.80).ConclusionBrain atrophy has a significant role in the discrimination between bvFTD and PPD. The use of visual rating scales, and in particular the fronto‐insula one, could increase the diagnostic accuracy in the clinical setting.
Systematic review of strategies to justify validity of instrumental variables in observational studies of dementia and neurodegenerative disease
Authors: Hiu Shaun , Yong Tingting , Teare M Dawn , Taylor John‐Paul 
Published: December 2023

AbstractBackgroundInstrumental variable (IV) analysis is a methodology used to study causal effects of treatments or exposures. If properly implemented, causal effects can be estimated even in the presence of unmeasured confounding. . Central to IV analysis is the identification of a valid instrument that satisfies three assumptions – one is empirically verifiable (Restriction) but the remainder require substantive knowledge and convincing argumentation (Exclusion restriction and Exchangeability). The objective of this study is to systematically review the strategies used to validate an IV in observational studies of dementia and neurodegenerative disease. This systematic review is pertinent given the increasing use of real‐world evidence to guide public health and regulatory decision‐making in lieu of randomised controlled trials.MethodsWe conducted our search using PubMed, PsycINFO, and Web of Science. We included published observational studies investigating the causal effect of some risk factor, exposure, or treatment using IV analysis and using either a sample of: i) adults without diagnosis of dementia or neurodegenerative disease and an outcome of incident diagnosis of dementia or neurodegenerative disease; or ii) adult patients diagnosed with dementia, major neurocognitive disorder, or neurodegenerative disease and a clinical outcome related to incident dementia, mortality, hospitalisation, institutionalisation, serious adverse outcomes, medication adherence, cognition, neuropsychiatric symptoms, and biomarkers of neurodegeneration. We will extract and categorise text information directly arguing for the assumptions of a valid IV and the type(s) of falsification tests used.Results927 unique articles were retrieved. Screening for eligibility and data extraction by two study authors are currently underway. Results will be presented at the conference.ConclusionsReviewing how variables have been reasoned to be valid IVs may help improve our understanding of the causal effects of treatments or exposures on dementia and neurodegenerative disease which may have relevance in shaping future therapeutic and management approaches.
Baseline plasma levels of ADAMTS13 predict cognitive decline and neurodegeneration among APOE‐ε4 carriers over a 7 year follow‐up period
Authors: Kresge Hailey A. , Khan Omair A. , Liu Dandan , Libby Julia B. , Robb W Hudson , Patterson Khiry L , Arul Albert B , Choi Min Ji , Oliver Nekesa , Whitaker Marsalas D , Houston Michelle L , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Robinson Renã AS , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundVon Willebrand Factor (VWF), a multimeric glycoprotein involved in hemostasis, and ADAMTS13, a metalloproteinase that cleaves VWF, are associated with dementia risk. In in vitro studies endothelial cells expressing apolipoprotein E (APOE)‐ε4 overexpress VWF but no clinical studies have investigated interactions between VWF or ADAMTS13 with APOE‐ε4 status in predicting brain health. We assessed whether VWF and ADAMTS13 levels predict longitudinal cognitive decline and atrophy, especially in APOE‐ε4 carriers.MethodsVanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) underwent blood draw, neuropsychological assessment, and brain magnetic resonance imaging (MRI) serially over a 7‐year period. Plasma abundance measures of VWF and ADAMTS13 at baseline were quantified using mass spectrometry. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological and brain MRI outcomes (including grey matter volume and an Alzheimer’s disease (AD) neuroimaging signature), adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, cognitive status, intracranial volume, APOE‐ε4 status, and follow‐up time. Models were repeated with an APOE‐ε4 interaction.ResultsLower baseline ADAMTS13 levels related to greater longitudinal decline in language, episodic memory, information processing speed, executive function, and visuospatial skills (p‐values<0.02) as well as temporal lobe, occipital lobe, and hippocampal atrophy (p‐values<0.02). APOE‐ε4 interacted with ADAMTS13, such that among APOE‐ε4 carriers, lower baseline ADAMTS13 related to greater decline in naming (p‐values< = 0.002), information processing speed (p = 0.006), executive function (p = 0.001), and visuospatial skills performances (p = 0.001) as well as greater occipital lobe atrophy (p = 0.002) and AD imaging signature thinning (p = 0.02). All results survive false discovery rate correction. By contrast, VWF did not relate to any outcomes (p‐values>0.08).ConclusionLower ADAMTS13 levels related to greater cognitive decline and neurodegeneration over a 7‐year follow‐up period, with effects driven by APOE‐ε4 carriers. VWF was unrelated to outcomes, potentially suggesting that ADAMTS13 relates to brain health independent of its role cleaving in VWF. While VWF is the only known substrate of ADAMTS13, ADAMTS13 may be involved in diverse biologic processes (e.g., inflammation, angiogenesis). Replication is needed to fully elucidate the role of VWF. Additional research is also needed to characterize mechanisms underlying interactions between ADAMTS13 and APOE‐ε4 in predicting brain health.
Mortality and risk of dementia in individuals with serious mental illness: a population‐based study
Authors: Stevenson‐Hoare Joshua O , Owen Michael J , Kirov George , Escott‐Price Valentina 
Published: December 2023

AbstractBackgroundIndividuals with mental illness such as schizophrenia experience dementia at greater rates than the general population(1). These disorders are also associated with shorter lifespan(2). Consequently, a person with mental illness may be more likely to experience dementia but less likely to live long enough to reach dementia onset. By using deeply phenotyped data across a large portion of person’s lifespan it is possible to examine the causal structure that may lay behind this seeming contradiction.MethodUsing a longitudinal medical record database of 4.5 million individuals in Wales, UK, we were able to follow individuals over a period of two decades. We identified nearly 1 million living individuals aged at least 45 in 1999, of whom one third had diagnoses of psychosis, mania, depression, or anxiety. We tested whether the development of dementia is associated with premorbid mental illness, using Cox regression survival analyses accounting for hospitalisation, history of medication, sex, social deprivation, and cooccurrence between disorders, as compared to matched controls.ResultControlling for the age of onset of mental illness and the reduced lifespan of individuals with these serious mental health disorders, we found a strong relationship between all mental illness and higher risk of dementia. The dementia onset was earlier in individuals with mental illness. We also found a complex relationship with hospitalisation and number of prescriptions, two metrics often associated with disease severity, when explaining mental illness‐related mortality and dementia.ConclusionAll studied mental illnesses are associated with the elevated risk of developing dementia, if individuals survive to a sufficient age. Of these illnesses, psychosis was the strongest risk factor for dementia development. Disease severity and treatment, defined by hospitalisation and medication, are also highly significant factors, with hospitalisation increasing risk of dementia and mortality.
References:
(1)Stroup et al. (2021) JAMA Psychiatry, https://doi.org/10.1001/jamapsychiatry.2021.0042

(2)Chang et al. (2010) BMC Psychiatry, https://doi.org/10.1186/1471‐244X‐10‐77
Altered Endogenous Expression of Alzheimer’s Risk Genes impacts Neural Morphology in a Large Cohort of Healthy study Participants
Authors: Bledsoe Xavier , Sale Rebecca L , Lin Phillip J , Gamazon Eric J 
Published: December 2023

AbstractBackgroundDysregulation of white matter tracts (WMTs) in the brain is a common feature of Alzheimer’s Disease (AD) and is associated with declining cognitive function. Two neuroimaging measures, Fractional Anisotropy (FA) and isometric volume fraction (ISOVF) represent WM integrity through quantifying organization of axon bundles and changes in extracellular fluid within the fiber tracts (as occurs in inflammation or degeneration) respectively. Previous work examining the genetic basis of WMT changes in AD largely focused on SNP‐level associations. Here, we leverage transcriptome wide association studies (TWAS) and Mendelian randomization (MR) to interrogate the expression‐mediated influence of AD genes on WMT integrity.MethodWe first perform a multi‐tissue TWAS for AD by applying JTI‐PrediXcan to summary statistics from the largest AD GWAS meta‐analysis (Bellenguez, 2022). This approach leverages tissue‐specific eQTL models trained on data from the Genotype‐Tissue Expression project and enriched via Joint Tissue imputation to identify associations between genetically regulated gene expression (GReX) and AD (Barbeira, 2018). We apply prediction performance thresholds and correct for multiple testing. We perform similar TWAS using JTI‐PrediXcan on neuroimaging data from 33,000 participants in the UK Biobank to identify tissue‐specific associations between GReX and WMTs (FA and ISOVF) (Smith, 2021). We integrate these studies to identify AD‐associated genes associated with changes in FA or ISOVF. We quantify the GReX causal effect on WMTs through the MR protocol, MR‐JTI, which assumes gene expression as the exposure (Zhou, 2020).ResultOur AD TWAS identifies 59 genes. 14 occur at the APOE locus and we replicate 2 additional genes prioritized in the initial GWAS. FUMA analysis of our gene set implicates the brain as the primary tissue of downregulation (Watanabe, 2017). Neuroimaging analysis of these genes highlights 5 WMTs and 2 genes. GReX of CR1 is causally associated with ISOVF of the right acoustic radiation and superior longitudinal fasciculus. GReX of INO80E is causally associated with FA of the left inferior longitudinal fasciculus and the bilateral superior thalamic radiations.ConclusionBy integrating TWAS of AD and neuroimaging data, we identify multiple significant, tissue‐specific, causal associations between AD‐associated GReX and the integrity of key WMTs associated with cognitive function.
Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?
Authors: Lanctôt Krista L. , Raket Lars Lau 
Published: December 2023

AbstractBackgroundRecent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.MethodAssess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.ResultBased on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.ConclusionQuantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated.