bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF SNAP‐25 Correlations with Synaptic Density by [11C]‐UCB‐J‐PET Imaging and AD Biomarkers
Authors: Wilson Rachael E , Jonaitis Erin M. , Langhough Rebecca E , Betthauser Tobey J , DiFilippo Alexandra H , Christian Bradley T. , Okonkwo Ozioma , Bendlin Barbara B , Chin Nathaniel A. , Carlsson Cynthia M , Asthana Sanjay , Johnson Sterling C , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundSynaptic dysfunction occurs prior to neuronal loss in the early stages of AD. A biomarker reflective of these changes could indicate AD before clinical manifestations. SNAP‐25 is a potential candidate, but the relationship between SNAP‐25 and established AD biomarkers is unclear. Further investigation is needed to determine the utility of this biomarker during the pre‐clinical phase.MethodSNAP‐25 was measured using the Quanterix Single molecule array platform. A partial validation was conducted to evaluate assay performance in CSF and EDTA plasma. A cross‐sectional pilot study was then performed by measuring SNAP‐25 in CSF from 54 participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (WI‐ADRC) cohorts. SV2A synaptic density was measured in each participant using [11C]‐UCB‐J‐PET. Amyloid and tau status was determined in a subset of the group using [11C]‐PiB (N = 52) and [18F]‐MK6240‐PET (N = 44), respectively. Additional CSF biomarkers (Aß42, pTau‐181, and tTau) were measured using the Roche Cobas e601 Elecsys platform. A confirmatory study was performed with 80 additional WRAP and WI‐ADRC participants (53A+, 27 A‐). These participants did not have [11C]‐UCB‐J‐PET imaging.ResultThe SNAP‐25 assay demonstrated excellent precision (<5% CV), recovery (96‐101%), and linearity in CSF. Plasma SNAP‐25 levels were detectable but inconsistent, suggesting matrix interference. In the pilot study, SNAP‐25 was highly correlated with CSF pTau‐181 and tTau (Figures 1A, 1B). SNAP‐25 was not correlated with CSF Aß42 (Figure 1C). A modest but significant correlation was observed with amyloid PET in the pilot study (Figure 2A) but not in the confirmatory study (Figure 3). SNAP‐25 did not correlate with SV2A density (Figure 2B) or fibrillary tau (Figure 2A). Mean SNAP‐25 levels were significantly different between amyloid‐ and tau‐positive groups compared to biomarker negative controls (p < 0.001 for amyloid, p < 0.05 for tau). Similar trends were observed in the confirmatory study (Figure 3).ConclusionThese results demonstrate a close relationship between SNAP‐25 and soluble tau in CSF, suggesting that CSF SNAP‐25 reflects early Aß‐induced neuronal impairment in a way that correlates with tau pathophysiology. This indicates that SNAP‐25 could be a useful biomarker of early neurodegeneration in pre‐clinical AD.
Impaired ability to smile in Alzheimer’s disease is associated with reduced brain volume of nucleus accumbens and pallidum, revealed by artificial intelligence
Authors: Iizuka Tomomichi , Kameyama Yumi Umeda , Fukasawa Makoto , Akishita Masahiro , Kameyama Masashi 
Published: December 2023

AbstractBackgroundPatients tend to lose the ability to smile during the clinical course of dementia. However, details of such impairment remain obscure presumably due to difficulty of quantifying facial expression. Feature extraction is now automated as a result of recent developments in artificial intelligence (AI). The authors applied a model to quantify impaired smile expression in patients with Alzheimer disease (AD). The relationship between the expression of a smile and subcortical volumes was also investigated.MethodThis study included 280 and 190 participants with AD and with normal cognition (NC), respectively. The faces of the participants were photographed as they smiled or maintained a neutral expression. Subcortical brain volume was assessed in 210 and 90 of those with AD and NC, respectively, using MRI and the FSL‐FIRST algorithm. Datasets of the photographs were prepared with combinations of smiling and neutral expression in NC and AD, smiling in AD and NC, and neutral expression in AD and NC, then binary discrimination proceeded using the VGG‐Face convolutional neural network (CNN).ResultThe accuracy of discriminating a smile from a neutral expression was of 92.3% in NC, and 61.2% in AD, indicating that a considerable proportion of patients with AD have difficulties forming a natural smile. 48.5% of smile AD were classified as negative in NC dataset. The smile/neutral‐NC scores for AD were robustly associated with the volume of the bilateral nucleus accumbens (right, r = 0.51, p = 2.59 × 10−15; left, r = 0.493, p = 2.89 × 10−14) and the bilateral pallidum (right, r = 0.266, p = 0.0000981; left, r = 0.256, p = 0.000174). The accuracy of discriminating between AD and NC was 95.2% with smile and 90.1% with a neutral expression, respectively (p = 0.0045). The neutral‐AD/NC score inversely correlated with the results of the MMSE (p = 1.62 × 10−7), but not with smile/neutral‐NC or smile‐AD/NC scores.ConclusionThe ability to form smile was impaired in AD and associated with nucleus accumbens and pallidum shrinkage. Such impairment enhanced the accuracy of facial discrimination between AD and NC, whereas a neutral expression was associated with cognitive function.
Amyloid‐β precursor protein facilitates spreading of tau pathology in Alzheimer models
Authors: van Eersel Janet , Przybyla Magdalena , Genoud Sian , Fath Thomas , Ke Yazi D. , Ittner Lars M. 
Published: December 2023

AbstractBackgroundSpreading of tau pathology between connected brain regions correlates with disease progression in Alzheimer’s disease (AD) and gives rise to distinct neuropathological stages. While seeding and spreading of tau pathology has been reproduced in cell and animal models, the understanding of the molecular pathways mediating tau spread remains limited. Binding of tau fibrils to the extracellular region of the Amyloid Precursor Protein (APP) was reported to result in the uptake of tau in a cell culture model. This raised the question whether APP may function as a tau fibril receptor during the trans‐neuronal spread of tau pathology in vivo, thereby contributing to disease progression.MethodTo study the effect of APP expression on tau spread we (1) injected APP KO mice with human AD brain extracts and analysed induction of tau pathology; (2) expressed an AAV‐based reporter construct in APP KO and KI mice and analyse tau spread; (3) cultured APP KO primary neurons in microfluidic devices and analysed tau spread (4) stimulated brain slices and primary neurons from APP KO and KI mice and analysed tau release.Result(1) AD brain extracts failed to induce tau pathology in APP KO mice; (2) APP KO mice showed reduced spreading of AAV‐dependent expression of human tau, whereas mutant human APP mice showed increased spread of tau; (3) spread of tau between connected neurons was reduced in microfluidic devices containing APP KO neurons compared to wild type neurons; (4) brain slices and primary neurons from APP KO mice showed reduced tau release after neuronal stimulation, whereas tissue from mutant human APP mice showed increase release of tau.ConclusionAPP facilitates neuronal release and spreading of tau. This process is augmented by pathogenic APP mutations and increased APP levels, and reduced in the absence of APP. Our data suggest APP as an integral part of spreading of tau pathology and delineates a novel role for pathogenic APP mutations in AD.
Childhood dementia: the collective impact and opportunities for intervention
Authors: Elvidge Kristina L , Christodoulou John , Farrar Michelle A , Tilden Dominic , Maack Megan , Valeri Madeline , Ellis Magda , Smith Nicholas JC ,   Childhood Dementia Working Group
Published: December 2023

AbstractBackgroundChildhood dementia is a devastating and under‐recognised group of conditions with a high level of unmet need. Typically monogenic in origin, this collective of neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in infancy, childhood or adolescence.MethodWe undertook a scoping review and burden of illness study to understand the spectrum of childhood dementia conditions and their impact. A literature review identified conditions that met the case definition and an expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective incidence, prevalence and life expectancy were modelled.ResultOver 140 individual genetic conditions were identified that can be consistently defined as childhood dementia with the largest proportion of births belonging to the lysosomal disease and mitochondrial disease categories. Collectively the incidence is surprisingly high at 1 in 2,900 births and the life expectancy is low, with most affected children not surviving into adulthood. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/).ConclusionThis scoping review highlights the importance of grouping these conditions as a phenotypic syndrome, rather than individually rare diseases, in keeping with the approach to adult dementia. Opportunities exist to address overlapping disease mechanisms and utilise therapeutic platforms for multiple childhood dementia conditions to tap into significant economies of scale. Collaboration with adult dementia researchers on common disease attributes is also expected to be mutually beneficial.By unifying these conditions, we have highlighted the many unmet needs of this significantly disadvantaged group of children and young people and the data presented here will enable advocacy for systemic change in treatment, care, and support for them and their families.
Human Herpes Simplex Virus‐1 Encoded ICP27 Promotes the Alternative Splicing of MAPT Resulting in increased 4R Ratios within Cells of Neuronal Origin
Authors: Miller Michael , Czajka Timothy , Ijezie Emmanuel , D'Brant Lianna , Jarvis Ava , Butler David , Murphy Eain Anthony 
Published: December 2023

AbstractBackgroundFamilial linked Alzheimer’s Disease (AD) accounts for a small percentage of current cases, with the remaining caused by unknown etiologies. Independent of causation, AD is defined by three common characteristics: inflammation, extracellular b‐amyloid aggregation and intracellular Tau accumulation. Human herpes simplex virus 1 (HSV‐1), a neurotropic virus found in ∼50% of the population, was recently linked to AD progression in clinical samples and animal models. HSV‐1 infections induce inflammation and APP cleavage producing Ab42, but a role for viral‐mediated Tau accumulation has not been defined. In healthy brains, alternative splicing of MAPT, the gene encoding Tau, results in equimolar ratios of 3R and 4R isoforms of Tau protein. However, in AD tissues, unequal ratios of either 3R or 4R results in Tau microtubule disassociation, hyperphosphorylation and aggregation. Host factors that regulate MAPT alternative splicing include SRPK1. Interestingly, HSV‐1 encodes a protein, ICP27, that impedes the SRPK1 functions. Thus, we hypothesized that
HSV‐1 infections alter MAPT neuronal splicing resulting in altered 3R/4R Tau ratios in an ICP27 dependent fashion
.MethodWe used infection with WT and mutant HSV‐1 and ectopic ICP27 expression to monitor MAPT splicing in iPSC‐derived 3D cortical organoids and 2D neuronal models.ResultsWe observed that 3D cortical organoids infected with HSV‐1 accumulate phospho‐Tau and increase MAPT 4R mRNA splicing. HSV‐1 infection of neuronal SHSY‐5Y cells, results in a significant increase in 4R isoform relative to 3R, which we did not observe when we infected these cells a virus that lacks ICP27 expression, suggesting that this viral protein is
necessary
for the altered splicing. Further, using lentiviruses that express either wild‐type ICP27 or a mutant ICP27 that lacks the SRPK1 interaction domain, we observed increased 4R splicing only with the wild‐type protein, revealing that ICP27 is
sufficient
for modulating Tau isoforms and that the SRPK1 domain is required. Finally, we found that levels of 4R splicing was increased within infected astrocytes, thus underscoring the impact HSV‐1 imparts on cells of both neuronal and non‐neuronal origin.ConclusionIn sum, our findings reveal the remaining critical third link in how neurotropic human herpesviruses can impact and influence AD progression.
The association between microbiome and white matter integrity in the elderly with youthful memory in superaging
Authors: Kim Bori.R. , Kim Geon Ha , Jeong Jee Hyang 
Published: December 2023

AbstractBackgroundAging‐related cognitive decline has been regarded as a normal consequence of aging. However, previous research on ‘SuperAgers’ suggests that such decline is not inevitable. The purpose of this study was to investigate the relationship between the microbiome and white matter integrity in SuperAgers, which may help us understand the mechanism that preserves memory function in these individuals.MethodWe enrolled a total of 115 elderly individuals aged 60 years or older with normal cognitive function, which was defined as scoring one standard deviation or more above the population norm on tests of memory, attention, language, visuospatial ability, and frontal function in the Seoul Neuropsychological Screening Battery. SuperAgers were defined based on their delayed recall scores compared to middle‐aged adults (45 years old) in both the Seoul Verbal Learning Test and the Rey‐Osterrieth Complex Figure Test. Diffusion tensor images were analyzed using tract‐based spatial statistics (TBSS). Parameters related to diffusion tensors were calculated at the voxel level to generate fractional anisotropy (FA) images using the DTIFit. FA values, a diffusion tensor parameter reflecting white matter fiber tract integrity, were measured and compared between SuperAgers and typical agers using the FSL randomise program. For microbiome analysis, EZ biocloud was used to perform alpha diversity, taxonomic hierarchy, and taxonomic composition analysis for each subject analysis. Group analysis was also conducted using the taxonomic composition values, and further group analysis was carried out using ACE, Chao1, and Jacknife, which are indicators of species richness. Statistical analyses were conducted using Statistical Package for Social Science 19.ResultCompared to typical agers, superagers showed a higher number of Firmicutes and Actinobacteria, which have been associated with higher cognitive function. However, there was no significant difference between superagers and typical agers. Additionally, an analysis of the association between p_firmicutes, c_mollicutes, o_lactobacilales and f_erysipelotrichaceae with white matter integrity showed no significant association.ConclusionBased on these results, it can be inferred that superagers may have a correlation with microbiome strains that are closely related to cognitive function, as well as white matter in the brain
Iron homeostasis alters neuro inflammation response during AD white matter degeneration: A HFE + APOE4 genetic study
Authors: Pang Ran 
Published: December 2023

AbstractBackgroundThe HFE gene involves regulation of iron metabolism that directly participates in white matter (WM) myelination and neuroinflammations processes, while ApoE4 mutation are known to affect normal myelination through disruptions of iron and lipid metabolisms. Taken together, it is important to investigate the collective effects of HFE and the ApoE4 mutations, focusing on iron metabolism and neuronal inflammation during AD WM degeneration.MethodDiffusion tensor imaging (DTI) MRI, cognitive and CSF biomarkers (sTREM2, Tau, Abete42) data were collected from ADNI database in the AD cohorts of ApoE4 carriers with and without HFEH63D polymorphism. Multivariate analysis with AMOS in SPSS software was used to establish and validate directed correlations using structural equation models (SEM).[1]
ResultProminent WM degeneration in AD is significantly attenuated in HFEH63D carriers (Fig.1). The negative and indirect correlation between HFEH63D genotype and CDR‐cog (Fig. 2) suggests a protective role by HFEH63D mutation on WM degeneration and cognitive decline in AD ApoE4 carriers. As indicated by the negative and direct correlation between sTREM2 and CDR‐cog, such a protective role during AD aging is likely due to the reduced neuroinflammation in the HFE polymorphism cohorts.ConclusionUnified multivariate analysis with SEM allowed us to establish directed/causative relationships between genotyping and AD neurodegeneration‐to‐cognitive‐decline within the ATN framework. Our SEM analysis demonstrated that the protective role in ADApoE4 carriers may involve in attenuated neuroinflammation by the altered iron management by HFEH63D polymorphism.Ref.[1]. Bagozzi, R. and Yi, Y. (1988) On the Evaluation of Structural Equation Models. Journal of the Academy of Marketing Sciences, 16, 74‐94. https://doi.org/10.1007/BF02723327
Calcineurin inhibition prevents hippocampal synaptic plasticity impairment induced by brain‐derived tau oligomers via modulation of the transcriptome
Authors: Scaduto Pietro , Kayed Rakez , Taglialatela Giulio 
Published: December 2023

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) strongly correlates with tau protein accumulation, with the most toxic species being in form of oligomers [1,2]. Due to the polymorphism of tau oligomers, isolating and testing brain‐derived tau oligomers (BDTO) directly from AD patients could provide new insights into tau toxicity. BDTO are potent inhibitors of long‐term potentiation (LTP) in hippocampal brain slices [3], however the involved mechanism is still not fully understood. We previously reported significantly reduced incidence of AD in aging humans chronically treated with a FDA‐approved calcineurin inhibitor, FK506, used as immunosuppressant after solid organ transplant [4]. Here we show that impairment of the synaptic functionality driven by BDTO is restored by calcineurin inhibition using FK506 via selective transcriptomic changes.MethodCombination of electrophysiological and RNA‐seq techniques were used. Ex‐vivo slices from 8‐12 weeks old C67BL/6J mice were treated with aCSF (Ctrl), BDTO (100nM) or BDTO+FK506. Field excitatory post‐synaptic potentials (fEPSPs) recordings were performed by stimulating the Schaffer collateral pathway, and recording electrode was located at the junction of the alveus and cornu ammonius 1 (CA1). After electrophysiological recordings, the hippocampus was isolated from the brain slice, snap frozen and processed for RNA‐seq.ResultFK506 treatment significantly ameliorated the BDTO‐induced attenuation of fEPSP. One‐way ANOVA followed by Tukey’s test, showed that BDTO caused reduction of fEPSP compared to Ctrl (p = 0.068). fEPSP was re‐established at physiological levels in the group BDTO+FK506 (vs Ctrl p = 0.603; vs BDTO p = 0.0163). A similar trend was observed when we analyzed the paired‐pulse ratio. Analysis of the transcriptome showed that FK506 modulates key synaptic transcripts impaired after BDTO treatment.ConclusionOur study provides evidence that FK506 has the potential to block the BDTO toxic effect on synaptic plasticity. These results suggest that FK506 may represent a promising therapeutic strategy for the treatment of AD. Further research is needed to elucidate the precise molecular mechanisms underlying FK506‐mediated neuroprotection and to explore its potential in in vivo models of AD.References: [1] PMID: 27105663, [2] PMID: 28420982, [3] PMID: 23050084, [4] PMID: 26401556Founding: NIH/NIA R01‐AG060718
Referral Patterns From Primary Care Clinicians to Specialists Among People With Cognitive Impairment Disorders, including Alzheimer’s Disease
Authors: Mearns Elizabeth S , Patel Anisha M , Jinnett Kimberly , Gaur Abhishek , Cobb Bryan R , Macaluso Christine J , Weiss Jonathan , Seleri Sheila , Win Nikki 
Published: December 2023

AbstractBackgroundA timely and accurate diagnosis of Alzheimer’s disease (AD) can optimize treatment outcomes; however, few people are referred to a specialist for reasons that are not well understood. The objective of this study was to evaluate referral to a specialist by a primary care clinician (PCC) or other healthcare provider (HCP) among people diagnosed with cognitive impairment disorders, including AD (CIDiAD).MethodThis retrospective cohort study analyzed claims data from the Optum de‐identified Normative Health Information database between 1/1/2016‐31/12/2021 (study period). Adults were required to have ≥2 ICD‐9/10‐CM diagnosis codes for AD from any provider during the study period. The index event was defined as the first CIDiAD diagnosis (Table 1) from a PCC or other HCP before or on the date of their diagnosis during the identification period (1/1/2017‐31/12/2020) (Table 2). Continuous medical enrollment was required in the pre‐ and postindex periods. No diagnoses of CIDiAD in the pre‐index period were allowed. People with a post‐index diagnosis of AD from a specialist comprised the referral cohort. Time to specialist referral was assessed, and characteristics of people who were or were not referred were summarized.ResultA total of 48,525 people with a CIDiAD diagnosis from a PCC or other HCP were included; of these, 13,074 (26.9%) were referred to a specialist. The overall median (IQR) time to first specialist visit was 10.0 (3.2‐20.7) months. Time to first specialist visit was longer for referrals from PCCs compared with those from other HCPs (10.8 [3.8‐21.6] vs 9.2 [2.8‐19.9] months, respectively; P<0.0001). No notable differences in sex, age, race and ethnicity, or geographic region were observed between people who were referred and those who were not (Table 3).ConclusionThe majority of people with CIDiAD were not referred to a specialist. Among people who were referred to a specialist, time to first visit was long. Approval of disease‐modifying therapies may accelerate referral to a specialist and shorten referral times as early diagnosis of AD becomes more important. Further analyses will inform geographic differences in specialist referral patterns.
FTIR analysis of neuronal‐like cells upon Aβ exposure
Authors: Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela 
Published: December 2023

AbstractBackgroundThe Aβ peptide is a key player in Alzheimer´s disease (AD) pathogenesis, tending to aggregate into oligomers and fibrils, and finally senile plaques; a major hallmark in AD brains. This peptide is extremely toxic to neurons, triggering several mechanisms, that ultimately inducing neuronal death. Brain metabolic alterations are also closely linked to disease pathogenesis. In this work, the effect of Aβ in the spectroscopic profile of distinct neuronal‐like cell lines was analyzed using Fourier Transform Infrared (FTIR) spectroscopy.MethodTwo neuroblastoma cell lines, human derived SH‐SY5Y and mouse derived N2a, were treated with 10 µM of Aβ25‐35 peptide for 48 h. After treatment, cells were detached, samples containing 1×105 cells were prepared and immediately frozen until FTIR analysis. Prior to analysis, cells were resuspended in PBS and FTIR spectra was acquired. Data was analyzed by partial least squares (PLS) multivariate analysis or using univariate approaches for the calculation of peak areas associated with the fingerprint region (1200‐900 cm−1). This corresponds to a spectral region assigned mostly to carbohydrates and nucleic acids.ResultPLS analysis of the fingerprint region showed a clear discrimination between the spectra of control and Aβ‐treated cells. The univariate analysis for the peak areas of this spectral region also presented significant differences between the two groups, for both cell lines.ConclusionThe spectroscopic profile of the two neuronal‐like cell lines was altered in response to Aβ treatment, particularly in the fingerprint region, supporting the contribution of this peptide to metabolic changes that can potential underly AD pathogenesis.This work was funded by Instituto de Biomedicine (iBiMED) under Grant UIDB/04501/2020 and UIDP/04501/2020; MV is supported by the individual PhD grant UI/BD/151354/2021.