bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF Biomarkers profile in siblings with Alzheimer’s disease carrying the ADAM10 nonsense mutation p.Tyr167*
Authors: Agüero Pablo , García‐Ayllón María‐Salud , Sáez‐Valero Javier , Sainz María José , Téllez Raquel , Guerrero‐López Rosa , Pérez Juilán Pérez , Jiménez‐Escrig Adriano , Gomez‐Tortosa Estrella 
Published: December 2020

AbstractBackgroundThe known genetic causes of EOAD are related to increased processing of the amyloid precursor protein (APP) through the amyloidogenic pathway, with subsequent pathological accumulation of Ab peptides. A decrease in non‐amyloidogenic processing of APP through α‐secretase proteolysis is also considered a straightforward mechanism triggering AD development. The disintegrin metalloproteinase 10 (ADAM10) has been identified as the major α‐secretase in the brain and some ADAM10 gene variants have been associated with higher susceptibility to develop late‐onset disease. In this study we analyze the CSF biochemical profile of two siblings with dementia of Alzheimer type (DAT) carrying a nonsense ADAM10 prodomain mutation to assess the physiopathological effect of the mutation.MethodClinical and biomarker study of a family with DAT associated with p.Tyr167* ADAM10 mutation. CSF analysis included AD core biomarkers (Lumipulse technology, Fujirebio) as well as Western blotting of ADAM10 species and the sAPPα and sAPPb peptides. A comparison was made with normal controls (n=12) and sporadic AD cases (n=12).ResultThe p.Tyr167* mutation was absent from public databases and segregated with the disease. CSF samples were available for two siblings. Ab42, total tau, and phosphorylated tau biomarkers in both were consistent with AD (Erlangen score of 4). ADAM10 isoforms in CSF (full‐length ∼ 55 kDa and truncated soluble ∼ 50 kDa) were decreased by around 50% and sAPPα peptide (both 110 and 120 kDa bands) was reduced by 70%, as compared to controls. sAPPb levels showed no changes. Interestingly, the sporadic AD cases showed a similar decrease in CSF ADAM10 levels to mutants, though their sAPPα and sAPPb levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings.ConclusionThe CSF biochemical profile in these siblings is consistent with α‐secretase haploinsufficiency and illustrates the role of ADAM10 in the amyloidogenic process. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model of sporadic late‐onset AD due to an age‐related down‐regulation of α‐secretase activity.
Improved performance of Elecsys CSF Abeta measurement achieved using the simple, unified routine‐use protocol for CSF collection
Authors: Hansson Oskar , Stomrud Erik , Zetterberg Henrik , Rutz Sandra , Manuilova Ekaterina , Logan Chad , Corradini Veronika , Blennow Kaj 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers amyloid‐β1–42 (Abeta42), amyloid‐β1–40 (Abeta40), phospho‐tau (pTau) and total tau (tTau) can support the diagnosis of Alzheimer’s disease (AD); pre‐analytical handling differences are a known source of variability in measured levels of these biomarkers. An industry consortium chaired by the Alzheimer’s Disease Association developed a simplified Routine‐Use CSF sample handling protocol intended for universal adoption in clinical practice.MethodCSF samples from patients with normal pressure hydrocephalus were collected per the Routine‐Use protocol for fresh CSF (n=3 aliquots per patient) and two clinical trial protocols (BioFINDER and Roche Trial) for frozen CSF (n=4 aliquots per patient). Abeta42, pTau and tTau concentrations were quantified by commercially available Elecsys® immunoassays; Abeta40 was measured using a research‐use only prototype immunoassay. Routine‐Use samples were measured for each biomarker within 48h of collection, and subsequently frozen and stored (–20°C; ≥1 week) and remeasured. BioFINDER and Roche Trial samples were stored (<–60°C; ≥1 week) before biomarker measurement. Freshly measured Routine‐Use results were evaluated versus comparator results by calculating mean percentage difference and aliquot‐to‐aliquot variability for all biomarkers. Similar analyses comparing Routine‐Use results following one freeze‐thaw cycle were performed using an updated Abeta42 CSF II (Gen2) assay (technical performance presented separately).ResultIn this interim analysis (N=24 patients), Abeta42 concentrations in Routine‐Use results were on average 13.6% (95% CI 10.3%, 17.0%; p<0.0001) and 31.7% (95% CI 26.0%, 37.3%; p<0.0001) higher than BioFINDER and Roche Trial results, respectively. Abeta40, pTau and tTau concentrations were similar across sample handling protocols. Lower aliquot‐to‐aliquot variability was observed for Routine‐Use Abeta42, Abeta40, Abeta42/40 ratio and pTau/Abeta42 ratio results versus comparator results (Table); for pTau and tTau, aliquot‐to‐aliquot variability was similar across protocols. Freeze‐thawing of Routine‐Use samples using the Gen2 assay resulted in a 2.24% (95% CI –3.88%, –0.60%; p=0.0096) mean decrease in Abeta42 concentrations and slightly elevated aliquot‐to‐aliquot variability versus fresh samples (mean coefficient of variation 2.61% versus 2.11%); pTau and tTau levels and the aliquot‐to‐aliquot variability were not significantly affected by freezing.ConclusionThe Routine‐Use protocol is reliable and robust (low fresh‐frozen effect), and has higher analyte recovery for Abeta42 and less aliquot‐to‐aliquot variability versus comparator protocols.
The Alzheimer’s disease protective R522 variant of PLCg2, consistently enhances PLCγ2 activation, depleting PI(4,5)P2 levels and altering cell function in in vitro and in vivo assays
Authors: Philips Thomas Ernest James , Maguire Emily , Menzies Georgina E , Sasner Michael , Williams Harriet M , Czubala Magdalena , Evans Neil , Cope Emma L , Sims Rebecca , Howell Gareth , Lloyd‐Evans Emyr , Williams Julie , Allen Nicholas D , Taylor Philip 
Published: December 2020

AbstractBackgroundRecent GWAS studies have identified the R522 variant in PLCg2 as protective against late onset Alzheimer’s disease (AD). Expression of PLCg2 in the brain is predominantly found in microglia. PLCg2 has been shown to catalyse the hydrolysis of PIP2 to DAG and IP3 leading to increased intracellular Ca2+. Intracellular Ca2+ has been linked to NLRP3 inflammasome activation and increased phagocytic activity. This suggests that the R522 variant may alter the response time of microglia in conditions such as AD.MethodUsing CRISPR‐engineering novel PLCG2‐R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model were generated. From these, primary murine microglia, murine macrophages and hIPSC derived microglia cultures were created. The role of PLCg2 in the intracellular Ca2+ was investigated by detecting cytoplasmic Ca2+ increase, following activation of PLCg2 in human (anti‐CD32) and murine (anti‐FcgII/III) models. This was further investigated using specific PLCg inhibitors and a GapmeR knockdown system. The phagocytic and endocytic activity of these cells was investigated using pHrodo‐Red bound zymosan, E.coli and dextran, and fluorescent amyloid oligomers. PIP2 levels were detected using immunostaining and mass ELISAs. Molecular dynamic stimulation was used to ensemble and analyse the variant.ResultCells with the R522 mutation demonstrate hyperfunctionality manifesting as enhanced cellular Ca2+ store release in response to physiologically relevant stimuli. This resulted in increased PIP2 depletion in the cells with the R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLCγ2‐R522 associated abnormalities led to impairments to phagocytosis and enhanced endocytosis. The variant was found to be in the auto‐inhibitory domain.ConclusionThese results indicate a gain of function mutation in PLCγ2 which increases calcium release from the ER but depletes substrate levels resulting in a smaller reservoir of PIP2 available for other functions. This is consistent with an alteration in the auto‐inhibitory domain. Phagocytosis, which has a larger PIP2 requirement, is decreased while endocytosis which has a lower PIP2 requirement is increased. PLCγ2 sits downstream of disease relevant pathways and as an enzyme is classically druggable thus raises the prospect of PLCγ2 as a therapeutic target for AD.
Region‐specific microglial dynamics in the brain of Alzheimer's patients
Authors: Mejias‐Ortega Marina , Sanchez‐Mejias Elisabeth , Navarro Victoria , Nuñez‐Diaz Cristina , Sanchez‐Varo Raquel , Jimenez‐Muñoz Sebastian , Davila Jose Carlos , Vitorica Javier , Gutierrez Antonia 
Published: December 2020

AbstractBackgroundThe neuroinflammatory process involving particularly microglial cells, constitutes a hallmark of Alzheimer´s disease (AD) and has been postulated as a critical factor in the disease progression since the identification of several genetic risk factors related to microglial functions. However, the microglial phenotypes in the human pathology have not been determined yet. In this sense, we have previously reported a limited activation and microglial degeneration in the hippocampus of AD patients in contrast to the proinflammatory response long observed in amyloidogenic models. Here, we have further examined the functional/phenotypic profile displayed by microglial cells (activation/degeneration) in two different and vulnerable brain areas of AD patients (frontal cortex and hippocampus).MethodCellular (immunohistochemistry and image analysis) and molecular (qPCR and western blots) approaches have been carried out in samples from non‐demented controls (Braak II) and AD cases (Braak V‐VI).ResultMicroglial cells from frontal cortex of AD patients showed a generalized and exacerbate activation similar to that observed in APP/PS1 mice. These strongly activated microglial cells, predominantly located surrounding amyloid plaques, could drive the AD pathology and, in consequence, could be implicated in the pathology progression. These findings in the frontal cortex were highly in contrast to the attenuated activation and degenerative morphology showed by microglial cells in the hippocampus of the same AD patients.ConclusionRegional differences in the microglial response exhibit the heterogeneity and complexity of the microglial phenotypes and suggest different functional states of these glial cells in a region‐specific manner. All together, these data need to be considered for better understand the immunological mechanisms underlying AD progression. Modulating brain inflammatory responses might be a promising avenue to prevent cognitive dysfunction in AD patients. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain and Junta de Andalucia UMA18‐FEDERJA211 (to AG), all co‐financed by FEDER funds from European Union.
Characterization of hippocampal amyloidosis induced by amyloid‐β in behaving mice
Authors: Iborra‐Lázaro Guillermo , Mayordomo‐Cava Jennifer , Sánchez‐Rodríguez Irene , Temprano‐Carazo Sara , Djebari Souhail , Gruart Agnès , Delgado‐Garcia Jose Maria , Navarro‐López Juan D. , Jimenez‐Diaz Lydia 
Published: December 2020

AbstractBackgroundIn early stages of Alzheimer’s disease, disruption of learning and memory processes that rely on hippocampal performance correlates with aberrant patterns of synchronous neuronal activity that arise prior to evident neurodegeneration. These disturbances emerge as a result of neuronal hyperexcitability and synaptic dysfunction induced by soluble forms of amyloid‐β (Aβ) peptide, which trigger an imbalance between excitatory and inhibitory neurotransmission systems. The molecular mechanisms underlying these alterations remain unclear but functional evidence points to alteration of neuronal excitability playing a pivotal role in early Aβ‐induced AD pathogenesis. Although Aβ
1‐42 and Aβ
1‐40 are widely known for their clinical relevance, Aβ
25‐35 has been proposed as the biologically active fragment. In contrast to other Aβ isoforms, Aβ
25‐35 does not generate ion‐permeable pores in neuronal membrane, but it has been shown to induce major neuropathological signs related to early AD stages. Hence, it has been extensively used to study the pathophysiological events related to Aβ‐induced neuronal dysfunction. It remains to be explored, however, whether Aβ
25‐35 mimics the neurotoxic effects on the hippocampus exhibited by other clinically relevant species such as Aβ
1‐42 (Sánchez‐Rodriguez et al., 2017, 2019, 2020).MethodsHere, we systematically characterized the effects of Aβ
25‐35 on hippocampal function at different —behavior, networks and synapses— levels of complexity in behaving mice prepared for chronic intracerebroventricular injections. Likewise, animals were implanted with electrodes for in vivo recordings at the hippocampal CA1 area and electrical stimulation of the Schaffer collateral pathway.ResultsOur data showed evident learning and memory impairments in hippocampal‐dependent tasks such as novel object recognition and open field habituation tests. Underlying these deficits, local field potential (LFP) recordings revealed an altered oscillatory activity. Additionally, theta and gamma rhythms, crucially involved in successful memory encoding, were abnormally increased. Lastly, we also found impairments in long‐term synaptic plasticity at the CA3‐CA1 synapse, where Aβ
25‐35 transformed long‐term potentiation (LTP) into long‐term depression (LTD).ConclusionsTaken together, these results support the notion that Aβ
25‐35‐mediated effects on synaptic properties and neural network activity mimicked those exerted by Aβ
1‐42. Thus, we verified the potentiality of the Aβ
25‐35 peptide to study the hippocampal pathophysiology of early amyloidosis.
Risk for Alzheimer's disease: a review of long‐term episodic memory encoding and retrieval fMRI studies
Authors: McDonough Ian M , Festini Sara B , Wood Meagan M 
Published: December 2020

AbstractBackgroundMany risk factors have been identified that predict future progression to Alzheimer’s disease (AD). However, clear links have yet to be made between these risk factors and how they affect brain functioning in early stages of AD.MethodWe conducted a narrative review and a quantitative analysis to better understand the relationship between nine categories of AD risk (i.e., brain pathology, genetics/family history, vascular health, head trauma, cognitive decline, engagement in daily life, late‐life depression, sex/gender, and ethnoracial group) and task‐evoked fMRI activity during episodic memory in cognitively‐normal older adults.ResultOur narrative review revealed widespread regional alterations of both greater and lower brain activity with AD risk. Nevertheless, our quantitative analysis revealed that a subset of studies converged on two patterns: AD risk was associated with (1) greater brain activity in frontal and parietal regions, but (2) reduced brain activity in hippocampal and occipital regions. The brain regions affected depended on the assessed memory stage (encoding or retrieval).ConclusionAlthough the results clearly indicate that AD risks impact brain activity, we caution against using fMRI as a diagnostic tool for AD at the current time because the above consistencies were present among much variability, even among the same risk factor.
Identification of hippocampal volume as a mediator of the association between APOE4 and dementia
Authors: Brenek Sixtine , Debette Stéphanie , Auriacombe Sophie , Amouyel Philippe , Chouraki Vincent , Meirhaeghe Aline , Damotte Vincent 
Published: December 2020

AbstractBackgroundThe apolipoprotein E ε4 allele (APOE4), vascular risk factors and neurodegenerative factors are known to be associated with dementia. This study aimed at identifying any mediating effect of those risk factors in the association existing between APOE4 and dementia.Methods1,197 participants from the French Three City Dijon Study without prevalent tumor or dementia were included. Among these participants, 72 developed dementia during the 12 years of follow‐up. Using regression and mediation analyses, we studied whether known risk factors for dementia i.e diabetes mellitus, hypercholesterolemia, hypertension, hippocampal volume or white matter hyperintensities could mediate the association between APOE4 and dementia. Regression models were adjusted for age, sex, education level (and total intracranial volume when imaging metrics were considered).ResultsHippocampal volume was a partial mediator of the association between APOE4 and dementia (mediation ratio = 8.7%, p=0.008). No mediation effect was found for hypercholesterolemia. No mediation analyses could be undertaken for the others factors due to the lack of their association with APOE4 in our sample.ConclusionIn this study, the association between APOE4 and dementia was partially mediated by hippocampal volume, suggesting a deleterious role of APOE4 in the hippocampus. This result warrants further replication in other cohorts, with higher sample sizes.
Validation of neuroinformatics algorithms, claims‐triage score, and proprietary brain health protocol for dementia care management for insurance markets: Establishing a gold standard in the Silver Tsunami
Authors: Rao Anitha , Miller Benjamin , Kulman Tanzila , Aggarwal Neelum T 
Published: December 2020

AbstractBackgroundAs the population ages globally, there will be an increased demand placed on the insurance sector to improve outcomes and quality of care for patients with neurodegenerative diseases. Established guidelines and standards of care exist and provide a framework for healthcare providers (HCP) to diagnose cognitive impairment (CI) and rule out other conditions that may mimic or exacerbate CI. Based on prior real world evidence, these guidelines are seldom adopted by HCPs and insurance claims processing teams.MethodsAs part of chronic illness insurance claims processing, proprietary neuroinformatics algorithms computed a patent‐pending claims triage score (CTS) and a digital brain health protocol (BHP). The CTS consists of a 1–5 score that provides a framework for utilization management and cognitive claims processing for chronic illness verification. An external neurology task force reviewed and validated the CTS and proprietary BHP to confirm they met standards of care and practice guidelines put forth by the American Academy of Neurology. Additional claims data was collected as part of the process.ResultsA total of 67 CTS and BHPs were completed (F = 41, M = 26). CTS had a sensitivity and specificity over 95%. Distribution of CTS are as follows: Score 1 (3%), Score 2 (15%), Score 3 (41.7%), Score 4 (25.3%), and Score 5 (7.4%). The external neurology task force agreed with the suggested workup computed by the neuroinformatics algorithms 98% of the time. Inter‐rater reliability was high. MMSE scores ranged from 1–30 and SPMSQ scores ranged from 0–10.ConclusionPractice guidelines optimize care and improve patient outcomes. No such standardized validated protocol exists for the insurance market to process chronic illness claims and this research highlights a first to market approach that combines predictive analytics and medical guidelines to impact the evaluation of neurodegenerative diseases in the insurance market.
Acceptability of a mental health care pathway to address dementia risk factors in primary care settings: A qualitative study
Authors: McAiney Carrie A , Berry Camryn , Parascandalo Fiona , Kates Nick , Saperson Karen , Dham Pallavi , Malik Noor , Rajji Tarek K 
Published: December 2020

AbstractBackgroundGiven the projected increases in dementia prevalence across the world, it is imperative that we identify and mitigate the potential impacts of reversible risk factors for developing dementia. Depression, anxiety and mild cognitive impairment (MCI) are examples of such risk factors. However, despite their relatively high prevalence rates among those age 60 and over, these conditions often go unrecognized and untreated. A growing body of evidence suggests that evidence‐based interventions in primary care can increase detection and treatment rates of these conditions, and may help to prevent or prolong the development of dementia. This presentation reports on qualitative data collected as part of a longitudinal cohort study examining the implementation and effectiveness of an Integrative Care Pathway (ICP) for depression, anxiety and MCI in primary care settings.MethodA qualitative descriptive design was used to examine the acceptability of the ICP by primary care providers. Two sets of focus groups were conducted with five participating primary care practices during the study. Participants varied by practice and included family physicians, nurses, allied health professionals, and administrative staff. Focus groups were audio‐recorded, transcribed verbatim, and analyzed using conventional content analysis.ResultThe findings indicate that providers had mixed reactions in terms of the acceptability of the ICP. The fact that the ICP was evidence‐based was a strength of the pathway and gave providers and patients reassurance regarding the management of depression, anxiety and MCI. However, the realities of primary care practice, particularly in terms of time constraints, indicated the need for flexibility in how the ICP is applied.ConclusionHaving access to evidence‐based resources can support primary care providers in managing mental health risk factors for dementia. However, resources need to reflect the culture and practices of primary care settings in order for them to be acceptable to providers.
Prevalence of cognitive deficit in elderly with depressive symptoms
Authors: Rosa Giovana Carolina Láo , Borges Sheila de Melo 
Published: December 2020

AbstractBackgroundDepression often presents with memory complaints and can impair memory functions. As dementia, depression is one of the major geriatric syndromes that compromises the quality of life of this population. Therefore, the aim of the present study was to assess the prevalence of cognitive impairment in the elderly with suggestive scores of depressive symptoms and to verify the relationship between cognitive screening tests and depressive symptoms in this population.MethodsA cross‐sectional study was carried out with 66 elderly people attended by Primary Health Units in the municipality of Santos, State of São Paulo, Brazil. To contemplate the objective of the present study, age, education and sex were analyzed, as well as cognitive screening tests such as the Mental State Mini‐Exam (MMSE), verbal fluency test (FV) animals category and the Clock Drawing Test (CDT). In addition, we analyzed data from the Geriatric Depression Scale (GDS‐15), which is a screening test for depressive symptoms.ResultsThe mean age was 70.8 ± 7.6 years, with the majority being women (n = 53; 80.3%); with a mean of 7.4 ± 4.0 years of schooling. The mean score of the GDS‐15 was 7.4 ± 1.6 points, with a higher frequency of mild depressive symptoms in the test classification (n = 63; 95.5%). Regarding cognitive tests, the mean of the MMSE was 25.5 ± 3.0 points, of the FV it was 13.6 ± 4.9 animals spoken in one minute and the TDR had a mean of 2.9 ± 1.6 points. To assess the correlation between the score of the cognitive screening tests and the classification of the GDS‐15, the Spearman's Correlation Coefficient (r) test was used. For statistical significance, we accept a p‐value <0.05. We observed a weak and negative correlation for GDS‐15 with MMSE (r = ‐0.26; P = 0.03), with CDT (r = ‐0.27: P = 0.02). There was no correlation with VF (r = ‐ 0.08: P = 0.5).ConclusionsThe study, both the MMSE and the CDT were shown to be more compromised in the population studied, these tests also being those that showed a correlation with the GDS‐15 scale.