Publications by authors named "Miguel Calero"

97 Publications

Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests.

Biomolecules 2021 Apr 19;11(4). Epub 2021 Apr 19.

Departamento de Proteínas y Ácidos Nucleicos, Instituto de Investigaciones Biológicas Clemente Estable, 11600 Montevideo, Uruguay.

Charcot-Marie-Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We compared the behavior profile of TrJ/+ and +/+ (wild-type) in open-field and elevated-plus-maze anxiety tests. In these tests, TrJ/+ showed an exclusive head shake movement, a lower frequency of rearing, but a greater frequency of grooming. In elevated-plus-maze, TrJ/+ defecate more frequently, performed fewer total entries, and have fewer entries to closed arms. These hippocampus-associated behaviors in TrJ/+ are consistent with increased anxiety levels. The expression of pmp22 and soluble PMP22 were evaluated in E17-hippocampal neurons and adult hippocampus by in situ hybridization and successive immunohistochemistry. Likewise, the expression of pmp22 was confirmed by RT-qPCR in the entire isolated hippocampi of both genotypes. Moreover, the presence of aggregated PMP22 was evidenced in unmasked granular hippocampal adult neurons and shows genotypic differences. We showed for the first time a behavior profile trait associated with anxiety and a differential expression of pmp22/PMP22 in hippocampal neurons of TrJ/+ and +/+ mice, demonstrating the involvement at the central level in an animal model of peripheral neuropathy (CMT1E).
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http://dx.doi.org/10.3390/biom11040601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074002PMC
April 2021

TREM2 expression in the brain and biological fluids in prion diseases.

Acta Neuropathol 2021 Jun 21;141(6):841-859. Epub 2021 Apr 21.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), L'Hospitalet de Llobregat, Spain.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.
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http://dx.doi.org/10.1007/s00401-021-02296-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113222PMC
June 2021

Medial Temporal Lobe Involvement in Human Prion Diseases: Implications for the Study of Focal Non Prion Neurodegenerative Pathology.

Biomolecules 2021 Mar 10;11(3). Epub 2021 Mar 10.

CIEN Foundation and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute of Health Carlos III, 28031 Madrid, Spain.

Human prion and non-prion neurodegenerative diseases share pathogenic mechanisms and neuropathological features. The lesion profile of a particular entity results from specific involvement of vulnerable neuron populations and connectivity circuits by a pathogenic protein isoform with strain-like properties. The lesion profile of the medial temporal lobe (MTL) was studied in postmortem tissue of 143 patients with human prion disease (HPD) including sporadic, genetic, and acquired forms. Most cases (90%) were classified according to PrP type and/or codon 129 status, in addition to a full neuropathological profile. Mixed histotypes represented 29.4% of total sporadic Creutzfeldt-Jakob disease (sCJD) cases. An intensity score of involvement including spongiosis and astrogliosis was determined for the amygdala, presubiculum, subiculum, entorhinal cortex, CA1 to CA4 sectors of the hippocampal cortex, and dentate gyrus. Connectivity hubs within the MTL presented the highest scores. Diverse lesion profiles were obtained for different types and subtypes of HPD. Impact of mixed PrP types on the MTL lesion profile was higher for sCJDMV2K cases than in other histotypes. Differences between MTL profiles was globally consistent with current evidence on specific strains in HPD. These results may be relevant for the analysis of possible strain effects in focal non-prion neurodegenerative conditions limited to the MTL.
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http://dx.doi.org/10.3390/biom11030413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998497PMC
March 2021

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 Feb 24;11(1):142. Epub 2021 Feb 24.

Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904832PMC
February 2021

The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration.

Antioxidants (Basel) 2021 Jan 16;10(1). Epub 2021 Jan 16.

Chronic Disease Programme, Instituto de Salud Carlos III, 28029 Madrid, Spain.

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.
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http://dx.doi.org/10.3390/antiox10010124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829956PMC
January 2021

Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid.

Gerontology 2021 Jan 11:1-9. Epub 2021 Jan 11.

Alzheimer's Disease Investigation Research Unit, CIEN Foundation, Institute of Health Carlos III, Queen Sofia Foundation Alzheimer Research Center, Madrid, Spain,

Background: The older population has been especially affected by the severe acute respiratory syndrome coronavirus 2 pandemic (COVID-19).

Objective: The aim of the study was to explore the incidence, severity, mortality rate, clinical features, and risk factors of symptoms of COVID-19 in home-dwelling older people, and its association with type of residence, cognitive deterioration, and neurodegenerative diseases.

Methods: Data about symptoms of COVID-19 were collected through a telephone survey in the cohort of 913 older volunteers of the Vallecas Project, aged 75-90 years, most of them (902) home-dwelling, in Madrid, Spain. The association of demographic and anthropometric measures, genetic polymorphisms, comorbidities, life habits, type of residence, and frailty surrogates were explored as potential risk factors for the incidence, severity, and mortality of COVID-19 in the older population.

Findings: Sixty-two cases reported symptoms compatible with COVID-19; 6 of them had died, 4 in their home and 2 in the nursing home. Moderate/severe cases were significantly older and more frequently males. The APOE ε4 allele was associated with the presence of symptoms of COVID-19. Higher systolic blood pressure, more intense smoking habit, more alcohol intake, lower consumption of coffee and tea, and cognitive impairment were associated with disease severity.

Conclusions: The estimated incidence of symptomatic COVID-19 in this older cohort of Madrid was 6.8%, with an overall mortality rate of 0.7% (18.2% in those living in a nursing home) and a fatality rate of 9.9%. Our exploratory study indicates that life habits, other clinical conditions and, the ε4 variant of the APOE gene are associated with the presence and clinical severity of coronavirus infection.
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http://dx.doi.org/10.1159/000513182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900450PMC
January 2021

Prodromal Alzheimer's Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer's Pathology.

Front Neurosci 2020 3;14:562581. Epub 2020 Dec 3.

Molecular Neuropathology, Physiological and Pathological Processes, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.

In humans, a considerable number of the autopsy samples of cognitively normal individuals aged between 57 and 102 years have revealed the presence of amyloid plaques, one of the typical signs of AD, indicating that many of us use mechanisms that defend ourselves from the toxic consequences of Aß. The human APP NL/F (hAPP NL/F) knockin mouse appears as the ideal mouse model to identify these mechanisms, since they have high Aß42 levels at an early age and moderate signs of disease when old. Here we show that in these mice, the brain levels of the hemoprotein Neuroglobin (Ngb) increase with age, in parallel with the increase in Aß42. , in wild type neurons, exogenous Aß increases the expression of Ngb and Ngb over-expression prevents Aß toxicity. , in old hAPP NL/F mice, Ngb knockdown leads to dendritic tree simplification, an early sign of Alzheimer's disease. These results could indicate that Alzheimer's symptoms may start developing at the time when defense mechanisms start wearing out. In agreement, analysis of plasma Ngb levels in aged individuals revealed decreased levels in those whose cognitive abilities worsened during a 5-year longitudinal follow-up period.
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http://dx.doi.org/10.3389/fnins.2020.562581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744294PMC
December 2020

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Lancet Neurol 2020 10 16;19(10):840-848. Epub 2020 Sep 16.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.

Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country.

Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10; heterozygous model p=1·01 × 10), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.

Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.

Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.
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http://dx.doi.org/10.1016/S1474-4422(20)30273-8DOI Listing
October 2020

Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease.

Mol Ther Methods Clin Dev 2020 Sep 6;18:558-570. Epub 2020 Jul 6.

Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.

Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.
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http://dx.doi.org/10.1016/j.omtm.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396971PMC
September 2020

An electrochemical immunosensor using gold nanoparticles-PAMAM-nanostructured screen-printed carbon electrodes for tau protein determination in plasma and brain tissues from Alzheimer patients.

Biosens Bioelectron 2020 Sep 5;163:112238. Epub 2020 May 5.

Department of Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, Madrid, 28040, Spain. Electronic address:

This work reports a new sensitive strategy for the determination of tau protein, a hallmark of Alzheimer's disease (AD), involving a sandwich immunoassay and amperometric detection at disposable screen-printed carbon electrodes (SPCEs) modified with a gold nanoparticles-poly(amidoamine) (PAMAM) dendrimer nanocomposite (3D-Au-PAMAM) covalently immobilized onto electrografted p-aminobenzoic acid (p-ABA). The capture antibody (CAb) was immobilized by crosslinking with glutaraldehyde (GA) on the amino groups of the 3D-Au-PAMAM-p-ABA-SPCE, where tau protein was sandwiched with a secondary antibody labeled with horseradish peroxidase (HRP-DAb). Amperometry at -200 mV (vs the Ag pseudo-reference electrode) upon the addition of hydroquinone (HQ) as electron transfer mediator and HO as the enzyme substrate was used to detect the immunocomplex formation. The great analytical performance of the immunosensor in terms of selectivity and low limit of detection (LOD) (1.7 pg mL) allowed the direct determination of the target protein in raw plasma samples and in brain tissue extracts from healthy individuals and post mortem diagnosed AD patients, using a simple and fast protocol.
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http://dx.doi.org/10.1016/j.bios.2020.112238DOI Listing
September 2020

Disposable immunoplatforms for the simultaneous determination of biomarkers for neurodegenerative disorders using poly(amidoamine) dendrimer/gold nanoparticle nanocomposite.

Anal Bioanal Chem 2021 Jan 30;413(3):799-811. Epub 2020 May 30.

Department of Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.

Early diagnosis in primary care settings can increase access to therapies and their efficiency as well as reduce health care costs. In this context, we report in this paper the development of a disposable immunoplatform for the rapid and simultaneous determination of two protein biomarkers recently reported to be involved in the pathological process of neurodegenerative disorders (NDD), tau protein (tau), and TAR DNA-binding protein 43 (TDP-43). The methodology involves implementation of a sandwich-type immunoassay on the surface of dual screen-printed carbon electrodes (dSPCEs) electrochemically grafted with p-aminobenzoic acid (p-ABA), which allows the covalent immobilization of a gold nanoparticle-poly(amidoamine) (PAMAM) dendrimer nanocomposite (3D-Au-PAMAM). This scaffold was employed for the immobilization of the capture antibodies (CAbs). Detector antibodies labeled with horseradish peroxidase (HRP) and amperometric detection at - 0.20 V (vs. Ag pseudo-reference electrode) using the HO/hydroquinone (HQ) system were used. The developed methodology exhibits high sensitivity and selectivity for determining the target proteins, with detection limits of 2.3 and 12.8 pg mL for tau and TDP-43, respectively. The simultaneous determination of tau and TDP-43 was accomplished in raw plasma samples and brain tissue extracts from healthy individuals and NDD-diagnosed patients. The analysis can be performed in just 1 h using a simple one-step assay protocol and small sample amounts (5 μL plasma and 2.5 μg brain tissue extracts). Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-02724-3DOI Listing
January 2021

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease.

Biomolecules 2020 02 12;10(2). Epub 2020 Feb 12.

Department of Neurology, National Reference Center for CJD Surveillance, University Medical Centre Göttingen, 37075 Göttingen, Germany.

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt-Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.
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http://dx.doi.org/10.3390/biom10020290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072321PMC
February 2020

Validation of a novel and accurate ApoE4 assay for automated chemistry analyzers.

Sci Rep 2020 02 7;10(1):2138. Epub 2020 Feb 7.

Chronic Disease Programme (UFIEC), CIBERNED, and CIEN Foundation, Queen Sofia Foundation's Alzheimer Center, Instituto de Salud Carlos III, Madrid, Spain.

The allele ε4 of the apolipoprotein E gene (APOE ε4) is the major genetic risk factor for non-dominantly inherited Alzheimer's Disease (AD). Current techniques for APOE ε4 carriers identification show good accuracy but have several disadvantages that limit its implementation in a clinical laboratory. These include the need for sample preprocessing, poor automation, low throughput, requirement of additional equipment, and high cost. We followed ISO 13485 guidelines to validate the e4Risk test, a new latex-enhanced immunoturbidimetric blood assay for apolipoprotein E4 (ApoE4) determination in human plasma samples. The test showed high performance in terms of lot to lot variability, precision, interferences, reagents stability, prozone, and detectability. Furthermore, diagnostic accuracy is almost equal (99%) to the gold standard, APOE ε4 genotyping by polymerase chain reaction (PCR). Furthermore, we demonstrated that the e4Risk test can be adapted to any clinical chemistry analyzer, including the high throughput analyzers present in most hospitals and clinical laboratories. The e4Risk test versatility, low cost, and easiness provides an excellent solution for APOE ε4 carriers identification using the same blood sample drawn for biochemical diagnostic work-up of AD patients, which can have important advantages for patient stratification in clinical trials, preventative strategies for AD, and clinical assessment of risk for brain amyloidosis.
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http://dx.doi.org/10.1038/s41598-020-58841-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005722PMC
February 2020

Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients.

Biomolecules 2019 11 28;9(12). Epub 2019 Nov 28.

Department of Neurology, National Reference Center for CJD Surveillance University Medical Center Göttingen, 37075 Göttingen, Germany.

The exploration of accurate diagnostic markers for differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous study on cerebrospinal fluid (CSF)-mitochondrial malate dehydrogenase 1 (MDH1) in sporadic Creutzfeldt-Jakob disease (sCJD) patients revealed a highly significant upregulation of MDH1. Here, we measured the CSF levels of MDH1 via enzyme-linked immunosorbent assay in a cohort of rare genetic prion disease cases, such as genetic CJD (gCJD) cases, exhibiting the E200K, V210I, P102L (Gerstmann-Sträussler-Scheinker syndrome (GSS)), or D178N (fatal familial insomnia (FFI)) mutations in the . Interestingly, we observed enhanced levels of CSF-MDH1 in all genetic prion disease patients compared to neurological controls (without neurodegeneration). While E200K and V210I carriers showed highest levels of MDH1 with diagnostic discrimination from controls of 0.87 and 0.85 area under the curve (AUC), FFI and GSS patients exhibited only moderately higher CSF-MDH1 levels than controls. An impact of the codon 129 methionine/valine (MV) genotype on the amount of MDH1 could be excluded. A correlation study of MDH1 levels with other neurodegenerative marker proteins revealed a significant positive correlation between CSF-MDH1 concentration with total tau (tau) but not with 14-3-3 in E200K, as well as in V210I patients. In conclusion, our study indicated the potential use of MDH1 as marker for gCJD patients which may complement the current panel of diagnostic biomarkers.
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http://dx.doi.org/10.3390/biom9120800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995564PMC
November 2019

Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment.

Biomolecules 2019 11 13;9(11). Epub 2019 Nov 13.

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.

The need for practical biomarkers for early diagnosis of Alzheimer's disease (AD) remains largely unmet. Here we investigated the use of blood-based microRNAs as prognostic biomarkers for AD and their application in a novel electrochemical microfluidic device for microRNA detection. MicroRNA transcriptome was profiled in plasma from patients with mild cognitive impairment (MCI) and AD. MicroRNAs Let-7b and microRNA-206 were validated at elevated levels in MCI and AD, respectively. MicroRNA-206 displayed a strong correlation with cognitive decline and memory deficits. Longitudinal follow-ups over five years identified microRNA-206 increases preceding the onset of dementia. MicroRNA-206 was increased in unprocessed plasma of AD and MCI subjects, detected by our microfluidic device. While increased Let-7b levels in plasma may be used to identify patients with MCI, changes in plasma levels of microRNA-206 may be used to predict cognitive decline and progression towards dementia at an MCI stage. MicroRNA quantification via a microfluidic device could provide a practical cost-effective tool for the stratification of patients with MCI according to risk of developing AD.
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http://dx.doi.org/10.3390/biom9110734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920950PMC
November 2019

Reconciling etiological views on Parkinson's disease.

Mov Disord 2019 11;34(11):1750-1752

Neurodegenerative disorders, Aging and Mental Health Unit, National Epidemiology Centre, Instituto de Salud Carlos III, Madrid, Spain.

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http://dx.doi.org/10.1002/mds.27875DOI Listing
November 2019

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

Alzheimers Dement 2019 10 28;15(10):1333-1347. Epub 2019 Aug 28.

Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.

Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets.

Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.

Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4950DOI Listing
October 2019

Age at onset in genetic prion disease and the design of preventive clinical trials.

Neurology 2019 07 6;93(2):e125-e134. Epub 2019 Jun 6.

From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK.

Objective: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.

Methods: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene () in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.

Results: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.

Conclusion: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
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http://dx.doi.org/10.1212/WNL.0000000000007745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656649PMC
July 2019

Frontotemporal lobar degeneration: Study of a clinicopathological cohort.

J Clin Neurosci 2018 Dec 19;58:172-180. Epub 2018 Oct 19.

Banco de Tejidos, Departamento de Neuropatología, Fundación Centro de Investigación en Enfermedades Neurológicas, Instituto de Salud Carlos III (FCIEN-ISCIII), Madrid, Spain.

Frontotemporal dementia results from different neurodegenerative diseases heterogeneous from a clinical, neuropathological and genetic point of view. Our main objective was to analyze the sociodemographic, clinical, neuropathological and molecular characteristics of cases with frontotemporal lobar degeneration from different Neurological Tissue Banks. FTD has been considered as a disease with onset below 65. However, diagnosis at higher ages is increasingly common. In our study, there was a correlation between symptoms and disease course with certain neuropathological diagnoses, with different distribution depending on age and sex. Combined pathology with Alzheimer's and vascular pathology was observed and presence of argyrophilic grains, with a different distribution in the different subgroups and a particular clinical and progression phenotype. Low percentage of APOE4 was detected. H1/H1 haplotype of the MAPT gene was the most frequent and appeared in relationship with 4R tauopathies. These results point to biologically significant differences between the different types of FTLD.
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http://dx.doi.org/10.1016/j.jocn.2018.10.024DOI Listing
December 2018

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases.

Mol Neurobiol 2019 Apr 30;56(4):2811-2821. Epub 2018 Jul 30.

Department of Neurology, University Medical School, Göttingen, Germany.

Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.
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http://dx.doi.org/10.1007/s12035-018-1251-1DOI Listing
April 2019

An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration.

Front Neurosci 2018 5;12:464. Epub 2018 Jul 5.

Chronic Disease Programme-CROSADIS, Instituto de Salud Carlos III, Madrid, Spain.

Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders.
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http://dx.doi.org/10.3389/fnins.2018.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041410PMC
July 2018

Characterization of Amyloid-β Plaques and Autofluorescent Lipofuscin Aggregates in Alzheimer's Disease Brain: A Confocal Microscopy Approach.

Methods Mol Biol 2018 ;1779:497-512

Chronic Disease Programme-CROSADIS, CIBERNED, Queen Sofia Foundation Alzheimer Center, CIEN Foundation, Instituto de Salud Carlos III, Madrid, Spain.

The study of brain pathology by fluorescence microscopy finds in the autofluorescence of the tissue an additional difficulty for the recognition of markers of interest. In particular, in the immunofluorescence study of brains from Alzheimer's disease (AD) patients, several approaches have been attempted to eliminate or mask the presence of autofluorescent aggregates. In the present work, we propose a method to characterize by fluorescent microscopy senile plaques discriminating them from autofluorescent aggregates, such as lipofuscin granules.This work describes four protocols carried out in human brain tissue of patients with AD, covering adequate tissue preparation, immunofluorescence acquisition, and data analysis: 1. Tissues processing of frozen samples for optimal epitope conservation. 2. Analysis of the fluorescence emission spectrum of the tissue by performing a confocal microscopy λ-scan. 3. Analysis of fluorescence emission of both intact and formic acid-treated tissues in four channels corresponding to the emission in blue, green, near red, and far-red regions. 4. Analysis a specific immunostaining of amyloid beta in senile plaques, using fluorescent-labeled antibodies by using specific emission channels to avoid detection of tissue autofluorescence.
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http://dx.doi.org/10.1007/978-1-4939-7816-8_31DOI Listing
July 2019

Detecting Circulating MicroRNAs as Biomarkers in Alzheimer's Disease.

Methods Mol Biol 2018 ;1779:471-484

Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

Alzheimer's disease is the most common form of dementia and is characterized by a progressive loss of cognitive functions. As the result of predicted demographic changes over the next decades, Alzheimer's disease is expected to be one of the most pressing medical and social challenges facing our generation. Current treatment strategies remain symptomatic. However, new approaches have shown promise in clinical trials, particularly in patients with only mild or moderate symptoms. Early detection of Alzheimer's disease is therefore of critical importance. Currently available diagnostic approaches (such as protein analysis in cerebrospinal fluid or neuroimaging), however, are expensive and invasive and therefore unsuitable for the screening of a large population. Consequently, Alzheimer's disease is generally diagnosed too late for effective intervention. MicroRNAs-readily measurable in biofluids and resistant to freeze-thaw and pH changes, have shown encouraging diagnostic potential in Alzheimer's disease. Several studies have attempted to correlate changes of specific microRNAs to disease progression using different approaches and profiling platforms including micro-arrays, RNA sequencing, and qPCR-based systems. In the present book chapter, we will describe the different steps involved in how to determine the microRNA profile in plasma samples from patients using the OpenArray platform.
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http://dx.doi.org/10.1007/978-1-4939-7816-8_29DOI Listing
July 2019

Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features.

J Alzheimers Dis 2018 ;63(3):1109-1117

Banco de Tejidos, Departamento de Neuropatología, Fundación Centro de Investigación en Enfermedades Neurológicas, Instituto de Salud Carlos III (FCIEN-ISCIII), Madrid, Spain.

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.
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http://dx.doi.org/10.3233/JAD-171115DOI Listing
June 2019

A fast and cost-effective method for apolipoprotein E isotyping as an alternative to APOE genotyping for patient screening and stratification.

Sci Rep 2018 04 13;8(1):5969. Epub 2018 Apr 13.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

Apolipoprotein E (apoE) is a 34 kDa glycoprotein involved in lipid metabolism. The human APOE gene encodes for three different apoE protein isoforms: E2, E3 and E4. The interest in apoE isoforms is high for epidemiological research, patient stratification and identification of those at increased risk for clinical trials and prevention. The isoform apoE4 is associated with increased risk for coronary heart and Alzheimer's diseases. This paper describes a method for specifically detecting the apoE4 isoform from biological fluids by taking advantage of the capacity of apoE to bind "specifically" to polystyrene surfaces as capture and a specific anti-apoE4 monoclonal antibody as reporter. Our results indicate that the apoE-polystyrene binding interaction is highly stable, resistant to detergents and acid and basic washes. The methodology here described is accurate, easily implementable, fast and cost-effective. Although at present, our technique is unable to discriminate homozygous APOE ε4/ε4 from APOE ε3/ε4 and ε2/ε4 heterozygous, it opens new avenues for the development of inexpensive, yet effective, tests for the detection of apoE4 for patients' stratification. Preliminary results indicated that this methodology is also adaptable into turbidimetric platforms, which make it a good candidate for clinical implementation through its translation to the clinical analysis routine.
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http://dx.doi.org/10.1038/s41598-018-24320-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899170PMC
April 2018

Nephrotic syndrome associated with severe hypertriglyceridemia in a pediatric patient: Answers.

Pediatr Nephrol 2018 11 12;33(11):2075-2078. Epub 2018 Mar 12.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

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http://dx.doi.org/10.1007/s00467-018-3919-1DOI Listing
November 2018

Nephrotic syndrome associated with severe hypertriglyceridemia in a pediatric patient: Questions.

Pediatr Nephrol 2018 11 12;33(11):2073-2074. Epub 2018 Mar 12.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

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http://dx.doi.org/10.1007/s00467-018-3894-6DOI Listing
November 2018

Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.

FASEB J 2018 07 9;32(7):3536-3546. Epub 2018 Feb 9.

Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Cientificas (CSIC), Sant Joan d'Alacant, Alicante, Spain.

Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The β-amyloid (Aβ) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aβ aa 1-42 (Aβ) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Aβ decreased nuclear levels of DNA-methyltransferase 1. However, RELN promoter methylation did not change in Aβ-treated cells or in AD brain extracts. Instead, the levels of ApoER2-CTF appeared significantly lower in Aβ-treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2-CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Aβ treatment, supporting the view that ApoER2-CTF exerts a modulatory role on reelin expression.-Mata-Balaguer, T., Cuchillo-Ibañez, I., Calero, M., Ferrer, I., Sáez-Valero, J. Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.
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http://dx.doi.org/10.1096/fj.201700736RRDOI Listing
July 2018

Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.

Alzheimers Dement 2018 06 3;14(6):751-763. Epub 2018 Feb 3.

Network Center for Biomedical Research in Neurodegenerative Diseases, (CIBERNED), Institute Carlos III, Ministry of Health, Hospitalet de Llobregat, Barcelona, Spain. Electronic address:

Introduction: Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown.

Methods: Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182).

Results: The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99-1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87-0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations.

Discussion: Increased NFL levels are a common feature in neurodegenerative dementias.
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http://dx.doi.org/10.1016/j.jalz.2017.12.008DOI Listing
June 2018