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The Aß42/40 ratio and the concentration of phosphorylated Tau181 in blood plasma represent attractive biomarkers for Alzheimer's disease. As a means for reducing potential matrix effects, which may interfere with plasma immunoassays, we have previously developed a pre-analytical sample workup by semi-automated immunoprecipitation. Here we test the compatibility of pre-analytical immunoprecipitations with automated Aß1-40, Aß1-42 and phosphorylated Tau181 immunoassays on the Lumipulse platform and compare the diagnostic performance of the respective immunoprecipitation immunoassay approaches with direct plasma measurements. 71 participants were dichotomized according to their Aß42/40 ratios in cerebrospinal fluid into the diagnostic groups amyloid-positive (n = 32) and amyloid-negative (n = 39). The plasma Aß1-42/1-40 ratio and phosphorylated Tau181 levels were determined on the Lumipulse G600II platform (Fujirebio) by direct measurements in EDTA-plasma or after Aß- or Tau-immunoprecipitation, respectively. Pre-analytical immunoprecipitation of Aß turned out to be compatible with the Lumipulse Aß assays and resulted in a numerical, yet statistically not significant increase in the area under the ROC curve for plasma Aß1-42/1-40. Additionally, we observed a significant increase in the standardised effect size (Cohen's D). Pre-analytical immunoprecipitation of Tau resulted in increased differences between the diagnostic groups in terms of median and mean phosphorylated Tau 181 levels. Furthermore, we observed a greater Cohen's d (p < 0.001) and a larger area under the ROC curve (p = 0.038) after Tau-IP. Our preliminary findings in a small, preselected sample indicate that pre-analytical immunoprecipitation may have the potential to improve the diagnostic performance of plasma biomarker immunoassays for Aß1-42/1-40 and phosphorylated Tau181 to predict brain amyloid deposition.
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Inflammation modifies the incidence and progression of Parkinson's disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with dementia with Lewy bodies (DLB) we show that: (1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aß1-42, t-Tau, p181-Tau, NFL and α-synuclein). (2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. (3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without the development of cognitive impairment. (4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until the development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment.
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The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?
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Environmental exposures to fine particulate matter (PM2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer's, Parkinson's and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.
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Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-Syn) represent the histopathological hallmarks of Parkinson's disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aß1-42, total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([18F]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCATriplication patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.
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BACKGROUND: Measurements of the amyloid-ß (Aß) 42/40 ratio in blood plasma may support the early diagnosis of Alzheimer's disease and aid in the selection of suitable participants in clinical trials. Here, we compared the diagnostic performance of fully automated prototype plasma Aß42/40 assays with and without pre-analytical sample workup by immunoprecipitation. METHODS: A pre-selected clinical sample comprising 42 subjects with normal and 38 subjects with low cerebrospinal fluid (CSF) Aß42/40 ratios was studied. The plasma Aß42/40 ratios were determined with fully automated prototype Elecsys® immunoassays (Roche Diagnostics GmbH, Penzberg, Germany) by direct measurements in EDTA plasma or after pre-analytical Aß immunoprecipitation. The diagnostic performance for the detection of abnormal CSF Aß42/40 was analyzed by receiver operating characteristic (ROC) analysis. In an additional post hoc analysis, a biomarker-supported clinical diagnosis was used as a second endpoint. RESULTS: Pre-analytical immunoprecipitation resulted in a significant increase in the area under the ROC curve (AUC) from 0.73 to 0.88 (p = 0.01547) for identifying subjects with abnormal CSF Aß42/40. A similar improvement in the diagnostic performance by pre-analytical immunoprecipitation was also observed when a biomarker-supported clinical diagnosis was used as a second endpoint (AUC increase from 0.77 to 0.92, p = 0.01576). CONCLUSIONS: Our preliminary observations indicate that pre-analytical Aß immunoprecipitation can improve the diagnostic performance of plasma Aß assays for detecting brain amyloid pathology. The findings may aid in the further development of blood-based immunoassays for Alzheimer's disease ultimately suitable for screening and routine use.
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Doença de Alzheimer , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Imunoprecipitação , Fragmentos de Peptídeos/líquido cefalorraquidiano , PlasmaRESUMO
Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established. Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers? Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aß1-42, t-Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences. Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum. Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system.
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The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.
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Doença por Corpos de Lewy , Doença de Parkinson , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença por Corpos de Lewy , Doença de Parkinson , Autofagia , Biomarcadores , Glucosilceramidase , Humanos , Plasticidade Neuronal , Neurotransmissores , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement. OBJECTIVE: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI). METHODS: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PDGBA patients compared to PDGBA_wildtype patients. RESULTS: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PDGBA_severe . INTERPRETATION: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , alfa-Sinucleína , Glucosilceramidase/genética , Humanos , Mutação/genética , Doença de Parkinson/genética , Esfingolipídeos , alfa-Sinucleína/genéticaRESUMO
Selected types of neurons in the central nervous system are associated with a specialized form of extracellular matrix. These so-called perineuronal nets (PNs) are supramolecular structures surrounding neuronal somata, proximal dendrites and axon initial segments. PNs are involved in the regulation of plasticity and synaptic physiology. In addition, PNs were proposed to carry neuroprotective functions as PN-ensheathed neurons are mostly spared of tau pathology in brains of Alzheimer patients. Recently, the neuroprotective action of PNs was confirmed experimentally, demonstrating (i) that mainly aggrecan mediates the neuroprotective function of PNs and (ii) that aggrecan seems to generate an external shielding preventing the internalization of pathological forms of tau. In the present study, we aimed at extending these findings and hypothesized that aggrecan further provides an intracellular protection by preventing mutation-triggered formation of pathological forms of tau. We used crossbreds of TauP301L mice and heterozygous aggrecan mice which are characterized by spontaneous deletion of the aggrecan allele. We analysed the extent of tau pathology in dependence of aggrecan protein amount by applying immunohistochemistry, Western blotting and ELISA. The results clearly indicate that aggrecan has no significant impact on tau aggregation in the brainstem of our mouse model. Still, reduced aggrecan levels were accompanied by increased levels of tau protein and reduced number of Tau-1-positive neurons, which indicate an increase in phosphorylation of tau. In conclusion, these data demonstrate a correlation between aggrecan and P301L mutation-triggered tau expression and phosphorylation in our bigenic mouse model.
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Neurônios , Proteínas tau , Agrecanas/genética , Agrecanas/metabolismo , Animais , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Fosforilação , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
BACKGROUND: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage. METHODS: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d), and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer's biomarkers (t-Tau, P-Tau, Aß42, and Aß40) were also measured. RESULTS: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB. CONCLUSIONS: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer's biomarker does not improve the differential diagnosis between AD and DLB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01876459 (AlphaLewyMa).
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Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides , Biomarcadores , Diagnóstico Diferencial , França , Humanos , Doença por Corpos de Lewy/diagnóstico , Sintomas Prodrômicos , alfa-Sinucleína , Proteínas tauRESUMO
The ratio of amyloid precursor protein (APP)669-711 (Aß-3-40)/Aß1-42 in blood plasma was reported to represent a novel Alzheimer's disease biomarker. Here, we describe the characterization of two antibodies against the N-terminus of Aß-3-x and the development and "fit-for-purpose" technical validation of a sandwich immunoassay for the measurement of Aß-3-40. Antibody selectivity was assessed by capillary isoelectric focusing immunoassay, Western blot analysis, and immunohistochemistry. The analytical validation addressed assay range, repeatability, specificity, between-run variability, impact of pre-analytical sample handling procedures, assay interference, and analytical spike recoveries. Blood plasma was analyzed after Aß immunoprecipitation by a two-step immunoassay procedure. Both monoclonal antibodies detected Aß-3-40 with no appreciable cross reactivity with Aß1-40 or N-terminally truncated Aß variants. However, the amyloid precursor protein was also recognized. The immunoassay showed high selectivity for Aß-3-40 with a quantitative assay range of 22 pg/mL-7.5 ng/mL. Acceptable intermediate imprecision of the complete two-step immunoassay was reached after normalization. In a small clinical sample, the measured Aß42/Aß-3-40 and Aß42/Aß40 ratios were lower in patients with dementia of the Alzheimer's type than in other dementias. In summary, the methodological groundwork for further optimization and future studies addressing the Aß42/Aß-3-40 ratio as a novel biomarker candidate for Alzheimer's disease has been set.
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Peptídeos beta-Amiloides/análise , Precursor de Proteína beta-Amiloide/análise , Imunoensaio/métodos , Doença de Alzheimer/metabolismo , Biomarcadores/sangue , Humanos , Testes Imunológicos , Imunoprecipitação , Fragmentos de Peptídeos/análiseRESUMO
Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, É synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.
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Doença de Alzheimer , Nanopartículas de Magnetita , Nanotubos , Tronco Encefálico , Criança , Cidades , Trato Gastrointestinal , Humanos , México , Agregados Proteicos , Titânio/toxicidade , Adulto Jovem , alfa-SinucleínaRESUMO
BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.
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Biomarcadores/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Priônicas/diagnóstico , Adulto , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Priônicas/sangue , Doenças Priônicas/líquido cefalorraquidiano , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Cerebrospinal fluid (CSF) non-phosphorylated tau (non-p-tau) is increased in sporadic Creutzfeldt-Jakob disease (CJD), but its accuracy in the differential diagnosis has not been previously established. Here, we first used a retrospective cohort of non-CJD (n = 135) and CJD (n = 137) cases to determine the optimal cutoff point for the discrimination of CJD cases. Next, we prospectively quantified non-p-tau and 14-3-3 protein in a cohort of 1427 cases received for CSF testing at the German National Reference Center for transmissible spongiform encephalopathies. Among them, 36 were subsequently diagnosed as CJD. The diagnostic accuracy of both proteins discriminating CJD cases was evaluated. Using a cutoff of 650 pg/mL, non-p-tau displayed 94.39% accuracy in discriminating CJD cases, while 92.92% accuracy was achieved by 14-3-3 using a cutoff of 20,000 AU/mL. Diagnostic test evaluation for both proteins showed a slightly better performance of non-p-tau compared to 14-3-3. The two biomarkers' concentrations showed a significant positive correlation, both in the total population and in CJD cases (p < 0.001). Finally, the analysis of CSF non-p-tau concentrations when undergoing pre-analytical factors showed high stability in front of temperature storage and freeze/thaw cycles. Therefore, we conclude that when used in the appropriate clinical context of a prion disease surveillance center, non-p-tau is a highly sensitive and specific diagnostic marker for CJD.
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Proteínas 14-3-3/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Diagnóstico Diferencial , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. OBJECTIVE: Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD? METHODS: Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PDGBA , 80 PDGBA _wildtype and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PDGBA . RESULTS: Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein. CONCLUSION: The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Glucosilceramidase , Doença de Parkinson , Glucosilceramidase/genética , Humanos , Corpos de Lewy , Mutação/genética , Doença de Parkinson/genética , alfa-Sinucleína/genéticaRESUMO
BACKGROUND: Patients with dementia with Lewy bodies reveal a variable pathology including alpha-synuclein, amyloid-beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha-synuclein. OBJECTIVE: Whether GBA1 mutations are associated with a CSF alpha-synuclein profile in dementia with Lewy bodies. METHODS: Screening of the GBA1 gene and single-nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha-synuclein, amyloid-beta1-42 , total-Tau, phospho-Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross-sectionally. RESULTS: Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha-synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype . CONCLUSION: Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha-synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha-synuclein-lowering compounds. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Glucosilceramidase/genética , Doença por Corpos de Lewy/genética , Mutação/genética , alfa-Sinucleína/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Expressão Gênica/genética , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/diagnóstico , Masculino , Pessoa de Meia-Idade , alfa-Sinucleína/genética , Proteínas tau/líquido cefalorraquidianoRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. This process leads to neuronal degradation and neuronal death. Phosphorylation of tau protein at threonine 231 (p-tau231) has been shown to be characteristic in post-mortem brain tissue of patients with AD and it can be sensitively detected in cerebrospinal fluid (CSF). Therefore, it may serve as a biomarker to support the diagnosis of AD. In this study, we analysed how well p-tau231 could differentiate between patients suffering from dementia either due or not due to AD by a sandwich enzyme immunoassay. CSF p-tau231 was significantly higher in patients with dementia due to AD than in those with dementia due to other causes. In addition, we studied different factors affecting p-tau231 levels in CSF. We found that apolipoprotein E genotype influences p-tau231 CSF levels. Gender and age did not affect p-tau231 levels in CSF. Our findings indicate that p-tau231 levels in CSF can be a valuable marker for the clinical diagnosis of AD.