scholarly journals Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

2021 ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

scholarly journals Association of CSF Proteins With Tau and Amyloid β Levels in Asymptomatic 70-year-olds 

2020 ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and Aβ42 in all individuals. Sixty-three proteins showed significant correlations with either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins to CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated to or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport that were associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore their role in AD pathophysiology.

scholarly journals Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract Background Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

scholarly journals Prevalence of preclinical Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 90 (19) ◽  
pp. e1682-e1691 ◽  
Author(s):  
Silke Kern ◽  
Henrik Zetterberg ◽  
Jürgen Kern ◽  
Anna Zettergren ◽  
Margda Waern ◽  
...  
Keyword(s):  
At Risk ◽  
Alzheimer Disease ◽  
Population Sample ◽  
Population Based ◽  
Classification Systems ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Total Tau ◽  
Preclinical Ad

ObjectiveTo determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden.MethodThe sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of β-amyloid (Aβ)42, Aβ40, total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging–Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score >0 were excluded, leaving 259 cognitively unimpaired individuals.ResultsThe prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T−/N− was 13.1%, A+/T−/N+ was 7.3%, A+/T+/N+ was 2.3%, A−/T−/N+ was 18.9%, and A−/T+/N+ was 4.6%. When the Dubois criteria were applied, the prevalence of asymptomatic at risk for AD was 36.7% and of preclinical AD was 9.7%. With the NIA-AA criteria, the prevalence of stage 1 was 13.1% and stage 2 was 9.7%. With the IWG-2 criteria, the prevalence of asymptomatic at risk for AD was 9.7%. TheAPOEε4 allele was associated with several of the categories. Men more often had total tau pathology, A+/T−/N+, preclinical AD according to Dubois 2016, asymptomatic at risk for AD according to the IWG-2 criteria, and NIA-AA stage 2.ConclusionThe prevalence of pathologic AD markers was very common (46%) in a representative population sample of 70-year-olds. The clinical implications of these findings need to be scrutinized further in longitudinal studies.

scholarly journals New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

2020 ◽  
Vol 52 (4) ◽  
pp. 556-568 ◽  
Author(s):  
Sun Ah Park ◽  
Song Mi Han ◽  
Chae Eun Kim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Response ◽  
Amyloid Β ◽  
Clinical Severity ◽  
Intercellular Adhesion Molecule ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Protein Clearance ◽  
New Biomarkers

Abstract Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer’s disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration- and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD.

scholarly journals Association of amyloid-β CSF/PET discordance and tau load 5 years later

Neurology ◽  
2020 ◽  
Vol 95 (19) ◽  
pp. e2648-e2657 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tau Pet

ObjectiveTo investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.MethodsWe included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET− participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET.ResultsAβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET− (n = 80) participants were overall similar to the CSF−/PET− (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET− group (1.20 ± 0.13) did not differ from CSF−/PET− (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET− participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET.ConclusionsAβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET− group has a distinctly better prognosis.

scholarly journals Markers of vitamin B12 status in relation to cerebrospinal fluid biomarkers and cognitive performance

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Babak Hooshmand ◽  
Franziska Koch ◽  
Patrik Fissler ◽  
Markus Otto ◽  
Hayrettin Tumani ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Vitamin B12 ◽  
Cognitive Performance ◽  
Amyloid Β ◽  
Binary Logistic Regression ◽  
Cognitive Status ◽  
University Hospital ◽  
Binary Logistic Regression Analysis ◽  
Csf Biomarkers ◽  
Total Tau

AbstractIntroduction: The association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer's type dementia which precede cognitive impairment has been investigated by only a few small studies and the results have been inconsistent.Aim: To investigate the associations of vitamin B12 related markers (vitamin B12, holotranscobalamin (HoloTC), homocysteine (tHcy), and methylmalonic acid (MMA)) with CSF total tau, Amyloid-β 42 (Aβ42) and cognitive performance.Methods: Data included 462 patients aged 40–94 years referred to the Memory Clinic at the Ulm University Hospital, Ulm, Germany between December 2009 and August 2015. Vitamin B12 and HoloTC were measured via chemiluminescence microparticle immunoassay, tHcy via chemiluminescence immunoassay and MMA via liquid chromatography mass specterometry. CERAD battery was used to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations.Results: After adjusting for age, sex, creatinine levels and APOEε4 status, higher values of vitamin B12 and lower values of MMA were associated with lower concentrations of CSF total-tau: the odds ratios (ORs) (95% confidence intervals (CI)) in a binary logistic regression analysis investigating the associations with total tau cut-off of 400 pg/ml were 0.39 (0.15–0.99) and 5.60 (1.93–16.26) for the highest quartile of B12 and MMA compared to the lowest, respectively. Furthermore, HoloTC, MMA, and tHcy were associated with several cognitive domains such as episodic memory and executive functioning. No relationships were found with Aβ42.Conclusions: Vitamin B12 and its related markers may be independent predictors of CSF biomarkers of Alzheimer's disease and cognitive status. Randomized controlled trials are needed to determine the importance of vitamin B12 supplementation on slowing structural brain changes and cognitive decline in older adults.

scholarly journals Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry

2020 ◽  
pp. 1-12
Author(s):  
Yusuke Seino ◽  
Takumi Nakamura ◽  
Tomoo Harada ◽  
Naoko Nakahata ◽  
Takeshi Kawarabayashi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Quantitative Measurement ◽  
Amyloid Β ◽  
High Sensitivity ◽  
Csf Biomarkers ◽  
Strongly Correlated ◽  
Csf Levels

Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38, 2199±725 pmol/L in Aβ1-40, 153.7±79.7 pmol/L in Aβ1-42, and 9.78±4.58 pmol/L in Aβ1-43. The ratio of the amounts of Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42, Aβ1-38/1-43, and Aβ1-40/Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.

scholarly journals CSF Biomarkers Profile in CADASIL—A Model of Pure Vascular Dementia: Usefulness in Differential Diagnosis in the Dementia Disorder

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Patrizia Formichi ◽  
Lucilla Parnetti ◽  
Elena Radi ◽  
Gabriele Cevenini ◽  
Maria Teresa Dotti ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Vascular Dementia ◽  
Tau Protein ◽  
Autosomal Dominant ◽  
Case Control ◽  
Csf Biomarkers ◽  
Total Tau ◽  
Csf Levels ◽  
T Tau ◽  
Phosphorylated Tau Protein

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is considered a model of pure vascular dementia (VD) because it occurs in young adults unlikely to have concomitant age and Alzheimer's Disease-(AD-) related pathology. CSF levels of -amyloid 1-42 (A42), total tau protein (t-tau), and phosphorylated tau-protein (p-tau), well accepted biomarkers of AD, were evaluated in 10 CADASIL patients, 22 AD patients, and 17 healthy age-matched subjects. Innotest -amyloid 1-42, Innotest hTAU-Ag, and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay were used to determine CSF biomarkers levels. A case-control statistical analysis was carried out. CSF A42 levels were significantly lower in CADASIL patients and considerable overlap with AD whereas t-tau and p-tau levels were normal and significantly different with respect to AD. A significant altered CSF biomarkers profile in a pure VD supports the use of CSF A42, t-tau, and p-tau levels in the differential diagnosis of VD and AD.

Diagnostic Validity Comparison Between Criteria Based on CSF Alzheimer’s Disease Biomarkers

2017 ◽  
Vol 32 (2) ◽  
pp. 101-107 ◽  
Author(s):  
Maria Empar Blanco-Cantó ◽  
J. A. Monge-Argilés ◽  
C. Pérez-Cejuela ◽  
C. Badía ◽  
L. Gabaldón ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Csf Biomarkers ◽  
Diagnostic Validity ◽  
High Likelihood ◽  
Disease Biomarkers ◽  
Csf Levels ◽  
T Tau ◽  
New Criteria ◽  
Mci Due To Ad

Aim: To compare the diagnostic validity of NIA-AA criteria, for AD CSF biomarkers, with our own new criteria. Materials and Methods: Between 2008 and 2011, 170 patients with Mild Cognitive Impairment (MCI) were included. CSF levels of Aβ1-42, T-tau, P-tau181, and ratios of T-tau/Aβ1-42 and P-tau181/Aβ1-42 were analyzed. In our criteria, we considered 3 or more abnormal variables indicative of a high likelihood of MCI due to AD. Results: After a clinical follow-up of 4.5 ± 1.2 years, 44 patients remained stable, 95 developed AD, 15 other forms of dementia, 7 died and 9 received other diagnoses. Using the NIA-AA criteria and our own criteria, the diagnostic validity of the CSF biomarkers was 58% versus 85%, specificity 84% versus 72%, PPV 82% versus 79% and NPV 61% versus 79%. Conclusion: The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

scholarly journals Integrative Brain Transcriptome Analysis Links Complement Component 4 and HSPA2 to the APOE ε2 Protective Effect in Alzheimer Disease

2020 ◽  
Author(s):  
Rebecca Panitch ◽  
Junming Hu ◽  
Jaeyoon Chung ◽  
Congcong Zhu ◽  
Gaoyuan Meng ◽  
...  
Keyword(s):  
Protective Effect ◽  
Amyloid Β ◽  
Oligodendrocyte Progenitor Cells ◽  
Expression Data ◽  
Complement Pathway ◽  
Tau Pathology ◽  
Total Tau ◽  
Brain Transcriptome ◽  
Complement Component 4

AbstractMechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer’s disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ε 2/ε 3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ε 2/ε 3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ε 2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

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