Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

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Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1–42 Analysis Results

Clinical Chemistry ◽

10.1373/clinchem.2017.281055 ◽

2018 ◽

Vol 64 (3) ◽

pp. 576-585 ◽

Cited By ~ 52

Author(s):

Betty M Tijms ◽

Eline A J Willemse ◽

Marissa D Zwan ◽

Sandra D Mulder ◽

Pieter Jelle Visser ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Β ◽

Amyloid Plaque ◽

Gaussian Mixture ◽

Mixture Modeling ◽

Memory Clinic ◽

The Past ◽

Gaussian Mixture Modeling ◽

Time Dependencies ◽

The Brain

AbstractBACKGROUNDLow cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ 1–42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1–42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.METHODSWe determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1–42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.RESULTSAβ 1–42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59); P = 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89–0.92) from at least 0.66 (95% CI, 0.64–0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67–0.70) vs at most 0.80 (95% CI, 0.79–0.82) for uncorrected data.CONCLUSIONSThis approach may also be useful to standardize Aβ 1–42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

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[P2-207]: CONCORDANCE BETWEEN CEREBROSPINAL FLUID AMYLOID-β AND [18 F]FLORBETABEN PET IN AN UNSELECTED COHORT OF MEMORY CLINIC PATIENTS

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.858 ◽

2017 ◽

Vol 13 (7S_Part_14) ◽

pp. P688-P688

Author(s):

Arno de Wilde ◽

Wiesje M. van der Flier ◽

Femke H. Bouwman ◽

Rik Ossenkoppele ◽

Wiesje Pelkmans ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Β ◽

Memory Clinic ◽

Unselected Cohort

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Absence of Pittsburgh Compound B Detection of Cerebral Amyloid β in a Patient With Clinical, Cognitive, and Cerebrospinal Fluid Markers of Alzheimer Disease

Archives of Neurology ◽

10.1001/archneurol.2009.279 ◽

2009 ◽

Vol 66 (12) ◽

Cited By ~ 136

Author(s):

Nigel J. Cairns ◽

Milos D. Ikonomovic ◽

Tammie Benzinger ◽

Martha Storandt ◽

Anne M. Fagan ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Amyloid Β ◽

Pittsburgh Compound B ◽

Cerebral Amyloid

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Cerebrospinal Fluid Tau and Amyloid β Proteins Do Not Correlate With Cognitive Functioning in Cognitively Impaired Memory Clinic Patients

CNS Spectrums ◽

10.1017/s1092852900000560 ◽

2010 ◽

Vol 15 (9) ◽

pp. 588-593 ◽

Cited By ~ 3

Author(s):

Petra E. Spies ◽

Jurgen A.H.R. Claassen ◽

Diane Slats ◽

Marcel G.M. Olde Rikkert ◽

Marcel M. Verbeek ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Cognitive Functioning ◽

Neuronal Damage ◽

Amyloid Β ◽

Absolute Amount ◽

Csf Biomarkers ◽

Memory Clinic ◽

Compensatory Mechanisms ◽

T Tau

ABSTRACTObjective: The aim of this study was to investigate the influence of cerebrospinal fluid (CSF), amyloid β42(Aβ42), phosphorylated tau181 (p-tau), and total tau (t-tau) on cognitive functioning.Methods: We analyzed the ability of the CSF biomarkers Aβ42, p-tau, and t-tau to predict the results on the Cambridge Cognitive Examination–Revised (CAMCOG-R), a cognitive screening test that assesses multiple cognitive domains, in 65 memory clinic patients (73.1±8.2 years) (n=30 probable Alzheimer's disease [AD], n=7 possible AD, n=12 non-AD dementia, n=16 mild cognitive impairment).Results: We found no correlations between CSF biomarkers and CAMCOG-R performance in the whole group, nor in subgroups based on aberrant biomarker concentrations.Discussion: Changed concentrations of CSF amyloid β42, p-tau, and t-tau cannot be directly linked to cognitive function in our sample of patients with cognitive impairment. Possibly, compensatory mechanisms such as cognitive reserve determine cognitive performance, rather than the absolute amount of damage caused by Aβ deposition and tangle formation. In addition, abnormal CSF biomarker concentrations may not be a direct reflection of the amount of neuronal damage, but merely serve as an indicator of AD pathology.Conclusion: While CSF biomarkers are valuable in establishing AD pathology, they cannot be used to predict severity of cognitive impairment.

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Upwards Drift of Cerebrospinal Fluid Amyloid-β 42 Over Twelve Years in a Consecutive Clinical Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-201506 ◽

2021 ◽

pp. 1-5

Author(s):

Anja Hviid Simonsen ◽

Christian Sandøe Musaeus ◽

Gitte Lund Christensen ◽

Steen Gregers Hasselbalch ◽

Gunhild Waldemar

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Β ◽

Diagnostic Biomarker ◽

Memory Clinic ◽

Clinical Cohort ◽

New Methods ◽

Diagnostic Work ◽

Work Up ◽

Diagnostic Work Up ◽

Historical Samples

Amyloid-β 1–42 (Aβ1–42) measured in the cerebrospinal fluid (CSF) can be used as a diagnostic biomarker for Alzheimer’s disease (AD) but an upward drift when using the INNOTEST ELISA has been suggested. We investigated the upwards drift of Aβ1–42 levels over a period of twelve years in a consecutive memory clinic cohort. We found a significant increase in Aβ1–42 from 2008 to 2019 independent of changes in tau. New methods for the quantification of CSF Aβ1–42 levels are being implemented but awareness of this upwards drift is crucial during the diagnostic work-up and when selecting historical samples for research.

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Cerebrospinal fluid sTREM2 in Alzheimer’s disease: comparisons between clinical presentation and AT classification

Scientific Reports ◽

10.1038/s41598-020-72878-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Anne-Brita Knapskog ◽

Kristi Henjum ◽

Ane-Victoria Idland ◽

Rannveig Sakshaug Eldholm ◽

Karin Persson ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Clinical Presentation ◽

Clinical Symptoms ◽

Amyloid Β ◽

Innate Immune ◽

Memory Clinic ◽

Factors Associated ◽

Age Related ◽

Soluble Trem2 ◽

Negative Controls

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

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