AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State

2020 ◽  
pp. 089198872094423
Author(s):  
Romel Ibarra ◽  
Marcia Radanovic ◽  
Marcos V. Pais ◽  
Leda L. Talib ◽  
Orestes V. Forlenza
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Total Sample ◽  
Routine Clinical Practice ◽  
Cognitive Test ◽  
Csf Biomarkers ◽  
Cognitive State ◽  
Csf Biomarker ◽  
T Tau ◽  
With Memory

Aim: Associations between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) with the severity of cognitive impairment are unclear. We examined the correlations between CSF biomarkers and cognitive performance in the AD continuum. Methods: We studied 143 elderly patients: cognitively unimpaired (n = 51), mild cognitive impairment (MCI) amnestic (n = 55) and nonamnestic (n = 20), and mild AD (n = 17) assessed with the Cambridge Cognitive Test (CAMCOG). We correlated total CAMCOG and its subdomains with CSF Aβ42, T-tau, p-tau levels, and Aβ42/p-tau. Results: In the total sample, T-tau and Aβ42/p-tau correlated with the total CAMCOG ( P < .01); all biomarkers correlated with memory ( P < .001); T-tau correlated with language ( P < .01). Conclusion: Memory and T-tau levels may be the most suitable parameters to reflect cognitive/CSF biomarker correlations. At present, such correlations are of little use in routine clinical practice.

scholarly journals 0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A23-A23
Author(s):  
R Mehra ◽  
R Bhambra ◽  
J Bena ◽  
L Bekris ◽  
J Leverenz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Csf Biomarkers ◽  
Significance Level ◽  
Unit Increase ◽  
T Tau ◽  
Age And Sex

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

scholarly journals Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

2015 ◽  
Vol 36 (3) ◽  
pp. 621-628 ◽  
Author(s):  
Sara Shams ◽  
Tobias Granberg ◽  
Juha Martola ◽  
Xiaozhen Li ◽  
Mana Shams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Serum Albumin ◽  
Amyloid Β ◽  
Cerebral Microbleeds ◽  
Csf Biomarkers ◽  
Barrier Dysfunction ◽  
T Tau

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

scholarly journals Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting

2009 ◽  
Vol 9 ◽  
pp. 961-966 ◽  
Author(s):  
Alessia Lanari ◽  
Lucilla Parnetti
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Clinical Setting ◽  
Cognitive Disorders ◽  
Correct Prediction ◽  
Csf Biomarkers ◽  
Routine Clinical Setting ◽  
T Tau

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Aβ42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.

Use of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Risk in Mild Cognitive Impairment and Subjective Cognitive Decline in Routine Clinical Care in Germany

2020 ◽  
Vol 78 (3) ◽  
pp. 1137-1148
Author(s):  
Claudia Bartels ◽  
Anna Kögel ◽  
Mark Schweda ◽  
Jens Wiltfang ◽  
Michael Pentzek ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Clinical Care ◽  
Subjective Cognitive Decline ◽  
Csf Biomarkers ◽  
Routine Clinical Care ◽  
Biomarker Analysis ◽  
Csf Biomarker

Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

scholarly journals Clinical utility of Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer’s Disease in Korea

2020 ◽  
Author(s):  
Jongmin Lee ◽  
Hyemin Jang ◽  
Sung Hoon Kang ◽  
Jaeho Kim ◽  
Ji-Sun Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Clinical Utility ◽  
Medical Center ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Characteristic Analysis ◽  
Csf Biomarker ◽  
T Tau

Abstract Background Cerebrospinal fluid (CSF) biomarkers are increasingly used in clinical practice for the diagnosis of Alzheimer’s disease (AD). We aimed to 1) determine cutoff values of CSF biomarkers for AD, 2) investigate their clinical utility by estimating a concordance with amyloid positron emission tomography (PET), and 3) apply AT (amyloid/tau) classification based on CSF results. Methods We performed CSF analysis in 51 normal controls (NC), 23 amnestic mild cognitive impairment (aMCI) and 65 AD dementia (ADD) patients at the Samsung Medical Center in Korea. We tried to develop cutoff of CSF biomarkers for differentiating ADD from NC using receiver operating characteristic analysis. We also investigated a concordance between CSF and amyloid PET results and applied AT classification scheme based on CSF biomarker abnormalities to characterize our participants. Results CSF Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) significantly differ across the three groups. The area under curve for the differentiation between NC and ADD was highest in t-tau/Aβ42(0.994) followed by p-tau/Aβ42(0.963), Aβ42(0.960) and t-tau (0.918). The concordance rate between CSF Aβ42 and amyloid PET results was 92%. Finally, AT classification based on CSF biomarker abnormalities led to a majority of NC categorized into A-T-(72%), aMCI as A + T-(52%)/A + T+(30%), and AD as A + T+(56%)/A + T-(41%). Conclusion CSF biomarkers had high sensitivity and specificity in differentiating ADD from NC and were as accurate as amyloid PET. The AT group distribution was comparable to those of previous studies, which may serve to predict the prognosis more accurately than amyloid PET alone in the future.

scholarly journals Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer’s Disease in Amnestic Mild Cognitive Impairment

2019 ◽  
Vol 9 (1) ◽  
pp. 100-113 ◽  
Author(s):  
Jung Eun Park ◽  
Kyu Yeong Choi ◽  
Byeong C. Kim ◽  
Seong-Min Choi ◽  
Min-Kyung Song ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Tau Protein ◽  
Amnestic Mild Cognitive Impairment ◽  
Csf Biomarkers ◽  
Cutoff Values ◽  
Prodromal Ad ◽  
T Tau

Background/Aims: Disease-modifying therapy for Alzheimer’s disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD. Methods: We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of Aβ1–42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau181) in CSF with INNOTEST enzyme-linked immunosorbent assay. Results: For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF Aβ1–42, t-Tau, and p-Tau181 were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/Aβ1–42 and ­p-Tau181/Aβ1–42 ratios defined cutoff values at 0.298 and 0.059, respectively. Conclusions: CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum.

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

CNS Spectrums ◽  
2010 ◽  
Vol 15 (9) ◽  
pp. 588-593 ◽  
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.

scholarly journals Millipore xMap® Luminex (HATMAG-68K): An Accurate and Cost-Effective Method for Evaluating Alzheimer's Biomarkers in Cerebrospinal Fluid

2021 ◽  
Vol 12 ◽  
Author(s):  
Erika Oliveira Hansen ◽  
Natalia Silva Dias ◽  
Ivonne Carolina Bolaños Burgos ◽  
Monica Vieira Costa ◽  
Andréa Teixeira Carvalho ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Diagnostic Accuracy ◽  
Cost Effective ◽  
Control Group ◽  
Csf Biomarkers ◽  
Older Individuals ◽  
Middle Income ◽  
Promising Tool ◽  
T Tau

Background: Alzheimer's disease (AD) biomarkers are of great relevance in clinical research, especially after the AT(N) framework. They enable early diagnosis, disease staging and research with new promising drugs, monitoring therapeutic response. However, the high cost and low availability of the most well-known methods limits their use in low and medium-income countries. In this context, Millipore xMap® Luminex may be a cost-effective alternative. In our study, using INNOTEST® as reference, we assess the diagnostic accuracy of Millipore xMap® and propose a cutoff point for AD.Methods: We performed lumbar puncture of seven older individuals with clinically defined AD, 17 with amnestic mild cognitive impairment (aMCI) and 11 without objective cognitive impairment-control group (CG). Cerebrospinal fluid (CSF) biomarkers concentrations for aB42, p-Tau, and t-Tau were measured by INNOTEST® and Millipore xMap®, and then the techniques were compared to assess the diagnostic accuracy of the new test and to define a cutoff.Results: INNOTEST® and Millipore xMap® measurements showed all correlations &gt;0.8 for the same biomarker, except for t-Tau that was 0.66. Millipore xMap® measurements showed a robust accuracy for all biomarkers, with AUC higher than 0.808 (t-Tau), and the best for Aβ42 (AUC = 0.952). The most accurate cutoffs were found at 1012.98 pg/ml (Aβ42), 64.54 pg/ml (p-tau), 3251.81 pg/ml (t-tau), 3.370 (t-Tau/Aβ42), and 0.059 (p-Tau/Aβ42).Conclusion: Given its good accuracy and cost-effectiveness, Milliplex xMap® tests seems a reliable and promising tool, especially for low and middle-income countries.

scholarly journals White Matter Hyperintensities Are No Major Confounder for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

2021 ◽  
Vol 79 (1) ◽  
pp. 163-175
Author(s):  
Linda J.C. van Waalwijk van Doorn ◽  
Mohsen Ghafoorian ◽  
Esther M.C. van Leijsen ◽  
Jurgen A.H.R. Claassen ◽  
Andrea Arighi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Linear Regression Analysis ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Csf Biomarker ◽  
T Tau

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

scholarly journals Effect of Patient-Specific Preanalytic Variables on CSF Aβ1–42 Concentrations Measured on an Automated Chemiluminescent Platform

2020 ◽  
Author(s):  
Jacqueline A Darrow ◽  
Amanda Calabro ◽  
Sara Gannon ◽  
Amanze Orusakwe ◽  
Rianne Esquivel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Patient Specific ◽  
Csf Biomarkers ◽  
Clinical Settings ◽  
Blood Contamination ◽  
Gradient Effect ◽  
Β Amyloid ◽  
The Impact ◽  
Gradient Effects

Abstract Background Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF β-amyloid 1–42 (Aβ1–42) concentrations. Methods Aβ1–42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients). Results Patient fasting did not significantly affect CSF Aβ1–42 levels. While assessing gradient effects, Aβ1–42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aβ1–42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aβ1–42 concentrations. Conclusions The preanalytical variables examined here do not have significant effects on Aβ1–42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aβ1–42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aβ1–42 concentrations once specimens have been frozen.

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