Comparison of Diagnostic Performances Between Cerebrospinal Fluid Biomarkers and Amyloid PET in a Clinical Setting

Jung, Na-Yeon; Kim, Eun Soo; Kim, Hyang Sook; Jeon, Sumin; Lee, Myung Sik; Pak, Kyoungjune; Lee, Jae Hyeok; Lee, Young Min; Lee, Kang Yoon; Shin, Jin‐Hong; Ko, Jun Kyeung; Lee, Jae Meen; Yoon, Jin A; Hwang, Chungsu; Choi, Kyung Un; Lee, Eun Chong; Seong, Joon Kyung; Huh, Gi Yeong; Kim, Dae Seong; Kim, Eun Joo

doi:10.3233/jad-191109

Cited by 20 publications

(22 citation statements)

References 79 publications

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“…Another aim of our study was to compare the concordance between the amyloid-PET and CSF Aβ biomarkers in the group of patients who underwent both the analyses. Regarding AD patients, we found a very low concordance (39%), which was different from previous works showing higher levels of concordance: Leuzy et al reported a concordance around 60% [52], Jung et al of 85% [53], de Wilde et al and Reimand et al of 91% [54,55]. Several alternative mechanisms have been proposed to explain discordance between amyloid-PET and CSF Aβ biomarkers.…”

Section: Discussioncontrasting

confidence: 99%

Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer’s Disease and Frontotemporal Dementia

Giacomucci

Mazzeo

Bagnoli

et al. 2021

JPM

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Background: The aims of this study were to compare the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of different cerebrospinal fluid (CSF) amyloid biomarkers and amyloid-Positron Emission Tomography (PET) in patients with a clinical diagnosis of Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD); to compare concordance between biomarkers; and to provide an indication of their use and interpretation. Methods: We included 148 patients (95 AD and 53 FTD), who underwent clinical evaluation, neuropsychological assessment, and at least one amyloid biomarker (CSF analysis or amyloid-PET). Thirty-six patients underwent both analyses. One-hundred-thirteen patients underwent Apolipoprotein E (ApoE) genotyping. Results: Amyloid-PET presented higher diagnostic accuracy, sensitivity, and NPV than CSF Aβ1–42 but not Aβ42/40 ratio. Concordance between CSF biomarkers and amyloid-PET was higher in FTD patients compared to AD cases. None of the AD patients presented both negative Aβ biomarkers. Conclusions: CSF Aβ42/40 ratio significantly increased the diagnostic accuracy of CSF biomarkers. On the basis of our current and previous data, we suggest a flowchart to guide the use of biomarkers according to clinical suspicion: due to the high PPV of both amyloid-PET and CSF analysis including Aβ42/40, in cases of concordance between at least one biomarker and clinical diagnosis, performance of the other analysis could be avoided. A combination of both biomarkers should be performed to better characterize unclear cases. If the two amyloid biomarkers are both negative, an underlying AD pathology can most probably be excluded.

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Section: Discussioncontrasting

confidence: 99%

Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer’s Disease and Frontotemporal Dementia

Giacomucci

Mazzeo

Bagnoli

et al. 2021

JPM

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“…The new biomarker panels are thought to be better than the established CSF biomarkers with respect to clinical correlations of AD, but not in discriminating AD from control samples based on previous findings from our 14 and other [46][47][48][49][50] research groups. The new biomarkers demonstrated abundant interconnections and some connections with CSF pTau181 levels, which contrast to no co-expression with the Aβ42 protein.…”

Section: Discussionmentioning

confidence: 97%

SWATH-MS analysis of cerebrospinal fluid to generate a robust battery of biomarkers for Alzheimer’s disease

Park

Jung

Park

et al. 2020

Sci Rep

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Cerebrospinal fluid (CSF) Aβ42 and tau protein levels are established diagnostic biomarkers of Alzheimer's disease (AD). However, their inadequacy to represent clinical efficacy in drug trials indicates the need for new biomarkers. Sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based mass spectrometry (MS) is an advanced proteomic tool for large-scale, high-quality quantification. In this study, SWATH-MS showed that VGF, chromogranin-A, secretogranin-1, and opioid-binding protein/cell adhesion molecule were significantly decreased in 42 AD patients compared to 39 controls, whereas 14-3-3ζ was increased (FDR < 0.05). In addition, 16 other proteins showed substantial changes (FDR < 0.2). The expressions of the top 21 analytes were closely interconnected, but were poorly correlated with CSF Aβ42, tTau, and pTau181 levels. Logistic regression analysis and data mining were used to establish the best algorithm for AD, which created novel biomarker panels with high diagnostic value (AUC = 0.889 and 0.924) and a strong correlation with clinical severity (all p < 0.001). Targeted proteomics was used to validate their usefulness in a different cohort (n = 36) that included patients with other brain disorders (all p < 0.05). This study provides a list of proteins (and combinations thereof) that could serve as new AD biomarkers. Cerebrospinal fluid (CSF) levels of Aβ1-42 (Aβ42), total Tau (tTau), and phosphorylated Tau181 (pTau181) are diagnostic markers of Alzheimer's disease (AD) 1,2. These biomarkers are currently used to confirm the core pathology of AD, i.e., Aβ and tau pathology, in deceased patients while they are alive 3 , and are also monitored in AD therapeutic trials 4. However, accumulating evidence has demonstrated a lack of utility of these markers after clinical onset of AD due to early concentration plateaus 5 and poor reflection of the clinical benefits of therapeutics that target them 6. CSF proteins related to synaptic function, neurodegeneration, inflammation, and Aβ metabolism have recently been suggested as supplementary biomarkers 7 ; however, they have not yet been clinically adopted.

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“…In 2018, the National Institute on Aging and Alzheimer’s Association of the United States proposed a shift of the diagnostic paradigm away from clinical symptoms or post mortem findings, towards criteria based on some combination of biomarkers in living persons 10 . While there has been some success in developing diagnostic tests based on analysis of markers in cerebrospinal fluid (CSF) 11 , 12 , the requirement for invasive sampling is especially onerous in this vulnerable and aged population. An ideal biomarker for diagnosis of incipient Alzheimer’s disease would be minimally invasive and yet highly sensitive to the brain pathology occurring at an early disease stage, thus perhaps enabling timely interventions.…”

Section: Introductionmentioning

confidence: 99%

The variability of functional MRI brain signal increases in Alzheimer's disease at cardiorespiratory frequencies

Tuovinen

Kananen

Rajna

et al. 2020

Sci Rep

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Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

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Comparison of Diagnostic Performances Between Cerebrospinal Fluid Biomarkers and Amyloid PET in a Clinical Setting

Cited by 20 publications

References 79 publications

Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer’s Disease and Frontotemporal Dementia

Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer’s Disease and Frontotemporal Dementia

SWATH-MS analysis of cerebrospinal fluid to generate a robust battery of biomarkers for Alzheimer’s disease

The variability of functional MRI brain signal increases in Alzheimer's disease at cardiorespiratory frequencies

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