Improved Differential Diagnosis of Alzheimer’s Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers

Khoonsari, Payam Emami; Shevchenko, Ganna; Herman, Stephanie; Remnestål, Julia; Giedraitis, Vilmantas; Brundin, RoseMarie; Gunnarsson, Malin Degerman; Kilander, Lena; Zetterberg, Henrik; Nilsson, Peter; Lannfelt, Lars; Ingelsson, Martin; Kultima, Kim

doi:10.3233/jad-180855

Cited by 35 publications

(35 citation statements)

References 44 publications

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“…VGF is a neuropeptide precursor believed to be important for dendritic growth and neuronal survival [32,33]. Lower CSF levels of VGF in FTD patients, as seen in our study, was recently demonstrated using mass spectrometry [34][35][36]. Van der Ende et al (2019) identified several proteins in CSF that differed between genetic FTD and controls of which seven were selected for validation by parallel reaction monitoring.…”

Section: Both Principal Component Analysis and Analysis Of Singlesupporting

confidence: 75%

“…VGF was found in lower levels in FTD due to GRN mutations, compared to controls. Although reaching statistical significance, VGF alone is not enough to distinguish FTD from other dementias as both our own and former studies have shown decreased levels in CSF from AD patients as well [36][37][38][39]. TN-R is an extracellular matrix protein expressed by oligodendrocytes and neurons [40,41].…”

Section: Both Principal Component Analysis and Analysis Of Singlementioning

confidence: 93%

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Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Remnestål

Öijerstedt

Ullgren

et al. 2020

Transl Neurodegener

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Background: The clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. There are, as of today, no biomarkers in clinical practice for diagnosing the disorders. Here, we aimed to find protein markers in cerebrospinal fluid (CSF) from patients with FTD, presymptomatic mutation carriers and non-carriers. Methods: Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD (bvFTD, n = 16) and progressive primary aphasia (PPA, n = 13), as well as presymptomatic mutation carriers (PMC, n = 16) and non-carriers (NC, n = 8). A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples. The findings were further examined in an independent cohort including 13 FTD patients, 79 patients with Alzheimer's disease and 18 healthy controls. Results: We found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals (PMC and NC) for 26 proteins. The analysis show patterns of separation between unaffected individuals and FTD patients, especially for those with a clinical diagnosis of bvFTD. The most statistically significant differences in protein levels were found for VGF, TN-R, NPTXR, TMEM132D, PDYN and NF-M. Patients with FTD were found to have higher levels of TN-R and NF-M, and lower levels of VGF, NPTXR, TMEM132D and PDYN, compared to unaffected individuals. The main findings were reproduced in the independent cohort. Conclusion: In this pilot study, we show a separation of FTD patients from unaffected individuals based on protein levels in CSF. Further investigation is required to explore the CSF profiles in larger cohorts, but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.

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Section: Both Principal Component Analysis and Analysis Of Singlesupporting

confidence: 75%

Section: Both Principal Component Analysis and Analysis Of Singlementioning

confidence: 93%

Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Remnestål

Öijerstedt

Ullgren

et al. 2020

Transl Neurodegener

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“…We found 29 proteomic CSF studies that investigated AD (Table 1) . Overall, the aims of the proteomics studies were to identify novel CSF biomarkers to distinguish AD vs. controls [33][34][35][36][37][38][40][41][42][43][44][45][46][47][48][49][50][51][52]54,55,57,58,61,62] or MCI vs. controls [37,40,41,52,56,57,60], that reflect MCI to AD progression [37,41,60], cognitive decline [33,59,61], MRI measures of atrophy [33,55] and to validate AD vs. control biomarkers [56,59]. Several studies also investigated associations of novel biomarkers with CSF amyloid, t-tau and p-tau [33,36,41,45,55,…”

Section: Search Strategymentioning

confidence: 99%

Cerebrospinal fluid proteomics and biological heterogeneity in Alzheimer’s disease: A literature review

Wesenhagen

Teunissen

Visser

et al. 2019

Critical Reviews in Clinical Laboratory Sciences

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Alzheimer's disease (AD) is the most common cause of dementia and is characterized by aggregation of amyloid and tau proteins in the brain. Results from genetic studies suggest that the pathophysiology underlying AD is complex, but studying this complexity in patients remains difficult. The cerebrospinal fluid (CSF) proteome contains a large number of proteins that can reflect ongoing biological processes. Proteomics techniques can be used to measure many proteins simultaneously in individual patients and may therefore provide an opportunity to study AD disease mechanisms. Here, we review the CSF proteomics literature to identify proteins consistently associated with AD, and perform pathway analyses on these proteins to study which biological processes may be involved in the disease. We performed a literature search of studies that investigated CSF proteomic alterations related to AD. We included original research articles when they measured at least 10 proteins in (antemortem) CSF in at least 10 individuals with AD, mild cognitive impairment (MCI) or controls. We examined if proteins were consistently related to AD, defined as consistent increase or decrease in AD vs. controls across studies. Next, we used the proteins identified as input to pathway analyses using Reactome to investigate which biological processes were enriched. In total, 29 studies were included that investigated AD-related changes to the CSF proteome, including a total of 1434 individuals with AD (of whom 47.1% had a CSF biomarker profile and 9.6% a postmortem examination consistent with AD) and 1380 controls. The studies reported 1 to 138 proteins associated with AD, of which 97 proteins were reported by two or more studies. Among proteins that were measured in more than one study, 27 (27.8%) showed consistent increases, 15 (15.5%) consistent decreases and 55 (56.7%) had contrasting results. Pathway analyses showed that AD-related proteins were enriched for hemostasis, lipoprotein and extracellular matrix pathways. These results indicate that proteomic alterations in CSF associated with AD reflect involvement of various biological pathways. The frequent occurrence of inconsistent protein level changes reported by different studies suggests that additional biological and/or (pre)analytical factors may influence the CSF proteome in AD, which should be further investigated in order to improve understanding of the biological complexity underlying AD.

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“…As such, FTLD and other forms of SNAP are likely to be overlooked in the presence of secondary AD pathology, 13 because biomarkers for SNAP are lacking. Moreover, because t‐tau concentrations are highly correlated with p‐tau, 14 there may be little added value of t‐tau when diagnosing AD using ATN 15–17 …”

Section: Introductionmentioning

confidence: 99%

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration

Cousins

Phillips

Irwin

et al. 2020

Alzheimer's & Dementia

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Introduction The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non‐Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU) using CSF total tau (t‐tau) to a modified strategy (ATNNfL) using CSF neurofilament light chain (NfL) in an autopsy cohort. Methods ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy‐confirmed AD (n = 67) and FTLD (n = 27). Results ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co‐occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as “Normal” (2%) than ATNTAU (14%). Discussion ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co‐occur.

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Improved Differential Diagnosis of Alzheimer’s Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers

Cited by 35 publications

References 44 publications

Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Cerebrospinal fluid proteomics and biological heterogeneity in Alzheimer’s disease: A literature review

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration

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