Benchmarking biomarker‐based criteria for Alzheimer's disease: Data from the Swedish Dementia Registry, SveDem

Rosén, Christoffer; Farahmand, Bahman; Skillbäck, Tobias; Nägga, Katarina; Mattsson, Niklas; Kilander, Lena; Religa, Dorota; Wimo, Anders; Blennow, Kaj; Winblad, Bengt; Zetterberg, Henrik; Eriksdotter, Maria

doi:10.1016/j.jalz.2015.04.007

Cited by 17 publications

(12 citation statements)

References 42 publications

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“…Cerebrospinal fluid Aβ42 concentrations led to misinterpretation of the AD CSF biomarker profile in 24.2% of our total population and notably in 18.7% of AD patients. This low performance of CSF Aβ42 is in perfect agreement with previous reports ( 7 , 10 , 18 , 20 , 36 , 37 ). The presence of CSF Aβ42 concentrations ≤700 ng/L in non-AD patients could reflect low total CSF amyloid load, while CSF Aβ42 >700 ng/L in AD patients could result from high amyloid load.…”

Section: Discussionsupporting

confidence: 93%

“…A recent meta-analysis highlighted significant heterogeneity in CSF Aβ42 values between different disease groups ( 9 ), reporting sensitivity and specificity ranging from 71 to 91% and 44 to 82%, respectively. Moreover, Rosen et al showed that “normal” CSF Aβ42 levels were observed in AD patients, leading to misinterpretation of the AD CSF biomarker profile in 23.2% of AD patients ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal Fluid Aβ40 Improves the Interpretation of Aβ42 Concentration for Diagnosing Alzheimer’s Disease

et al. 2015

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The combination of decreased amyloid β42 (Aβ42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer’s disease (AD). Previous studies showed significant heterogeneity in CSF Aβ42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide β42/β40 ratio has better diagnostic performance than Aβ42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid β40 peptide (Aβ40) for biological diagnosis of AD when CSF Aβ42 levels failed. CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T-Tau ≥ 400 ng/L, P-Tau181 ≥ 60 ng/L, and Aβ42 ≤ 700 ng/L. CSF Aβ40 was assayed in AD patients with CSF Aβ42 levels above 700 ng/L and non-AD patients with CSF Aβ42 levels below 700 ng/L. CSF Aβ40 levels were higher in AD than non-AD patients. The receiver operator characteristic curves of CSF Aβ40 and the Aβ42/Aβ40 ratio defined AD cut-off values at 12,644 ng/L and 0.06, respectively. In AD patients with non-pathological CSF Aβ42, CSF Aβ40 concentration was able to correct 76.2% of cases when expressed as CSF Aβ42/Aβ40 ratio and 94.7% of cases when used alone. Using CSF Aβ42 and then CSF Aβ40, the percentage of misinterpreted AD patients fell to 1.0%. CSF Aβ40 concentration improved interpretation of Aβ42 level for the diagnosis of AD. CSF Aβ40 alone showed better diagnostic performance than the amyloid peptide Aβ42/Aβ40 ratio. The added value of determining CSF Aβ40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Aβ40 Improves the Interpretation of Aβ42 Concentration for Diagnosing Alzheimer’s Disease

et al. 2015

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“…Although these protein biomarkers have promising diagnostic, prognostic, and therapeutic benefits, recent literature explores their limitations. Interestingly, only 77.2% of 2357 AD patients expressed disease related CSF Aβ and either T-tau or P-tau protein values (Hoglund et al, 2015 ; Rosén et al, 2015 ). MiRNA appears to predict and diagnose AD with greater sensitivity, even during mild cognitive impairment.…”

Section: Methodsmentioning

confidence: 99%

The MiRNA Journey from Theory to Practice as a CNS Biomarker

Stoicea

Lakis

et al. 2016

Front. Genet.

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MicroRNAs (miRNAs), small nucleotide sequences that control gene transcription, have the potential to serve an expanded function as indicators in the diagnosis and progression of neurological disorders. Studies involving debilitating neurological diseases such as, Alzheimer's disease, multiple sclerosis, traumatic brain injuries, Parkinson's disease and CNS tumors, already provide validation for their clinical diagnostic use. These small nucleotide sequences have several features, making them favorable candidates as biomarkers, including function in multiple tissues, stability in bodily fluids, a role in pathogenesis, and the ability to be detected early in the disease course. Cerebrospinal fluid, with its cell-free environment, collection process that minimizes tissue damage, and direct contact with the brain and spinal cord, is a promising source of miRNA in the diagnosis of many neurological disorders. Despite the advantages of miRNA analysis, current analytic technology is not yet affordable as a clinically viable diagnostic tool and requires standardization. The goal of this review is to explore the prospective use of CSF miRNA as a reliable and affordable biomarker for different neurological disorders.

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“…The study cohort was further sub-classified into biochemically positive or negative profile according to the international working group (IWG-2) [28]. The following cutoffs for pathological biomarker concentrations were used: Aβ42 ≤ 550 pg/mL, T-tau ≥ 400 pg/mL, P-tau > 60 pg/mL for patients < 60 years, and P-tau > 80 for patients ≥ 60 years [29]. Pathological concentrations of Aβ42 and at least either T-tau or P-tau were required for a biochemical AD positive classification.…”

Section: Subject Cohortmentioning

confidence: 99%

“…Proportions in the full study cohort. Mean (SD) 62 (18) 95 (40) 83 (33) 59 (29) 55 (15) 51 (24) 53 (21) 49 (25) Mdn (IQR) 89 (67-114) 80 (57-104) 53 54 48…”

Section: Figure Legendsmentioning

confidence: 99%

Apolipoprotein E genotypes and longevity across dementia disorders

Skillbäck

Lautner

Mattsson

et al. 2018

Alzheimer's & Dementia

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Benchmarking biomarker‐based criteria for Alzheimer's disease: Data from the Swedish Dementia Registry, SveDem

Abstract: About a quarter of clinically diagnosed AD patients did not have an AD-indicative CSF biomarker profile. This discrepancy may partly reflect incorrect (false positive) clinical diagnosis or a lack in sensitivity of the biomarker assays.

Cited by 17 publications

References 42 publications

Cerebrospinal Fluid Aβ40 Improves the Interpretation of Aβ42 Concentration for Diagnosing Alzheimer’s Disease

Cerebrospinal Fluid Aβ40 Improves the Interpretation of Aβ42 Concentration for Diagnosing Alzheimer’s Disease

The MiRNA Journey from Theory to Practice as a CNS Biomarker

Apolipoprotein E genotypes and longevity across dementia disorders

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