Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer’s disease

Alexopoulos, Panagiotis; Werle, Lukas; Roesler, Jennifer; Thierjung, Nathalie; Gleixner, Lena; Yakushev, Igor; Laskaris, Nikolaos A.; Wagenpfeil, Stefan; Gourzis, Philippos; Kurz, Alexander; Perneczky, Robert

doi:10.1186/s13195-016-0220-z

Cited by 21 publications

(14 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In accordance with previous studies [ 35 , 38 – 40 , 42 ], the HL group showed the highest risk of progression to AD, irrespective of the use of either Aβ42 or the Aβ42/40 ratio for biomarker-based classification. Regarding prognosis in the conflicting biomarker categories, in our study the percentage of MCI patients classified as IAP or SNAP who converted to AD was not very different from each other (close to 50%) and did not differ much whether CSF Aβ42 alone or the Aβ42/40 ratio, combined with Tau and p-Tau, was used.…”

Section: Discussionsupporting

confidence: 91%

“…This categorization also includes subgroups of conflicting biomarker results, namely patients with biomarkers positive for amyloidosis but negative for neurodegeneration and patients with normal amyloid markers but positive for neurodegeneration. A number of studies, using CSF Aβ42, t-Tau and p-Tau, as well as imaging markers, have investigated the prognostic relevance of these biomarker-based categories in MCI patients [ 35 – 42 ]. General agreement exists as to the risk of progression to AD being higher in patients with all biomarkers positive for AD and lowest in patients with no positive biomarkers for AD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment

et al. 2018

View full text Add to dashboard Cite

BackgroundCerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer’s disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD.MethodsOur baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging–Alzheimer Association criteria for MCI.ResultsWhen using the core CSF biomarkers (Aβ42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing Aβ42 by the Aβ42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42–59%) and in the proportion of interpretable biological profiles (61–75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization.ConclusionsOur results confirm the usefulness of the CSF Aβ42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0362-2) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment

et al. 2018

View full text Add to dashboard Cite

show abstract

“…At 2‐year follow‐up, 45% of patients with amyloid positive MCI and 20% of MCI with SNAP had progressed to dementia 23 . Constellations with conflicting CSF biomarker findings (eg, neurodegeneration without amyloid—SNAP) are not currently considered by IWG or NIA‐AA classifications 34 . In some patients presenting the typical multidomain amnesic phenotype used to defined probable AD, no AD tissue pathology was found 22,29 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of ATN Alzheimer biomarkers: 60‐month follow‐up results from the Argentine Alzheimer's Disease Neuroimaging Initiative

Allegri

Méndez

Calandri

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

View full text Add to dashboard Cite

Purpose To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine‐Alzheimer's Disease Neuroimaging Initiative (arg‐ADNI) cohort. Methods Twenty‐three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aβ; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aβ42), tau (T: CSF phosphorylated‐tau), and neurodegeneration (N: CSF total‐tau, fluorodeoxyglucose [FDG]‐PET scan, or structural magnetic resonance imaging [MRI] scan). Results A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non‐AD pathophysiology (SNAP, A‐T‐N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5‐year follow‐up were 85% in A+T+N+ MCI patients and 50% in A‐T‐N+ patients. Conclusions We present initial 5‐year follow‐up results of a regional ADNI based on AD biomarkers and the ATN classification.

show abstract

“…CSF Aβ42, together with t-tau and p-tau, are biomarkers accepted as supportive of an AD diagnosis [ 75 , 247 ] (Table 2 ), and evidence suggests they may be prognostic of disease progression in both cognitively normal individuals [ 84 , 209 ] and those with mild cognitive impairment (MCI) [ 5 , 9 , 91 , 133 ]. CSF Aβ42 has the potential to discriminate AD from FTLD but shows significant overlap with other non-AD dementias [ 80 ].…”

Section: Aβ Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

show abstract

Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer’s disease

Cited by 21 publications

References 58 publications

Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment

Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment

Prognostic value of ATN Alzheimer biomarkers: 60‐month follow‐up results from the Argentine Alzheimer's Disease Neuroimaging Initiative

Current state of Alzheimer’s fluid biomarkers

Contact Info

Product

Resources

About