Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

Blennow, Kaj

doi:10.1007/bf03206605

Cited by 103 publications

(147 citation statements)

References 145 publications

(169 reference statements)

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“…Clearly, both variables showed a wide range. According to Blennow, the level of Aβ 1−42 in CSF is age independent and should be in AD patients about 50% of the value of healthy subjects [40]. This is almost the case in our study.…”

Section: Demographic Datasupporting

confidence: 68%

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Haldenwanger

Eling

Kastrup

et al. 2010

JAD

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Abstract. Decreased delayed recall, decreased amyloid-β peptides (Aβ1−42), and increased tau protein concentration in cerebrospinal fluid (CSF) are generally regarded to be valid neuropsychological and biological markers for Alzheimer's disease (AD). Previous studies failed to demonstrate clear-cut correlations between neuropsychological impairment and CSF markers. In this study we test recent models of disease progression, that propose that changes in CSF biomarkers already reach a plateau in a preclinical phase, before cognitive decline begins, that is, even before MCI can be diagnosed. We recruited 73 patients with probable AD (n = 36) and mild cognitive impairment (MCI) (amnesic MCI = 25; non-amnesic MCI = 12). We used the CERAD-NP, a widely used neuropsychological battery with norms for different age and education groups, and additional neuropsychological tests for assessing the cognitive profile of these patient groups. We found a significant correlation between Aβ1−42 in the CSF and memory performance for amnesic MCI patients, but not for non-amnesic MCI and AD patients. All other correlations between cognitive tasks and Aβ1−42 were not significant. Tau protein concentration in the CSF was not correlated with any neuropsychological marker in any of the patients groups. We conclude that the decrease of Aβ1−42 in the CSF mirrors disease progression during the early stages up into AD and therefore is not restricted to the preclinical phase. The decrease of Aβ1−42 reaches a plateau only in the full blown demented syndrome and further functional disease progression is then related to neurodegeneration without further reduction of Aβ1−42 in the CSF.

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Section: Demographic Datasupporting

confidence: 68%

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Haldenwanger

Eling

Kastrup

et al. 2010

JAD

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“…A large number of studies have replicated these findings. A decrease in CSF Ab 1-42 to about 50% of the level in cognitively normal elderly subjects has been regularly reported, whereas an increase in CSF t-tau to approximately 300% of the level in cognitively normal elderly subjects and a less evident growth in CSF p-tau to about 200% have been repeatedly detected [71]. Such biomarkers show 80-95% of sensitivity and specificity in the dementia phase of the pathology [71,72].…”

Section: Ad Dementiamentioning

confidence: 96%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

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105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…19,20 Nevertheless, levels of decreased Ab 1-42 and increased tau can also be found in other dementias, such as VAD, 21 DLB, 22 FTLD 23 and CJD. 24 At a sensitivity of 85% for AD detection, the diagnostic value of these biomarkers for the exclusion of non-Alzheimer dementias was therefore limited to 58%.…”

Section: Ab1-42 Levels In Csf: Neurochemical Detection Of Admentioning

confidence: 99%

Validation of amyloid-β peptides in CSF diagnosis of neurodegenerative dementias

et al. 2007

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Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-b (Ab) peptide patterns, using the quantitative Ab-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Ab1-38. The main outcome measures were a striking decrease of Ab1-42 in AD (P = 7.4 Â 10 À19 ), and most interestingly a pronounced decrease of Ab1-38 in FTD (P = 9.6 Â 10 À7 ). Moreover, a novel peptide that most probably represents an oxidized a-helical form of Ab1-40 (Ab1-40 ox ) displayed a highly significant increase in DLB (P = 3.7 Â 10 À3) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Ab peptide abundances (Ab1-X%) was clearly superior to absolute CSF Ab levels. Ab1-42% and Ab1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Ab1-40 ox % yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Ab1-38 levels as measured by the Ab-SDS-PAGE/immunoblot and MSD, respectively. CSF Ab peptides may reflect disease-specific impact of distinct neurodegenerative processes on Ab peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

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Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

Cited by 103 publications

References 145 publications

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer's Disease

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Validation of amyloid-β peptides in CSF diagnosis of neurodegenerative dementias

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