CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease

Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, 81675 München, Germany.
Neurology (Impact Factor: 8.29). 06/2011; 77(1):35-8. DOI: 10.1212/WNL.0b013e318221ad47
Source: PubMed


To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI).
A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPα, sAPPβ, tau, and Aβ(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves.
The MCI-AD group had significantly higher sAPPβ concentrations than the MCI-NAD and the FTD groups. A combination of sAPPβ, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPβ and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Aβ(1-42) and sAPPα did not significantly contribute to the models.
These findings suggest that sAPPβ may be clinically useful, and superior to Aβ(1-42), in the early and differential diagnosis of incipient AD.

Download full-text


Available from: Panagiotis Alexopoulos, Feb 25, 2014
18 Reads
  • Source
    • "Thus it is of great importance to diagnose AD at an early stage and perform effective interventions before cognitive symptoms emerge. Although some cerebrospinal fluid (CSF) biomarkers and amyloid imaging have been established to detect AD pre-clinically [5], [6], these are not suitable for large scale screening programs in consideration of the invasiveness and a host of comorbidities. Taking into account these facts, finding proteins from peripheral blood samples that could identify AD may be useful for pre-symptomatic. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral blood Apolipoprotein E (ApoE) levels have been proposed as biomarkers of Alzheimer's disease (AD), but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker. We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD) and 95% confidence interval (CI) were used to estimate the association between ApoE levels and AD risk. Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was -5.59 mg/l (95% CI: [-8.12, -3.06]). The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type. Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.
    PLoS ONE 02/2014; 9(2):e89041. DOI:10.1371/journal.pone.0089041 · 3.23 Impact Factor
  • Source
    • "The establishment of aMCI biomarkers would be of benefit to clinicians as the biomarkers could be used as objective diagnostic tools, thus allowing early or pre-symptomatic identification of AD, aiding treatment decisions, monitoring disease progress, and providing opportunities for prevention by population screening (Henry et al., 2012). The methods used to search for biomarkers of MCI include neuroimaging techniques (Small et al., 2006; Hämäläinen et al., 2007), cerebrospinal fluid analysis (Perneczky et al., 2011), genetic analysis (Zhang et al., 2012) and electroencephalography (EEG), both quantitative EEG (see Jackson and Snyder, 2008) and event-related potentials (ERPs; see Jackson and Snyder, 2008 and Vecchio and Määttä, 2011). The use of ERP technique in the search for aMCI biomarkers is founded on three essential characteristics designated as ideal (see Hampel et al., 2010): it is non-invasive, simple to measure and inexpensive. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been suggested that changes in some event-related potential (ERP) parameters associated with controlled processing of stimuli could be used as biomarkers of amnestic mild cognitive impairment (aMCI). However, data regarding the suitability of ERP components associated with automatic and involuntary processing of stimuli for this purpose are not conclusive. In the present study, we studied the Mismatch Negativity (MMN) component, a correlate of the automatic detection of changes in the acoustic environment, in healthy adults and adults with aMCI (age range: 50-87 years). An auditory-visual attention-distraction task, in two evaluations separated by an interval of between 18 and 24 months, was used. In both evaluations, the MMN amplitude was significantly smaller in the aMCI adults than in the control adults. In the first evaluation, such differences were observed for the subgroup of adults between 50 and 64 years of age, but not for the subgroup of 65 years and over. In the aMCI adults, the MMN amplitude was significantly smaller in the second evaluation than in the first evaluation, but no significant changes were observed in the control adult group. The MMN amplitude was found to be a sensitive and specific biomarker of aMCI, in both the first and second evaluation.
    Frontiers in Aging Neuroscience 12/2013; 5:79. DOI:10.3389/fnagi.2013.00079 · 4.00 Impact Factor
  • Source
    • "Several studies have failed to show any differences in the levels of these biomarkers between AD patients and controls [30,34,63,80,81]. One study found higher levels of sAPPβ in MCI patients compared with controls [81], and another that MCI patients that upon follow up developed AD had higher levels of sAPPβ than patients that didn’t [82]. However, Hertze et al. found no differences in sAPP levels in MCI patients with incipient AD compared with stable MCIs or patients that developed other dementias [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The diagnostic guidelines of Alzheimer's disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.
    Molecular Neurodegeneration 06/2013; 8(1):20. DOI:10.1186/1750-1326-8-20 · 6.56 Impact Factor
Show more