Analysis of 27 vascular-related proteins reveals that NT-proBNP is a potential biomarker for Alzheimer's disease and mild cognitive impairment: A pilot-study
Introduction
Alzheimer's disease (AD) is a severe neurodegenerative disease resulting in progressive impairment in memory and cognition. The disorder is pathologically characterized by extracellular beta-amyloid plaque deposition, intraneuronal tau pathology, neuronal cell death, vascular dysfunction and inflammatory processes. Since life expectancy in the general population increased within the last 100 years from about 40 to about 80 years and age is the main risk factor for AD, the number of patients suffering from AD and mixed forms of dementia will dramatically increase within the next 50 years. It is expected that there will be about 80 million AD patients worldwide in 2050. It will be essential to delay and counteract symptoms in AD and to start therapeutic treatment as early as possible. A valid and easily accessible diagnostic procedure should be the basis for an early treatment (Humpel, 2010).
A probable diagnosis of AD can be established with a confidence of > 90%, based on clinical criteria, laboratory tests, neuroimaging and neuropsychological evaluation (Desai and Grossberg, 2005). Definitive diagnosis of AD requires a post mortem detection of beta-amyloid plaques and tau-pathology (Fradinger and Bitan, 2005, McKeel et al., 2004). However, an early sensitive diagnosis of AD is still difficult because early symptoms are frequently masked by a variety of disorders, including vascular changes or cognitive deficits caused by depression. Established laboratory markers of AD are limited to the analysis of 3 biomarkers in cerebrospinal fluid (CSF): beta-amyloid(1–42) and total tau and phospho-tau-181 (Blasko et al., 2006, Blennow, 2005, Hampel et al., 2010a, Zetterberg et al., 2010). However, CSF analysis is limited due to the invasive collection. Further, CSF analysis does so far not distinguish between AD and other forms of dementia, such as e.g. vascular dementia or frontotemporal lobe dementia. Thus there is a great need to search for biomarkers in blood. Several studies have been conducted in blood samples in order to establish specific changes of proteins. Despite these great efforts, no specific blood biomarker could be established as a biomarker yet (Borroni et al., 2006, Hampel et al., 2010b, Humpel, 2010, Kurz et al., 2002, Lewczuk and Wiltfang, 2008, Pelech, 2008).
AD shares many of the risk factors of cerebrovascular disease. There is increasing supportive evidence that vascular risk factors contribute to the pathogenesis of AD (De la Torre, 2002, Humpel, 2011, Iadecola, 2004, Kudo et al., 2000, Zlokovic, 2005). Mixed pathology (AD plus vascular pathology) is increasingly being identified in autopsy studies of people aged 80 or over with dementia, and not all vascular autopsy changes are well covered by MRI imaging. However, it is speculated that neurodegeneration in AD may arise from a chronic mild cerebrovascular dysregulation caused by continuous exposure to the risk factors over years (Humpel, 2011), which precedes hypoperfusion (De la Torre, 2002, Iadecola, 2004). Some supportive epidemiological studies (De la Torre, 2002, Humpel, 2010, Rocchi et al., 2009, Zlokovic, 2005) suggest that these risk factors could be old age, atherosclerosis, stroke, diabetes, hyperhomocysteinemia, hypertension, hyperlipidemia, head injury, transient silent strokes, high serum viscosity, thrombogenic factors, cardiac disease, the apolipoprotein E4 allele, smoking, alcohol consumption, high cholesterol, fat food, reduced vitamin B12 uptake, high fibrinogen levels, depression, and others. Blood plasma may be a rich source of biomarkers in AD and may reflect a systemic metabolic signature of AD or be a change in plasma secondary to a disease-specific process in the brain (Mattila and Frey, 1995).
In the present pilot study, we examine whether plasma proteins related to the vascular system are altered in MCI or AD. These proteins include markers involved in wound healing (for example, alpha2-macroglobulin, fibronectin, thrombomodulin, keratinocyte growth factor, platelet-derived growth factor, thrombopoietin, thrombospondin, tissue plasminogen activator and inhibitor, fibrinogen) as well as markers involved in cardiovascular pathology and atherosclerosis (for example, N-terminal prohormone of brain natriuretic peptide, TNF-related apoptosis-inducing, programmed cell death protein 1, myeloperoxidase, neutrophil gelatinase-associated lipocalin, receptor for Advanced Glycation Endproducts (RAGE), serum Amyloid A, TNF-like weak inducer of apoptosis, tissue inhibitors of metalloproteinases (-1 and -2), beta-defensin-2, apolipoprotein A-1 and B-100 (ApoB-100), oxidized low density lipoprotein (oxLDL) and antibodies against oxidized lipids (oLAb). However, these selected vascular proteins comprise only a small number of possible vascular proteins. We have selected these proteins because they represent pathophysiological processes involved in neurodegenerative diseases. Some of these proteins have been reported to be up- or downregulated in previous reports. The availability of commercial (multiplex) ELISA kits was also a selection criterion. The present pilot study will reveal whether a single protein or a set of vascular proteins is altered in MCI and/or Alzheimer patients who don't suffer from a clinically significant vascular disease.
Section snippets
Study design
A total number of 110 participants (healthy controls, AD and MCI) was included in this study during a time period of 2004–2012. All patients were older than 60 years and were recruited from the Memory Clinics at the Department of Psychiatry in Innsbruck or the Landeskrankenhaus Hall/Tirol in Austria. Healthy subjects were also recruited at this site. They were mainly healthy caregivers and volunteers. Subjective cognitive impairment was an exclusion criterion for healthy subjects. Psychiatrists
Selection of patients
In the first study, 80 subjects were included with the following diagnosis: 23 healthy controls (age 71 ± 1.4 years), 24 MCI patients (age 74 ± 1.6 years) and 33 AD patients (age 81 ± 1.0 years; Table 1A). In the second part of this study, we analyzed a larger sample size including 110 participants (Table 1B). A one way ANOVA did not reveal a statistical difference between the “screening” and “NT-proBNP” groups with respect to all variables. In this set of experiment, we also included a group of young
Discussion
In the present study, we measured 27 vascular-related proteins which may directly or indirectly contribute to the pathology found in AD and MCI patients. We showed that 8 proteins were significantly increased in AD patients when compared to healthy subjects. However, only NT-proBNP levels were increased in both MCI and AD patients compared to healthy subjects. Thus, NT-proBNP may be a sensitive marker for MCI and AD.
Disclosure statement
There are no actual or potential conflicts of interests.
Acknowledgment
The study was supported by a Translational Project of the Austrian Science Funds (L429-B05). We thank Ursula Kirzenberger–Winkler for excellent technical help.
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