ReviewCSF biomarkers for mild cognitive impairment and early Alzheimer's disease
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Introduction: diagnostic markers for MCI and AD
Alzheimer's disease (AD) is the most common form of dementia. The prevalence and incidence of AD appear to be fairly constant and stable over time [1]. As the prevalence of AD doubles every 5.1 years, (from 1% in the age group 65–69 years, to 39% at 90–95 years [2]) the total prevalence of dementia is a growing socio-economical and medical problem for the western world [3]. In view of existing and emerging therapeutic compounds there is a great need for reliable biochemical diagnostic markers,
Rationale for CSF analysis
The blood brain barrier restricts the flow of proteins to and from the brain. We have about 150 ml CSF, which is in direct contact with the (extracellular space of the) brain. Biochemical changes that reflect pathological processes of the brain are reflected in the CSF, which can be considered as “a window to the brain”. A diagnostic marker for AD should reflect a central pathogenic process of the disorder, in other words, the degeneration of the neurons and their synapses [12], [13] and the
β-Amyloid (Aβ)
One of the major findings in AD research was that β-amyloid is the main protein constituent of plaques [92]. Aβ is produced continuously as a soluble protein during normal cellular metabolism and is secreted into the extracellular space and, thus, into the CSF [15], [16]. Aβ is a proteolytic product of the single membrane-spanning protein, amyloid precursor protein (APP) [93]. The APP gene is located on chromosome 21 [17]. APP has three major alternate splicing variants with 770, 751, or 695
Tau protein
Tau is a normal brain phosphoprotein that promotes the assembly and stability of neuronal axons by binding to microtubules [49]. There are six different isoforms of tau in the human brain that vary in size from 352 to 441 amino acids, with molecular weights of ≈50–65 kDa [50] (Fig. 2). In AD, hyperphosphorylated tau is the principal component of paired helical filaments (PHFs), which form neurofibrillary tangles, neuropil threads and senile plaque neurites [51] (Fig. 3). These formations result
CSF biomarkers in mild cognitive impairment (MCI) and incipient AD
The biomarkers have been studied in mild AD with Mini-Mental State Examination (MMSE) scores above 23-25. Low Aβ(1-42), high T-tau and high P-tau levels were found with sensitivity figures comparable to those found in later stages of the disease [34], [46], [78], [79], [80], [81].
In cases with incipient AD several studies have demonstrated low Aβ(1-42), high T-tau and high P-tau levels compared to controls. These results are similar with the results found in patients with (early) AD. even the
Lumbar puncture
Lumbar puncture (LP) has to be performed to obtain CSF. This procedure has a bad reputation being prone to cause post-lumbar puncture headache (PLPH). In patients over the age of 60 with cognitive impairment, this side effect is however unusual with an incidence below 2% [37], [90] and therefore a widely overestimated problem (Fig. 4).
The diagnostic value of CSF markers
More than 50 studies have evaluated the diagnostic value of CSF markers for AD cases, finding high levels of T-tau and P-tau, and low Aβ(1-42) levels, with
Summary
In this paper, we have focused on the diagnostic performance of CSF biomarkers for (incipient) AD. Most studies evaluated the biomarkers as isolated tests; it is, therefore, necessary to stress that the CSF biomarkers should be used in addition to the clinical and paraclinical evaluation as applied in the diagnostic work up of dementia. No one would think of diagnosing myocardial infarction mere on a biomarker as troponine or creatinine kinase but would use the combined information of
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