Review
CSF biomarkers for mild cognitive impairment and early Alzheimer's disease

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Abstract

A correct clinical diagnosis, early in the course of Alzheimer's disease (AD), is of importance given the currently available symptomatic treatment with acetylcholine esterase inhibitors. The development of disease-modifying drugs like β-sheet breakers or γ- and β-secretase inhibitors, emphasizes the need of improved diagnostic accuracy, especially in patients with mild cognitive impairment (MCI) that have incipient AD. Therefore, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field.

Three cerebrospinal fluid biomarkers (the 42 amino acid form of β-amyloid (Aβ), total tau, and phospho tau) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal aging, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. If these biomarkers are used in combination with a careful medical history, clinical examination, standard laboratory tests and imaging techniques of the brain, the diagnostic accuracy may be appropriate for the clinical evaluation of MCI cases.

Section snippets

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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