Elsevier

The Lancet Neurology

Volume 2, Issue 10, October 2003, Pages 605-613
The Lancet Neurology

Review
CSF markers for incipient Alzheimer's disease

https://doi.org/10.1016/S1474-4422(03)00530-1Get rights and content

Summary

Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and β-secretase and γ-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-β may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.

Section snippets

Diagnostic markers

The introduction of effective symptomatic treatment of AD with acetylcholinesterase inhibitors has highlighted the importance of early and accurate diagnosis of AD. However, the most commonly used criteria for the clinical diagnosis of AD was outlined almost 20 years ago by the National Institute of Neurological and Disorders and Stroke and the Alzheimer Disease and Related Disorders (NINCDS–ADRDA) Work Group.3 These criteria largely depend on the exclusion of other dementias. Although the

State and stage markers for AD

The degenerative process in AD probably starts 20–30 years before the clinical onset of the disease.6 During this preclinical phase of AD, plaque and tangle loads increase, and at a certain threshold the first symptoms appear. There are no data to suggest that the intensity of the disease process (ie, the rate of neuronal degeneration and plaque and tangle formation) changes during the disease process. Diagnostic markers for AD can be divided into two groups: state markers and stage markers.

CSF markers for AD

The CSF is in direct contact with the extracellular space of the brain, and hence biochemical changes in the brain affect the CSF. Because AD pathology is restricted to the brain, CSF is an obvious source of biomarkers for AD. Biochemical markers for AD should reflect the central pathogenetic processes (ie, the neuronal degeneration, the deposition of amyloid-β peptide [Aβ] in plaques, and the hyperphosphorylation of tau with subsequent formation of tangles; figure 1). Possible biomarkers for

1–42

Aβ is the major component of plaques.18 It is a proteolytic cleavage product from the amyloid precursor protein: APP is cleaved by β-secretase to release a large N-terminal derivative called β-sAPP, which is cleaved by γ-secretase to release free Aβ.

The first reports on CSF Aβ as a biomarker for AD were disappointing, and results ranged form a slight decrease in AD to no change.19, 20, 21 In these studies total Aβ in the CSF was measured. After research showed that there are two major

Specificity and sensitivity of CSF markers for AD Tau protein

An increase in the total concentration of tau protein in the CSF has been found in many studies of AD; concentrations are about three times higher in patients with AD than in control individuals. For the most commonly used method, the “Innogenetics ELISA”,9 sensitivity and specificity figures are available from 36 different studies, which include about 2500 AD patients and 1400 controls (figure 4).9, 12, 24, 27, 30, 33, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,

1–42

In patients with AD, a decrease in CSF concentration of Aβ1–42 to about 50% of that in control individuals has been recorded. For the most commonly used method,24, 72 the “Innogenetics ELISA”, sensitivity and specificity figures are available from 13 different studies, which include about 600 patients with AD and 450 control individuals (figure 5).24, 26, 27, 46, 47, 50, 54, 57, 58, 59, 63, 72, 73 with specificity at 90%, the mean sensitivity of CSF Aβ1–42 to discriminate between AD and normal

Limitations of CSF studies in clinically diagnosed patients

Almost all data on the diagnostic capacity of CSF markers come from studies of clinically diagnosed patients. This introduces a risk of circular evidence—ie, the diagnostic performance of CSF markers cannot be higher than the accuracy of the clinical diagnostic criteria used. Some patients who fulfil the NINCDS-ADRDA criteria3 for AD have other disorders. Further, there is an overlap between AD and other dementias. Neuropathological studies have shown that a high proportion (40–80%) of

Complications after lumbar puncture

Lumbar puncture is often avoided because of fear of post-lumbar-puncture headache. However, the incidence of this headache is strictly age-related and less common in individuals over 60 years of age than in younger individuals.86 Furthermore, the incidence of post-lumbar-puncture headache is even lower (<2%) in patients admitted for assessment of cognitive symptoms, most of whom have only minimal discomfort.81, 87 Thus, a spinal tap in the geriatric populations is a safe procedure when done by

Search strategy and selection criteria

Data were identified by searches on MEDLINE and references from relevant articles. The search terms “Alzheimer”, “CSF”, and either “tau” or “amyloid” were used. CSF markers that have been assessed in more than ten studies, by independent research groups using different methods, were considered. Only studies that include sensitivity and specificity figures, or in which such figures could be calculated from graphs, were included. Studies were excluded if they included mixed control groups,

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