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,
ReviewCSF markers for incipient Alzheimer's disease
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
Aβ1–42
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,
Aβ1–42
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
References (87)
Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment
Lancet Neurol
(2003)- et al.
Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease
Neurosci Lett
(1997) - et al.
Cerebrospinal fluid amyloid beta(1–42) levels in the mild cognitive impairment stage of Alzheimer's disease
Exp Neurol
(2001) - et al.
Low cerebrospinal-fluid concentrations of soluble amyloid beta-protein precursor in hereditary Alzheimer's disease
Lancet
(1992) - et al.
Peptide composition of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease
Arch Biochem Biophys
(1993) - et al.
Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization
Neurosci Lett
(2000) - et al.
Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease
Neurosci Lett
(1999) - et al.
Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients
Neurosci Lett
(2000) - et al.
Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients: an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay
Am J Pathol
(2002) - et al.
Transient increase in CSF total tau but not phospho-tau after acute stroke
Neurosci Lett
(2001)
Combination assay of CSF tau, A beta 1–40 and A beta 1–42(43) as a biochemical marker of Alzheimer's disease
J Neurol Sci
Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group
Neurobiol Aging
Levels of total tau and tau protein phosphorylated at threonine 181 in patients with incipient and manifest Alzheimer's disease
Neurosci Lett
Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer's disease
Neurosci Lett
Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease
Brain Res
No increase in cerebrospinal fluid tau protein levels in patients with vascular dementia
Neurosci Lett
Cerebrospinal protein tau is elevated in early Alzheimer's disease
Neurosci Lett
Increased cerebrospinal fluid cAMP levels in Alzheimer's disease
Brain Res
CSF t-tau and CSF-Aβ42 as predictors of development of Alzheimer's disease in patients with mild cognitive impairment
Neurosci Lett
“Mini Mental State” A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment
Neurosci Lett
Mild cognitive impairment: clinical characterization and outcome
Arch Neurol
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of department of health and human services task force on Alzheimer's disease
Neurology
Clinical-neuropathological correlations in Alzheimer's disease and related dementias
Arch Neurol
Diagnostic accuracy of Alzheimer's disease: a clinicopathological study
Acta Neuropathol
A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques
Neurology
Cerebrospinal fluid markers for Alzheimer's disease evaluated after acute ischemic stroke
J Alzheimer Dis
Tau protein in cerebrospinal fluid: a biochemical diagnostic marker for axonal degeneration in Alzheimer's disease?
Mol Chem Neuropathol
A critical discussion of the role of neuroimaging in mild cognitive impairment
Acta Neurol Scand
One-carbon metabolism and other biochemical correlates of cognitive impairment as visualized by principal component analysis
J Geriatr Psychiatry Neurol
CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects
Neurology
Combined Analysis of CSF Tau Levels and [(123)I]Iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer's disease
Am J Psychiatry
Cerebrospinal fluid levels of total-tau, phospho-tau and Aβ42 predicts development of Alzheimer's disease in patients with mild cognitive impairment
Acta Neurol Scand
Detection of τ proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay
J Neurochem
Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer's disease
Neurology
Amyloid plaque core protein in Alzheimer's disease and Down syndrome
Proc Natl Acad Sci USA
Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients
Proc Natl Acad Sci USA
Concentrations of amyloid beta protein in cerebrospinal fluid of patients with Alzheimer's disease
Ann Neurol
Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue
J Neurochem
Development of a specific diagnostic test for measurement of β-amyloid(1–42)
Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease
Ann Neurol
Decreased beta-amyloid1–42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease
Neurology
Decreased CSF β-amyloid42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of β-amyloid induced by separate mechanisms
Dementia Geriatr Cogn Disord
Cited by (1093)
Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer's disease? An umbrella review
2024, IBRO Neuroscience ReportsRecent trends in treatment strategies for Alzheimer<sup>'</sup>s disease and the challenges: A topical advancement
2024, Ageing Research Reviews