CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease
Introduction
Decreased cerebrospinal fluid (CSF) amyloid β (1-42) (Aβ42) in Alzheimer's disease (AD) is associated with intracerebral deposition of neuritic plaques, mainly composed of Aβ42 (Blennow and Hampel, 2003, Strozyk et al., 2003). Increased CSF tau protein (tau) is considered to be a reflection of neuronal degeneration, caused by intraneuronal accumulation of neurofibrillary tangles containing (phosphorylated) tau (Blennow and Hampel, 2003, Clark et al., 2003, Consensus Report of the Working Group, 1998). Especially CSF phosphorylated tau (Ptau) is increased in AD compared to other types of dementia (Blennow and Hampel, 2003, Schoonenboom et al., 2004). Although the combination of CSF Aβ42, tau and Ptau provides reasonable accuracy in the differentiation of AD from controls, CSF concentrations of these biomarkers do overlap between groups (Hulstaert et al., 1999, Schoonenboom et al., 2004).
Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) has been found to be an early and sensitive marker for AD (Wahlund et al., 2000) and is assumed to reflect underlying neuronal loss of the hippocampus and the temporal lobe. However, MTA may also be present in other types of dementia and absence of MTA does not exclude the diagnosis AD, especially in the early stages (Wahlund et al., 2000). The latter particularly applies to early-onset AD (EAD), where MTA is often not prominently present (Galton et al., 2000, Kemp et al., 2003).
Relatively little is known about the association between MTA and CSF markers, while both are presumed to reflect Alzheimer pathology. From post mortem work it is known that hippocampal volume is a good indicator of the amount of plaques and tangles deposition (Csernansky et al., 2004, Gosche et al., 2002, Silbert et al., 2003), which led us to suspect an association with CSF Aβ42 and (P)tau. An association between MTA and (P)tau would provide further evidence for the notion that both are measures of neuronal degradation or neuronal loss (Bobinski et al., 2000, De Leon et al., 2004, Jack et al., 2002). In addition, while MTA has become a widely used marker in AD diagnosis, CSF markers still have to be established as such. The aim of this study was twofold: first, to study the association between CSF markers and MTA, to provide insight whether both types of markers reflect the same neuropathological substrate. The second aim was to investigate whether both disease markers are independent predictors for the diagnosis AD. Therefore, we studied the relations between CSF Aβ42, tau, and Ptau with MTA in AD and controls. Furthermore, diagnostic accuracy of MTA and the combination of CSF Aβ42, tau and Ptau was compared in AD versus controls.
Section snippets
Participants
Sixty-one AD patients and 32 controls younger than 85 years old were recruited consecutively at the memory clinic of the Alzheimer Center, VU University Medical Center, Amsterdam. All patients underwent a standardized diagnostic work-up, including medical history, informant interview, physical and neurological examination, screening laboratory tests, EEG, and magnetic resonance imaging (MRI). The majority of patients underwent detailed neuropsychological testing. However, the test-protocol
Results
AD patients and controls were well matched for age and gender (Table 1). There were no differences between groups in the prevalence of history of hypertension, diabetes mellitus, or myocardial infarction (p > 0.10). Median disease duration in AD was 4 years (range 0.5–11 years), median MMSE was 20 (9–28) in AD and 29 (25–30) in controls (p < 0.001). CSF Aβ42 levels were decreased and CSF tau and Ptau-181 levels were increased in AD patients compared to controls. MTA score was significantly higher
Discussion
In the present study, we could not demonstrate cross-sectional relations between CSF Aβ42, tau and Ptau-181 with MTA in AD or controls. Both MTA and the combination of CSF Aβ42, tau and Ptau-181 contributed independently to the diagnosis AD. Our data suggest that CSF analysis is most sensitive in the absence of MTA, and especially among younger patients.
Only a few studies investigated the cross-sectional relation between CSF biomarkers and atrophy on MRI in small groups of patients (Bouwman et
Disclosure
There are no actual or potential conflicts of interest, including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence their work, that need to be disclosed by the authors.
Acknowledgements
Niki S.M. Schoonenboom was partly funded through a grant from Alzheimer Nederland, Bunnik (V2001-023). Additional funding was received from the Stichting Alzheimer and Neuropsychiatry Foundation, Amsterdam.
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