Whole-brain atrophy rate and CSF biomarker levels in MCI and AD: A longitudinal study

https://doi.org/10.1016/j.neurobiolaging.2008.06.016Get rights and content

Abstract

Objectives

To assess associations between cerebrospinal fluid (CSF) biomarker levels and MRI-based whole-brain atrophy rate in mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Methods

We included 99 patients (47 AD, 29 MCI, 23 controls) who underwent lumbar puncture at baseline and repeat MRI. A subgroup of 48 patients underwent a second lumbar puncture. CSF levels of beta-amyloid1–42 (Aβ1–42), tau and tau phosphorylated at threonine-181 (P-tau181), and whole-brain atrophy rate were measured.

Results

Across groups, baseline Aβ1–42 and tau were modestly associated with whole-brain atrophy rate. Adjusted for age, sex and diagnosis, we found no association between Aβ1–42 or tau, and whole-brain atrophy rate. By contrast, high CSF levels of P-tau181 showed a mild association with a lower whole-brain atrophy rate in AD but not in controls or MCI patients. Finally, whole-brain atrophy rate was associated with change in MMSE, but change in CSF biomarker levels was not.

Conclusions

Whole-brain atrophy rate and CSF levels of Aβ1–42, tau or P-tau181 provide complementary information in patients with MCI and AD.

Introduction

Both cerebrospinal fluid (CSF) biomarkers and magnetic resonance imaging (MRI) are increasingly used to detect and characterise brain changes associated with Alzheimer's disease (AD) in vivo. In CSF, decreased Aβ1–42 levels and increased tau, and P-tau181 levels are thought to reflect the presence of AD pathology (Blennow and Hampel, 2003). These CSF biomarkers have been shown to differentiate patients with AD from control subjects with reasonable accuracy (Wiltfang et al., 2005). Moreover, these changes can be detected in patients with mild cognitive impairment (MCI) who will progress to AD (Bouwman et al., 2007a, Hansson et al., 2006). Brain tissue loss (atrophy) secondary to the neurodegenerative disease process can be visualized and measured using MRI. Whole-brain atrophy rate, measured from serial MRI, correlates well with disease and clinical progression in patients with MCI and AD (Fox et al., 1999, Fox et al., 2005, Jack et al., 2004).

Although both MRI and CSF biomarkers have been shown to be valuable markers of disease in MCI and AD (Waldemar et al., 2007, Wiltfang et al., 2005), the relation between these markers has been less well studied. In cross-sectional studies, CSF biomarkers have been reported not to be related to MRI measures of atrophy, suggesting that these markers reflect different aspects of Alzheimer type neuropathology (Schonknecht et al., 2003, Schoonenboom et al., 2007). However, longitudinal studies are needed, to clarify the relationship between these markers. The few studies that have reported CSF biomarkers and MRI measures in a longitudinal design, have used relatively small sample sizes, and have shown conflicting results in terms of whether or not these markers are associated (de Leon et al., 2006, Hampel et al., 2005, Wahlund and Blennow, 2003).

The objective of the present investigation was to assess whether MRI measures and CSF biomarkers are related or provide independent information. We therefore assessed the relationship between baseline levels of CSF Aβ1–42, tau, and P-tau181 and whole-brain atrophy rate in patients with AD, MCI, and controls. In addition, we studied the association between longitudinal change of these CSF biomarker levels, whole-brain atrophy rates, and change in cognitive function.

Section snippets

Patients

We included 47 patients with AD, 29 patients with MCI and 23 controls with baseline CSF and repeat MRI scans from our memory clinic. All patients underwent lumbar puncture (LP) at baseline and MRI at baseline and follow-up. At follow-up, 48 patients (20 AD, 17 MCI, 11 controls) agreed to undergo a second lumbar puncture. Follow-up time was defined as time between the two MRI scans (mean interval 1.7 years, standard deviation 0.7; range 11 months to 4 years). Patients underwent a standardized

Results

Demographic and clinical data are presented by patient group in Table 1. MCI patients were older when compared to AD patients. We found no difference in sex or follow-up time. Annualized whole-brain atrophy rate differed between diagnostic groups (p < 0.001). We also found group differences for baseline Aβ1–42 (p < 0.001), tau, and P-tau181 (both p < 0.01). By contrast, annualized change in CSF Aβ1–42, tau, and P-tau181 levels over time did not differ between patient groups (all p > 0.49).

To

Discussion

The major finding of this study is that, notwithstanding modest correlations of baseline CSF biomarker levels and whole-brain atrophy rate across groups, hardly any association within diagnostic groups was found. Whole-brain atrophy rate was associated with clinical progression, measured by change in MMSE score, but longitudinal changes in the CSF biomarker levels were not. Thus, MRI and CSF biomarkers appear to reflect different aspects of AD: whole-brain atrophy rate appears to be linked to

Conflict of interest

The authors report no conflicts of interest.

Acknowledgements

J.D. Sluimer is recipient of grant 03514 from the ISAO (Internationale Stichting Alzheimer Onderzoek) and supported by the Image Analysis Center (IAC). The Alzheimer Centre VUmc is supported by Stichting Alzheimer Nederland and Stichting VUMC funds. The clinical database structure was developed with funding from Stichting Dioraphte.

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