Whole-brain atrophy rate and CSF biomarker levels in MCI and AD: A longitudinal study
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.
References (35)
- et al.
CSF markers for incipient Alzheimer's disease
Lancet Neurol.
(2003) - et al.
CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment
Neurobiol. Aging
(2007) - et al.
Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment
Neurobiol. Aging
(2006) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Mild cognitive impairment
Lancet
(2006) - et al.
Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study
Lancet Neurol.
(2006) - et al.
Analysis and validation of automated skull stripping tools: a validation study based on 296 MR images from the Honolulu Asia aging study
Neuroimage
(2006) - et al.
CSF Abeta42, Tau and phosphorylated Tau, APOE epsilon4 allele and MCI type in progressive MCI
Neurobiol. Aging
(2007) - et al.
Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study
Lancet Neurol.
(2006) - et al.
Cerebrospinal fluid tau levels in Alzheimer's disease are elevated when compared with vascular dementia but do not correlate with measures of cerebral atrophy
Psychiatry Res.
(2003)
Advances in functional and structural MR image analysis and implementation as FSL
Neuroimage
Accurate, robust, and automated longitudinal and cross-sectional brain change analysis
Neuroimage
Cerebrospinal fluid biomarkers for disease stage and intensity in cognitively impaired patients
Neurosci. Lett.
Longitudinal changes of CSF biomarkers in memory clinic patients
Neurology 2007
Usefulness of longitudinal measurements of beta-amyloid1–42 in cerebrospinal fluid of patients with various cognitive and neurologic disorders
Clin. Chem.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol. (Berl.)
Rates of global and regional cerebral atrophy in AD and frontotemporal dementia
Neurology
Cited by (73)
An Association Between Large Optic Cupping and Total and Regional Brain Volume: The Women's Health Initiative
2023, American Journal of OphthalmologyPredicting diagnosis 4 years prior to Alzheimer's disease incident
2022, NeuroImage: ClinicalLinear regression
2019, Machine Learning: Methods and Applications to Brain DisordersMRI-based evaluation of structural degeneration in the ageing brain: Pathophysiology and assessment
2019, Ageing Research ReviewsLongitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease
2017, Neurobiology of AgingCitation Excerpt :There is however increasing interest in adopting longitudinal neuroimaging techniques as adjunctive markers of disease progression with the expectation that MRI measurements may provide better sensitivity and precision than standard clinical measures (Jack et al., 2003; Nestor et al., 2008; Schott et al., 2005). In this regard, advances in neuroimaging analyses have contributed to the validation of whole-brain atrophy rates (Smith et al., 2002) as sensitive markers of disease progression in mild cognitive impairment (MCI; Sluimer et al., 2010), frontotemporal dementia (Knopman et al., 2009), and Alzheimer's disease (AD; Fox and Freeborough, 1997; Mak et al., 2015b). In addition, ventricular enlargement has emerged as another viable surrogate but not nonspecific marker of neurodegeneration in MCI and AD (Ferris et al., 2009; Jack et al., 2004; Nestor et al., 2008).