PET imaging of amyloid deposition in patients with mild cognitive impairment
Introduction
Mild cognitive impairment (MCI) represents a transitional phase between normal ageing and dementia disorders, especially Alzheimer's disease (AD). Patients with MCI have an increased risk of developing AD (Petersen et al., 1999). At present there is great interest in finding diagnostic tools for detection of an increased risk of developing AD. The diagnostic accuracy of current and commonly used MCI criteria is low to moderate (Visser et al., 2005). Both structural and functional neuroimaging have shown promising results in improving MCI diagnosis. Results suggest that changes in glucose metabolism, measured by means of [18F]-2-deoxy-d-glucose (FDG) positron emission tomography (PET), might have a predictive value in the detection of MCI patients at a high risk of developing AD (Arnaiz et al., 2001, Chetelat et al., 2003, Drzezga et al., 2003). Similarly, magnetic resonance imaging (MRI) used in the assessment of brain atrophy and deterioration in the hippocampus, and entorhinal and temporal neocortical volumes, has been used to discriminate MCI patients at a risk of developing AD (Chetelat and Baron, 2003, Kordower et al., 2001). Cerebrospinal fluid (CSF) Aβ1-42 and Tau have been studied as potential biomarkers in MCI. They have shown prognostic value in discriminating MCI patients that will develop AD (Blennow and Hampel, 2003, Buerger et al., 2005, Hansson et al., 2006, Herukka et al., 2005). Longitudinal studies involving MRI and CSF measurements might provide synergistic and improved sensitivity and specificity in prognostic studies of conversion from MCI to AD (de Leon et al., 2006). Recently, various PET ligands used in amyloid imaging in vivo have been developed (Klunk et al., 2001, Shoghi-Jadid et al., 2002, Verhoeff et al., 2004). Promising results have been obtained with N-methyl [11C] 2-(4′-methylaminophenyl)-6-hydroxy-benzothiazole (PIB), which was found to discriminate successfully between AD patients and age-matched healthy controls (Klunk et al., 2004). Since then several studies have been performed studying AD patients with PIB-PET. We have evaluated the longitudinal changes of PIB retention and found PIB showing quite stable PIB binding in AD patients despite progression in cerebral glucose metabolism and cognition (Engler et al., 2006). The use of voxel-based methods for studying amyloid depositions has also been implemented complementing earlier region of interest based analysis (Kemppainen et al., 2006, Ziolko et al., 2006). One recent study showed an interaction between the PIB binding and the rate of grey matter atrophy (Archer et al., 2006). The link between PIB binding, glucose metabolism and cognitive status has been studied previously (Edison et al., 2006, Engler et al., 2006, Klunk et al., 2004). Amyloid imaging in healthy elderly subjects using PIB showed high PIB in 4 out of 41 non-demented subjects (Mintun et al., 2006). Recently, Small et al. using the amyloid ligand FDDNP presented a study of MCI patients that showed intermediate levels of binding compared to healthy volunteers and AD patients (Small et al., 2006). The separation of healthy versus demented subjects measured with FDDNP seems to be somewhat lower than with PIB (Small et al., 2006), although future studies comparing these tracers would be advisable.
The aim of this study was to measure (by PET) PIB retention in the brains of MCI patients and analyse its relationship with cerebral glucose metabolism, cognitive function and CSF biomarkers and conversion to AD.
Section snippets
MCI patients
Twenty-one MCI patients (mean age 63.3 ± 7.8 (S.D.) years) were recruited from the Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. The patients had been referred from the primary care centres in the community for investigation of suspected dementia development. All patients were examined at the clinic according to the same comprehensive procedure, which included physical examination, evaluation of neurological and psychiatric status, blood (including
MCI patients
The demographic information regarding the MCI patients is seen in Table 1. During clinical follow-up of the MCI patients after the performed PET scans seven of the MCI patients converted to AD after 8.1 ± 6.0 months (S.D.) after their respective PET scans. The diagnosis of AD was based on comprehensive clinical examination as mentioned in Section 2 and according to the criteria of NINCDS-ADRDA (McKhann et al., 1984). These seven MCI patients will below be considered as MCI converters and the
Discussion
MCI is considered as a transitional stage between normal aging and dementia, especially early AD. There are problems and limitations of the clinical diagnosis of MCI. In this study we describe the measurement of PIB retention by means of PET imaging in a group of MCI patients from an academic medical centre where the subjects were recruited among clinical patients referred to the geriatric department by primary care physicians in the Stockholm area. It is known that MCI may have a multitude of
Conflicts of interest
A.W., A.R., B.L. are employed by Uppsala Imanet GE HealthCare, Uppsala, Sweden. The dementia program within Imanet which this manuscript is a part of has been driven since the start as an academic program and the employees have no financial benefit of the work. None of the other authors have any conflict of interest.
Acknowledgements
Financial support from the Swedish Research Council (project 05817, A.N.), the foundation for Old Servants (A.N.), Stohne's foundation (A.N.), the KI foundations (A.N.), the Alzheimer Foundation in Sweden (A.N.), Swedish Brain Power (A.N., B.L.), the EC-FP5-projec tNCI-MCI and the EC-FP6-project DiMI, LSHB-CT-2005-512146, QLK6-CT-2000-00502 (A.N.) is gratefully acknowledged.
References (46)
- et al.
CSF markers for incipient Alzheimer's disease
Lancet Neurol.
(2003) - et al.
Early diagnosis of Alzheimer's disease: contribution of structural neuroimaging
Neuroimage
(2003) - 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. Psychiatry Res.
(1975) - 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.
Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
Life Sci.
(2001) - et al.
Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease
Am. J. Geriatr. Psychiatry
(2002) - 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.
Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease
Neuroimage
(2006) Diagnostic and Statistical Manual of Mental Disorders
(1994)