Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the most common cause of dementia (Blennow et al., 2006). The microscopic hallmarks of AD are senile plaques, in which β-amyloid is the major component, together with neurofibrillary tangles containing tau protein. The underlying disease process probably starts decades before the clinical onset of the disease (Blennow et al., 2006). The first symptoms of subjects with incipient AD are usually mild impairment of episodic memory. These individuals may fulfill the criteria of mild cognitive impairment (MCI), but they are not yet demented, because they have normal global cognitive functioning and activities of daily living are unaffected (Gauthier et al., 2006, Petersen, 2004). However, MCI is a prevalent syndrome in elderly, with a multitude of causes (Gauthier et al., 2006, Petersen, 2004). Although approximately 40–60% of the subjects with MCI develop AD within 4–6 years, many individuals with MCI are cognitively stable over time or even return to a normal functional level (Gauthier et al., 2006, Petersen, 2004).
Methods to accurately detect incipient AD among subjects with MCI are urgently needed (Blennow et al., 2006, Chong and Sahadevan, 2005). Several disease-modifying drugs, which aim to arrest the disease process, are under development, such as β-amyloid immunotherapy and β-sheet breakers (Blennow et al., 2006). Animal studies have shown that such disease-arresting therapies will probably be most efficient in the early stages of the disease, before the neurodegeneration has become too widespread and the subjects are already demented.
The cerebrospinal fluid (CSF) biomarkers tau and β-amyloid1–42 (Aβ42) can be used to detect preclinical AD in MCI populations with relatively high diagnostic accuracy (Blennow and Hampel, 2003, Hampel et al., 2004, Hansson et al., 2006). Measurements of regional cerebral blood flow (rCBF) can also be used to predict progression to AD in patients with MCI. Several studies using single photon emission computed tomography (SPECT) have shown that decreased rCBF in temporo-parietal cortex and posterior cingulate cortex can identify incipient AD among subjects with MCI (Borroni et al., 2006, Hirao et al., 2005, Huang et al., 2003, Huang et al., 2007, Johnson et al., 1998). For example, the hitherto largest rCBF study on patients with MCI, comprising 23 patients who developed AD and 54 patients who were cognitively stable during a follow-up period of 2.2 years, showed that reduced rCBF in the left parietal cortex can predict AD with an area under the receiver operating characteristic (ROC) curve of 75% (Huang et al., 2003). Similarly, results from flourodeoxyglucose (FDG)-positron emission tomography (PET) studies have shown decreased metabolism in temporo-parietal regions or posterior cingulate cortex in subjects with MCI who will subsequently develop AD (Arnaiz et al., 2001, Chetelat et al., 2005, Drzezga et al., 2005, Mosconi et al., 2004).
The diagnostic accuracy of SPECT for prediction of AD among subjects with MCI tends to be somewhat lower compared with CSF biomarkers (Chong and Sahadevan, 2005). Cerebrospinal fluid tau and Aβ42 are markers of the underlying molecular disease process and they seem to be altered very early in the neuropathological process (Blennow and Hampel, 2003, Hansson et al., 2006). However, these CSF biomarkers do not seem to predict the rate of disease progression, i.e. they are equally changed in MCI subjects who will develop AD within 1 year as in patients who will convert to AD after, e.g. 3 years (Hansson et al., 2006). On the other hand, changes in rCBF become more pronounced as the disease progresses (Huang et al., 2007, Kogure et al., 2000). Therefore, early changes in rCBF may provide the clinician with important information to identify those MCI patients who will run the risk to develop AD within a relatively short time period.
Only one study has so far assessed the diagnostic value of combining rCBF and CSF biomarkers for the prediction of AD. Okamura and colleagues measured rCBF and CSF tau (but not CSF Aβ42) at baseline in 7 cognitively stable MCI patients and in 17 patients with MCI who developed AD after a mean follow-up of 3 years (Okamura et al., 2002). The authors showed that a baseline index of CSF tau and rCBF in posterior cingulate cortex was useful in predicting AD (Okamura et al., 2002). In the present study, baseline rCBF assessments were performed in 167 MCI subjects, of whom 69 patients developed AD during a follow-up period of 4–6 years (see Section 3). Thirty-three age-matched, healthy elderly were used as controls. Moreover, baseline CSF was analyzed for Aβ42, total tau and phophorylated tau (P-tau) in 75–76% of the MCI subjects and 85% of the controls (see Section 3). The aims of the present study were the following: (1) to confirm the usefulness of rCBF-measurements to predict development of AD by using a larger number of patients with MCI and a longer follow-up time than earlier published studies; (2) to evaluate the added value of combining rCBF with CSF biomarkers to detect incipient AD; (3) to investigate whether rCBF or CSF markers can predict the rate of disease progression in the MCI patients who will later on develop AD.
Section snippets
MCI patients and healthy controls
One hundred and sixty seven patients with MCI, who underwent rCBF measurements at baseline, were recruited at Malmö University Hospital, Sweden. At baseline, they underwent physical, neurological and psychiatric examination, careful clinical history and functional assessment. Moreover, computed tomography (CT) of the brain and cognitive tests were performed. The criteria of MCI were those defined by Petersen and collaborators (Petersen, 2004, Petersen et al., 1999), which include: (i) memory
Subjects
Out of the 167 MCI subjects with rCBF measurements obtained at baseline, 70 patients (42%) were cognitively stable when followed for more than 4 years (mean follow-up time, 5.2 years; range, 4.0–6.8 years). Three subjects (2%) died before 4 years of follow-up. Due to uncertainty of their cognitive stability they were excluded from the study. During the 4–6 years of follow-up, 69 of the subjects with MCI at baseline (41%) developed AD. Moreover, 25 MCI patients (15%) progressed to other forms of
Discussion
We conducted a relatively large clinically based study, evaluating the use of combining rCBF and CSF biomarkers in patients with MCI to assess the risk of future development of AD. The relative risk of progression to AD was increased in patients with MCI who had decreased rCBF in parietal cortex at baseline (adjusted hazard ratio 3.1). Furthermore, the MCI patients with pathological levels of both CSF Aβ42 and tau at baseline were at high risk of developing AD (adjusted hazard ratio 13.4). The
Conflict of interest statement
None.
Acknowledgements
This work was supported by the Swedish Alzheimer foundation, the Segerfalk Foundation, Stiftelsen Gamla Tjänarinnor, the Swedish Research Council and Skane county council's research and development foundation.
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