Neural correlates of Alzheimer's disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients

Abstract

Alzheimer's disease is the most common form of dementia. Its prodromal stage amnestic mild cognitive impairment is characterized by deficits of anterograde episodic memory. The development of standardized imaging inclusion criteria has to be regarded as a prerequisite for future diagnostic systems. Moreover, successful treatment requires isolating imaging markers predicting the disease. Accordingly, we conducted a systematic and quantitative meta-analysis to reveal the prototypical neural correlates of Alzheimer's disease and its prodromal stage. To prevent any a priori assumptions and enable a data-driven approach only studies applying quantitative automated whole brain analysis were included. Finally, 40 studies were identified involving 1351 patients and 1097 healthy control subjects reporting either atrophy or decreases in glucose utilization and perfusion. The currently most sophisticated and best-validated of coordinate-based voxel-wise meta-analyses was applied (anatomical likelihood estimates). The meta-analysis reveals that early Alzheimer's disease affects structurally the (trans-)entorhinal and hippocampal regions, functionally the inferior parietal lobules and precuneus. Results further may suggest that atrophy in the (trans-)entorhinal area/hippocampus and hypometabolism/hypoperfusion in the inferior parietal lobules predicts most reliably the progression from amnestic mild cognitive impairment to Alzheimer's disease, whereas changes in the posterior cingulate cortex and precuneus are unspecific. Fully developed Alzheimer's disease involved additionally a frontomedian-thalamic network. In conclusion, the meta-analysis characterizes the prototypical neural substrates of Alzheimer's disease and its prodromal stage amnestic mild cognitive impairment. By isolating predictive markers it enables successful treatment strategies in the future and contributes to standardized imaging inclusion criteria for Alzheimer's disease as suggested for future diagnostic systems.

Figure 1

Summary of the meta-analysis flow according to the QUOROM statement (Moher et al., 1999). Number of studies reported for mild cognitive impairment/Alzheimer's disease (AD).

Figure 2

Results of the quantitative meta-analyses (anatomical likelihood estimates) for amnestic mild cognitive impairment (MCI). Reductions of glucose utilization (FDG-PET, fluorodeoxyglucose positron emission tomography), of perfusion or atrophy (MRI, magnetic resonance imaging). Left side is left.

Figure 3

Results of the quantitative meta-analyses (anatomical likelihood estimates) for Alzheimer's disease (AD). Reductions of glucose utilization (FDG-PET, fluorodeoxyglucose positron emission tomography), of perfusion or atrophy (MRI, magnetic resonance imaging). Left side is left.

Figure 4

Prediction of Alzheimer's disease. Neural impairments in converters that developed from mild amnestic cognitive impairment (MCI) to Alzheimer's disease later (Conv), and non-converters with stable mild cognitive impairment (Nconv) according to the quantitative meta-analyses (anatomical likelihood estimates, ALE). Co control subjects. First three upper rows ALE maps for contrasts in the single studies. Lower row comparison between the first and second ALE map. Studies reporting reductions of glucose utilization, of perfusion or atrophy were pooled. Left side is left.