Abstract
Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by (11)C-labelled Pittsburgh compound B positron emission tomography imaging. However, some individuals tolerate high brain amyloid-β loads without developing symptoms, while others progressively decline, suggesting that events in the brain downstream from amyloid-β deposition, such as regional brain atrophy rates, play an important role. The main purpose of this study was to understand the relationship between the regional distributions of increased amyloid-β and the regional distribution of increased brain atrophy rates in patients with mild cognitive impairment. To simultaneously capture the spatial distributions of amyloid-β and brain atrophy rates, we employed the statistical concept of parallel independent component analysis, an effective method for joint analysis of multimodal imaging data. Parallel independent component analysis identified significant relationships between two patterns of amyloid-β deposition and atrophy rates: (i) increased amyloid-β burden in the left precuneus/cuneus and medial-temporal regions was associated with increased brain atrophy rates in the left medial-temporal and parietal regions; and (ii) in contrast, increased amyloid-β burden in bilateral precuneus/cuneus and parietal regions was associated with increased brain atrophy rates in the right medial temporal regions. The spatial distribution of increased amyloid-β and the associated spatial distribution of increased brain atrophy rates embrace a characteristic pattern of brain structures known for a high vulnerability to Alzheimer's disease pathology, encouraging for the use of (11)C-labelled Pittsburgh compound B positron emission tomography measures as early indicators of Alzheimer's disease. These results may begin to shed light on the mechanisms by which amyloid-β deposition leads to neurodegeneration and cognitive decline and the development of a more specific Alzheimer's disease-specific imaging signature for diagnosis and use of this knowledge in the development of new anti-therapies for Alzheimer's disease.
Highlights
The formation of amyloid plaques in the brain, mainly consisting of insoluble amyloid-b protein fragments, is thought to be a major factor that leads to degradation of neurons and to the development of Alzheimer’s disease (Braak and Braak, 1991)
We tested two hypotheses: (i) increased amyloid-b levels in mild cognitive impairment are associated with increased brain atrophy rates; and (ii) the spatial distribution of elevated amyloid-b in mild cognitive impairment is associated with a characteristic pattern of increased and spatially distributed atrophy rates across brain structures typically involved in Alzheimer’s disease pathology, such as the medial temporal lobe, Amyloid-b burden and atrophy rate in mild cognitive impairment precuneus and posterior cingulate cortices
There are two major findings in this study: first, high amyloid-b levels, detected by 11C-labelled Pittsburgh compound B (11C-PiB) PET imaging, in mild cognitive impairment are associated with increased brain atrophy rates, detected by longitudinal MRI
Summary
The formation of amyloid plaques in the brain, mainly consisting of insoluble amyloid-b protein fragments, is thought to be a major factor that leads to degradation of neurons and to the development of Alzheimer’s disease (Braak and Braak, 1991). Studies of cognitively normal elderly subjects suggest that the presence of amyloid-b, as detected by 11C-PiB PET, is associated with a risk of developing symptomatic Alzheimer’s disease (Klunk et al, 2004; Mintun et al, 2006; Kemppainen et al, 2007; Morris et al, 2009). These results have raised the possibility that 11C-PiB PET may detect preclinical Alzheimer’s disease when treatment intervention may be most effective. To detect both spatially localized as well as spatially distributed effects of amyloid-b retention on the progression of regional brain atrophy we utilized novel multivariate statistical methods for image analysis
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