Role of β-Amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment
Related Experiment Video
Updated: Apr 1, 2026
Hybrid PET/MRI Imaging of Alzheimer's Disease Based on 18F-AV-1451
Published on: April 18, 2025
David S Knopman1, Clifford R Jack2, Emily S Lundt3
1Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota2Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota.
Importance:
To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).
Objective:
To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.
Design, Setting, And Participants:
Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography.
Main Outcomes And Measures:
Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions.
Results:
In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups.
Conclusions And Relevance:
Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
Insights
Individuals with mild cognitive impairment (MCI) and both amyloidosis and neurodegeneration (A+N+) show worsening brain metabolism and volume. Those with suspected non-Alzheimer pathophysiology (A-N+) do not exhibit these changes.
Area of Science:
- Neurology
- Neuroimaging
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) pathophysiology involves β-amyloidosis and neurodegeneration.
- Mild cognitive impairment (MCI) is a transitional stage preceding AD dementia.
- Understanding the progression of AD pathology in MCI is crucial for early intervention.
Purpose of the Study:
- To model how β-amyloidosis and neurodegeneration predict hypometabolism and atrophy expansion in MCI.
- To define the role of these pathologies in the progression of cortical changes in MCI.
Main Methods:
- Longitudinal observational study (2006-2015) of 96 participants with MCI (>70 years).
- Characterization of participants based on β-amyloidosis (A+ or A-) and neurodegeneration (N+ or N-) using PET imaging (11C-Pittsburgh compound B and 18F-FDG).
- Assessment of regional gray matter volumes and FDG uptake (SUVR) in temporal and parietal regions.
Main Results:
- The A+N+ group showed significantly lower baseline FDG SUVR and gray matter volume compared to A+N- and A-N- groups.
- A+N+ individuals exhibited significant longitudinal declines in FDG SUVR and gray matter volume in multiple brain regions.
- The A-N+ group (suspected non-Alzheimer pathophysiology) did not show significant longitudinal declines compared to control groups.
Conclusions:
- The A+N+ profile in MCI predicts worsening metabolism and volume in temporal and parietal areas, indicating early isocortical involvement in the AD pathway.
- Individuals with MCI and suspected non-Alzheimer pathophysiology lack a distinct longitudinal volumetric or metabolic profile.
- These findings support a model where combined amyloidosis and neurodegeneration drive AD progression from MCI.
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