Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum
- Department of Neurology, National Neuroscience Institute, Singapore
- Duke-NUS Medical School, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore
- Centre for Sleep and Cognition and Centre for Translational MR Research,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal, and Departments of Neurology, Neurosurgery, Psychiatry, Pharmacology and Therapeutics, McGill University, Canada
- Montreal Neurological Institute, McGill University, Canada
- Department of Neurology & Neurosurgery, McGill University, Canada
- Department of Electrical and Computer Engineering, National University of Singapore, Singapore
- Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore
Figures
Figure 1 with 2 supplements
Study design schematic.
Seven hundred and eight participants with either healthy cognition (CN), mild cognitive impairment (MCI) or dementia were studied. Twelve brain seeds covering the key regions of hippocampus, the …
Figure 1—figure supplement 1
Flowchart of participant pool selection.
For the main analysis, in total 812 participants who underwent 3T MRI scan were selected. Of these participants, group comparisons of the grey matter volume and brain metabolism were performed …
Figure 1—figure supplement 2
Subject ordering for SVC modelling within each pathology group.
The participants were ordered by their diagnosis. In the main ordering method (panel A), CN was followed by MCI, and MCI was followed by probable AD. The validation ordering method (panel B) did not …
Figure 2 with 1 supplement
The integrity of brain metabolic networks in participants with and without amyloid pathology across cognitive stages.
(A) Brain slices of metabolic covariance networks associated with each brain seed. Brain metabolic network resemabled canonical brain networks. The intensity of colorbar represents bootstrap ratios, …
Figure 2—figure supplement 1
The integrity of brain metabolic networks in participants with and without amyloid pathology across cognitive stages (validation dataset 1).
(A) Brain slices of metabolic covariance networks associated with each brain seed defined from FDG-PET data highlighted in blue circles. Brain metabolic network resemabled canonical brain networks. …
Figure 3 with 1 supplement
The integrity of brain structural networks in participants with and without amyloid pathology across cognitive stages.
(A) Brain slices of structural covariance networks associated with each brain seed. The intensity of colorbar represents bootstrap ratios, derived from dividing the weight of the singular-vector by …
Figure 3—figure supplement 1
The integrity of brain structural networks in participants with and without amyloid pathology across cognitive stages (validation dataset 1).
(A) Brain slices of structural covariance networks associated with each brain seed defined from grey matter volume data highlighted in blue circles. The intensity of colorbar represents bootstrap …
Figure 4 with 1 supplement
Brain metabolic and structural networks had differential stage-dependent associations with memory in amyloid positive individuals.
Data from the main dataset (panel A) and validation dataset 1 (panel B) exhibited consistent stage-dependent memory-network association trajectory from cognitively normal to dementia stage in …
Figure 4—figure supplement 1
Differential stage-dependent associations of metabolic and structural network scores with memory impairment in amyloid positive individuals (validation analyses).
Solid curves represent the mean associations (beta coefficients) of brain network scores with memory as a function of advancing AD continuum estimated from 100 replicates (metabolic in red; …
Figure 5 with 4 supplements
Stage-dependent association of brain hippocampal structural network with memory performance in A-T- and A-T +pathology groups.
Data from the main dataset (panel A) and validation dataset 1 (panel B) exhibited consistent stage-dependent memory-network association trajectory from cognitively normal stage to dementia stage in …
Figure 5—figure supplement 1
Differential stage-dependent associations of metabolic and structural network scores with memory impairment in A-T- and A-T +pathology groups (validation analyses).
Solid curves represent the mean associations (beta coefficients) of brain network scores with memory as a function of advancing AD continuum estimated from 100 replicates (metabolic in red; …
Figure 5—figure supplement 2
Differential stage-dependent associations of demographic variables with memory impairment in different pathology groups (main dataset).
Solid curves represent the mean associations (beta coefficients) of brain network scores with memory as a function of advancing AD continuum estimated from 100 replicates. The dashed curves …
Figure 5—figure supplement 3
Differential stage-dependent associations of demographical variables with memory impairment in different pathology group (validation dataset 1).
Solid curves represent the mean associations (beta coefficients) of brain network scores with memory as a function of advancing AD continuum estimated from 100 replicates. The dashed curves …
Figure 5—figure supplement 4
Variable selection frequency distribution for permuted datasets using sparse varying-coefficient (SVC) model.
To assess the specificity of the selected networks, we randomly permuted the memory scores 100 times across the participants. For each of the 100 permuted data sets, we repeated the SVC modelling …
Author response image 1
Metabolic sensorimotor network and the network scores.
A. Brain slice of metabolic covariance network associated with the primary motor cortex seed. B. The summary of individual-level metabolic network scores (mean and median) presented in half-violin …
Tables
Table 1
Subject demographics for the main study cohort.
| A-T- | A-T+ | A+T-/A+T + | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CN | MCI | probable AD | CN | MCI | probable AD | CN | MCI | probable AD | |||
| N | 30 | 74 | 4 | 80 | 75 | 7 | 85 | 225 | 128 | ||
| Age, years | 65.12~85.16 | 56.08~88.51 | 69.56~90.50 | 56.53~84.47 | 55.15~88.83 | 60.79~80.76 | 60.19~90.08 | 55.38~91.57 | 55.96~90.46 | ||
| 72.24±4.54 | 69.78±7.20d | 77.37±9.11m | 71.95±5.87 | 70.21±8.16 | 74.57±7.70 | 75.37±6.59 | 73.17±6.93 | 74.12±8.19 | |||
| Gender (M/F) | 12/18 | 39/35 | 4/0 | 45/35 | 38/37 | 6/1 | 37/48 | 127/98 | 72/56 | ||
| Handedness (R/L) | 29/1 | 60/14 | 4/0 | 69/11 | 67/8 | 7/0 | 79/6 | 203/22 | 118/10 | ||
| Education, years | 16.63±2.68 | 16.45±2.59 | 17.50±1.29 | 16.88±2.67 | 16.00±2.65 | 16.71±2.43 | 16.34±2.36 | 16.12±2.74 | 15.78±2.71 | ||
| APOE e4 (+/-) | 6/24 | 16/58 | 0/4 | 16/64 | 17/58 | 1/6 | 38/47md | 140/85cd | 93/35cm | ||
| Memory | 1.28±0.66md | 0.75±0.64cd | –0.12±0.68cm | 1.17±0.57md | 0.55±0.62cd | –0.40±0.67cm | 0.97±0.63md | 0.20±0.63cd | –0.87±0.53cm | ||
| MMSE | 28.70±1.68d | 28.62±1.31d | 25.75±2.36cm | 29.15±0.99md | 28.29±1.64cd | 23.86±2.19cm | 29.02±1.17md | 27.81±1.86cd | 23.21±2.24cm | ||
| CDR-SOB | 0.02±0.09md | 1.22±0.60cd | 4.38±3.04cm | 0.05±0.15md | 1.20±0.76cd | 4.57±1.40cm | 0.05±0.17md | 1.53±0.90cd | 4.64±1.70cm | ||
| ICV | 1523.77±152.57 | 1520.05±127.78 | 1540.83±36.50 | 1554.01±128.10 | 1559.14±147.96 | 1566.75±221.76 | 1524.87±148.29 | 1558.61±148.25 | 1549.78±163.05 | ||
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Note: Data on age are range and mean ± SD. Data on education, ICV, and memory are mean ± SD. Data on memory are in z-scores. Abbreviations: CN = cognitively normal; MCI = mild cognitive impairment; AD = Alzheimer's disease; A = β-amyloid; T = tau; ‘+’ = positive; ‘-’ = negative; y = years; M = male; F = female; R = right; L = left; MMSE = Mini-Mental State Exam; CDR-SOB = Clinical Dementia Rating Sum of Box; ICV = intracranial volume. Superscripts (‘c’, ‘m’, ‘d’) represent significant group difference with CN, MCI and probable AD, respectively.
Additional files
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Supplementary file 1
Participants demographics for network seed definition step.
- https://cdn.elifesciences.org/articles/77745/elife-77745-supp1-v2.docx
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Supplementary file 2
Study participant demographics of the validation dataset 1 for the PLS-SVC model.
- https://cdn.elifesciences.org/articles/77745/elife-77745-supp2-v2.docx
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Supplementary file 3
Study participant demographics of the validation dataset 2 for the SVC model.
- https://cdn.elifesciences.org/articles/77745/elife-77745-supp3-v2.docx
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Supplementary file 4
The coordinates of the peak foci of regions showing difference in metabolism and grey matter volume between probable AD and healthy controls.
- https://cdn.elifesciences.org/articles/77745/elife-77745-supp4-v2.docx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/77745/elife-77745-transrepform1-v2.docx
