Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease
Rik Ossenkoppele, Brendan I Cohn-Sheehy, Renaud La Joie, Jacob W Vogel, Christiane Möller, Manja Lehmann, Bart N M van Berckel, William W Seeley, Yolande A Pijnenburg, Maria L Gorno-Tempini, Joel H Kramer, Frederik Barkhof, Howard J Rosen, Wiesje M van der Flier, William J Jagust, Bruce L Miller, Philip Scheltens, Gil D Rabinovici, Rik Ossenkoppele, Brendan I Cohn-Sheehy, Renaud La Joie, Jacob W Vogel, Christiane Möller, Manja Lehmann, Bart N M van Berckel, William W Seeley, Yolande A Pijnenburg, Maria L Gorno-Tempini, Joel H Kramer, Frederik Barkhof, Howard J Rosen, Wiesje M van der Flier, William J Jagust, Bruce L Miller, Philip Scheltens, Gil D Rabinovici
Abstract
Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, "visual variant," n=93), logopenic variant primary progressive aphasia (lvPPA, "language variant," n=74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n=114) and late age-of-onset (LOAD, >65 years, n=114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n=80). Even at the earliest clinical stage (CDR=0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD.
Keywords: Alzheimer's disease; atrophy; default mode network; early-onset dementia; language; logopenic variant primary progressive aphasia; magnetic resonance imaging (MRI); memory; posterior cortical atrophy; vision; voxel-based morphometry.
© 2015 Wiley Periodicals, Inc.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6869616/bin/HBM-36-4421-g001.jpg)
Figure 2
Atrophy maps of Alzheimer's disease…
Figure 2
Atrophy maps of Alzheimer's disease variants compared with controls. Regional differences between healthy…
Figure 3
The intersection of distinct Alzheimer's…
Figure 3
The intersection of distinct Alzheimer's disease phenotypes. Binarized maps of significant voxelwise differences…
Figure 4
Mean W‐score maps across quartiles…
Figure 4
Mean W‐score maps across quartiles for distinct Alzheimer's disease variants. Mean W‐score maps…
Figure 5
Mean W‐score atrophy values within…
Figure 5
Mean W‐score atrophy values within distinct intrinsic connectivity networks. The y‐axis represents mean…
- Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants.Lehmann M, Madison C, Ghosh PM, Miller ZA, Greicius MD, Kramer JH, Coppola G, Miller BL, Jagust WJ, Gorno-Tempini ML, Seeley WW, Rabinovici GD. Lehmann M, et al. Neurobiol Aging. 2015 Oct;36(10):2678-86. doi: 10.1016/j.neurobiolaging.2015.06.029. Epub 2015 Jul 16. Neurobiol Aging. 2015. PMID: 26242705 Free PMC article.
- White Matter Degeneration in Atypical Alzheimer Disease.Caso F, Agosta F, Mattavelli D, Migliaccio R, Canu E, Magnani G, Marcone A, Copetti M, Falautano M, Comi G, Falini A, Filippi M. Caso F, et al. Radiology. 2015 Oct;277(1):162-72. doi: 10.1148/radiol.2015142766. Epub 2015 May 27. Radiology. 2015. PMID: 26018810
- Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease.Lehmann M, Ghosh PM, Madison C, Laforce R Jr, Corbetta-Rastelli C, Weiner MW, Greicius MD, Seeley WW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Lehmann M, et al. Brain. 2013 Mar;136(Pt 3):844-58. doi: 10.1093/brain/aws327. Epub 2013 Jan 28. Brain. 2013. PMID: 23358601 Free PMC article.
- [Posterior cortical atrophy--a new dementia syndrome or a form of Alzheimer's disease?].Pantel J, Schröder J. Pantel J, et al. Fortschr Neurol Psychiatr. 1996 Dec;64(12):492-508. doi: 10.1055/s-2007-996595. Fortschr Neurol Psychiatr. 1996. PMID: 9053390 Review. German.
- Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies.Chapleau M, Aldebert J, Montembeault M, Brambati SM. Chapleau M, et al. J Alzheimers Dis. 2016 Oct 4;54(3):941-955. doi: 10.3233/JAD-160382. J Alzheimers Dis. 2016. PMID: 27567843 Review.
- Pathway-specific polygenic risk scores correlate with clinical status and Alzheimer's-related biomarkers.Schork NJ, Elman JA. Schork NJ, et al. Res Sq. 2023 Mar 1:rs.3.rs-2583037. doi: 10.21203/rs.3.rs-2583037/v1. Preprint. Res Sq. 2023. PMID: 36909609 Free PMC article.
- Diagnosis and Management of Posterior Cortical Atrophy.Yong KXX, Graff-Radford J, Ahmed S, Chapleau M, Ossenkoppele R, Putcha D, Rabinovici GD, Suarez-Gonzalez A, Schott JM, Crutch S, Harding E. Yong KXX, et al. Curr Treat Options Neurol. 2023;25(2):23-43. doi: 10.1007/s11940-022-00745-0. Epub 2023 Feb 8. Curr Treat Options Neurol. 2023. PMID: 36820004 Free PMC article. Review.
- Early-onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset.Tort-Merino A, Falgàs N, Allen IE, Balasa M, Olives J, Contador J, Castellví M, Juncà-Parella J, Guillén N, Borrego-Écija S, Bosch B, Fernández-Villullas G, Ramos-Campoy O, Antonell A, Rami L, Sánchez-Valle R, Lladó A. Tort-Merino A, et al. Ann Clin Transl Neurol. 2022 Dec;9(12):1962-1973. doi: 10.1002/acn3.51689. Epub 2022 Nov 17. Ann Clin Transl Neurol. 2022. PMID: 36398437 Free PMC article.
- A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer's disease.Inglese M, Patel N, Linton-Reid K, Loreto F, Win Z, Perry RJ, Carswell C, Grech-Sollars M, Crum WR, Lu H, Malhotra PA; Alzheimer’s Disease Neuroimaging Initiative; Aboagye EO. Inglese M, et al. Commun Med (Lond). 2022 Jun 20;2(1):70. doi: 10.1038/s43856-022-00133-4. Commun Med (Lond). 2022. PMID: 36372852
- Linking Personalized Brain Atrophy to Schizophrenia Network and Treatment Response.Ji GJ, Zalesky A, Wang Y, He K, Wang L, Du R, Sun J, Bai T, Chen X, Tian Y, Zhu C, Wang K. Ji GJ, et al. Schizophr Bull. 2023 Jan 3;49(1):43-52. doi: 10.1093/schbul/sbac162. Schizophr Bull. 2023. PMID: 36318234 Clinical Trial.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Age of Onset
- Aged
- Alzheimer Disease / classification
- Alzheimer Disease / pathology*
- Alzheimer Disease / physiopathology
- Animals
- Aphasia, Primary Progressive / pathology*
- Aphasia, Primary Progressive / physiopathology
- Atrophy / pathology
- Cerebral Cortex / pathology*
- Cerebral Cortex / physiopathology
- Female
- Humans
- Male
- Middle Aged
- Nerve Net / pathology*
- Nerve Net / physiopathology
- Phenotype
- Syndrome
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6869616/bin/HBM-36-4421-g002.jpg)
Figure 3
The intersection of distinct Alzheimer's…
Figure 3
The intersection of distinct Alzheimer's disease phenotypes. Binarized maps of significant voxelwise differences…
Figure 4
Mean W‐score maps across quartiles…
Figure 4
Mean W‐score maps across quartiles for distinct Alzheimer's disease variants. Mean W‐score maps…
Figure 5
Mean W‐score atrophy values within…
Figure 5
Mean W‐score atrophy values within distinct intrinsic connectivity networks. The y‐axis represents mean…
- Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants.Lehmann M, Madison C, Ghosh PM, Miller ZA, Greicius MD, Kramer JH, Coppola G, Miller BL, Jagust WJ, Gorno-Tempini ML, Seeley WW, Rabinovici GD. Lehmann M, et al. Neurobiol Aging. 2015 Oct;36(10):2678-86. doi: 10.1016/j.neurobiolaging.2015.06.029. Epub 2015 Jul 16. Neurobiol Aging. 2015. PMID: 26242705 Free PMC article.
- White Matter Degeneration in Atypical Alzheimer Disease.Caso F, Agosta F, Mattavelli D, Migliaccio R, Canu E, Magnani G, Marcone A, Copetti M, Falautano M, Comi G, Falini A, Filippi M. Caso F, et al. Radiology. 2015 Oct;277(1):162-72. doi: 10.1148/radiol.2015142766. Epub 2015 May 27. Radiology. 2015. PMID: 26018810
- Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease.Lehmann M, Ghosh PM, Madison C, Laforce R Jr, Corbetta-Rastelli C, Weiner MW, Greicius MD, Seeley WW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Lehmann M, et al. Brain. 2013 Mar;136(Pt 3):844-58. doi: 10.1093/brain/aws327. Epub 2013 Jan 28. Brain. 2013. PMID: 23358601 Free PMC article.
- [Posterior cortical atrophy--a new dementia syndrome or a form of Alzheimer's disease?].Pantel J, Schröder J. Pantel J, et al. Fortschr Neurol Psychiatr. 1996 Dec;64(12):492-508. doi: 10.1055/s-2007-996595. Fortschr Neurol Psychiatr. 1996. PMID: 9053390 Review. German.
- Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies.Chapleau M, Aldebert J, Montembeault M, Brambati SM. Chapleau M, et al. J Alzheimers Dis. 2016 Oct 4;54(3):941-955. doi: 10.3233/JAD-160382. J Alzheimers Dis. 2016. PMID: 27567843 Review.
- Pathway-specific polygenic risk scores correlate with clinical status and Alzheimer's-related biomarkers.Schork NJ, Elman JA. Schork NJ, et al. Res Sq. 2023 Mar 1:rs.3.rs-2583037. doi: 10.21203/rs.3.rs-2583037/v1. Preprint. Res Sq. 2023. PMID: 36909609 Free PMC article.
- Diagnosis and Management of Posterior Cortical Atrophy.Yong KXX, Graff-Radford J, Ahmed S, Chapleau M, Ossenkoppele R, Putcha D, Rabinovici GD, Suarez-Gonzalez A, Schott JM, Crutch S, Harding E. Yong KXX, et al. Curr Treat Options Neurol. 2023;25(2):23-43. doi: 10.1007/s11940-022-00745-0. Epub 2023 Feb 8. Curr Treat Options Neurol. 2023. PMID: 36820004 Free PMC article. Review.
- Early-onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset.Tort-Merino A, Falgàs N, Allen IE, Balasa M, Olives J, Contador J, Castellví M, Juncà-Parella J, Guillén N, Borrego-Écija S, Bosch B, Fernández-Villullas G, Ramos-Campoy O, Antonell A, Rami L, Sánchez-Valle R, Lladó A. Tort-Merino A, et al. Ann Clin Transl Neurol. 2022 Dec;9(12):1962-1973. doi: 10.1002/acn3.51689. Epub 2022 Nov 17. Ann Clin Transl Neurol. 2022. PMID: 36398437 Free PMC article.
- A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer's disease.Inglese M, Patel N, Linton-Reid K, Loreto F, Win Z, Perry RJ, Carswell C, Grech-Sollars M, Crum WR, Lu H, Malhotra PA; Alzheimer’s Disease Neuroimaging Initiative; Aboagye EO. Inglese M, et al. Commun Med (Lond). 2022 Jun 20;2(1):70. doi: 10.1038/s43856-022-00133-4. Commun Med (Lond). 2022. PMID: 36372852
- Linking Personalized Brain Atrophy to Schizophrenia Network and Treatment Response.Ji GJ, Zalesky A, Wang Y, He K, Wang L, Du R, Sun J, Bai T, Chen X, Tian Y, Zhu C, Wang K. Ji GJ, et al. Schizophr Bull. 2023 Jan 3;49(1):43-52. doi: 10.1093/schbul/sbac162. Schizophr Bull. 2023. PMID: 36318234 Clinical Trial.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Age of Onset
- Aged
- Alzheimer Disease / classification
- Alzheimer Disease / pathology*
- Alzheimer Disease / physiopathology
- Animals
- Aphasia, Primary Progressive / pathology*
- Aphasia, Primary Progressive / physiopathology
- Atrophy / pathology
- Cerebral Cortex / pathology*
- Cerebral Cortex / physiopathology
- Female
- Humans
- Male
- Middle Aged
- Nerve Net / pathology*
- Nerve Net / physiopathology
- Phenotype
- Syndrome
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6869616/bin/HBM-36-4421-g003.jpg)
Figure 4
Mean W‐score maps across quartiles…
Figure 4
Mean W‐score maps across quartiles for distinct Alzheimer's disease variants. Mean W‐score maps…
Figure 5
Mean W‐score atrophy values within…
Figure 5
Mean W‐score atrophy values within distinct intrinsic connectivity networks. The y‐axis represents mean…
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6869616/bin/HBM-36-4421-g004.jpg)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6869616/bin/HBM-36-4421-g005.jpg)
Source: PubMed