Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

McKenna E Williams¹, Jeremy A Elman², Tyler R Bell², Anders M Dale³, Lisa T Eyler⁴, Christine Fennema-Notestine⁵, Carol E Franz², Nathan A Gillespie⁶, Donald J Hagler Jr⁷, Michael J Lyons⁸, Linda K McEvoy⁷, Michael C Neale⁶, Matthew S Panizzon², Chandra A Reynolds⁹, Mark Sanderson-Cimino¹⁰, William S Kremen²

Affiliations

¹ Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. Electronic address: mewillia@health.ucsd.edu.
² Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ Department of Radiology, University of California San Diego, La Jolla, CA, USA; Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Desert Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA.
⁵ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁶ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁷ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
⁹ Department of Psychology, University of California Riverside, Riverside, CA, USA.
¹⁰ Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

PMID: 37343448
PMCID: PMC10676195
DOI: 10.1016/j.neurobiolaging.2023.05.004

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

McKenna E Williams et al. Neurobiol Aging. 2023 Sep.

. 2023 Sep:129:185-194.

doi: 10.1016/j.neurobiolaging.2023.05.004. Epub 2023 May 9.

Authors

Affiliations

¹ Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. Electronic address: mewillia@health.ucsd.edu.
² Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ Department of Radiology, University of California San Diego, La Jolla, CA, USA; Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Desert Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA.
⁵ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁶ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁷ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
⁹ Department of Psychology, University of California Riverside, Riverside, CA, USA.
¹⁰ Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

PMID: 37343448
PMCID: PMC10676195
DOI: 10.1016/j.neurobiolaging.2023.05.004

Abstract

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

Keywords: Alzheimer’s disease; Cortical thickness; Mean diffusivity; Neuroimaging; Signatures.

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Figures

**Figure 1.. Linear relationships among AD signatures and *global* mean cortical thickness in cognitively normal individuals.**
Overall, higher MD signatures are associated with lower thickness/volume signatures (a). The signatures display strong relationships with *global* mean cortical thickness (b and c). These models include only CN individuals; partial residuals after controlling for age and scanner strength differences are displayed.

**Figure 2.. Subgroup differences in a) maintenance of thickness/volume signatures, b) level of global mean cortical thickness, c) level of MD signatures, and d) maintenance of memory performance.**
Both groups had higher cortical thickness/volume signatures at wave 1 and differed in MD signatures (high vs. low). However, the HighCT-HighMD group had lower cortical thickness/volume scores compared to the HighCT-LowMD group at baseline, so all models controlled for baseline values of this measure. All were CU at wave 1. Model D additionally controls for baseline memory performance.

**Figure 3.**
Correlations between cortical thickness or hippocampal volume and MD within individual regions belonging to each signature for a) HighCT-LowMD subgroup and b) HighCT-HighMD subgroup. Warmer colors (orange, red) represent positive correlations, and cooler colors (green, blue) represent negative correlations. White asterisks indicate significant regional correlations after FDR correction for multiple comparisons.

**Figure 4.. Proposed models of changes in cortical thickness/volume and cortical MD along the AD continuum.**
Background gradient colors represent stages (blue = age-related changes not tied to a pathological process; yellow = increased risk for AD; orange = clinical AD). a) Model adapted from Montal and colleagues (2018). Biphasic changes in MD mirror changes in cortical thickness. b) Model in line with results from VETSA. According to our model, changes in cortical MD precede changes in cortical thickness/volume, and increased cortical MD is associated with AD-related changes. Cortical thickness/volume follows a biphasic pattern of changes, whereby it initially increases among individuals at-risk for AD-related changes before decreasing with progression of disease pathology and onset of clinical symptoms. A transient decrease in MD was not observed. If MD follows a biphasic trajectory as previously suggested, it may be that the inflection point occurred prior to our baseline timepoint. Alternatively, AD-related change in MD may by monotonic. These two possibilities are indicated with dashed lines. c) Proposed trajectory for individuals at lower risk of developing AD (e.g., HighCT-LowMD subgroup), depicting relatively stable thickness/volume and MD signatures. AD-related changes may still emerge for this group, but would occur later according to this model.

See this image and copyright information in PMC

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Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

Affiliations

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical