TY - JOUR
T1 - In vivo cortical diffusion imaging relates to Alzheimer’s disease neuropathology
AU - Torso, Mario
AU - Ridgway, Gerard R.
AU - Valotti, Michele
AU - Hardingham, Ian
AU - Chance, Steven A.
AU - Brewer, James
AU - Lopez, Oscar
AU - Hyman, Bradley
AU - Grabowski, Thomas
AU - Sano, Mary
AU - Chui, Helena
AU - Albert, Marilyn
AU - Morris, John
AU - Kaye, Jeffrey
AU - Wisniewski, Thomas
AU - Small, Scott
AU - Trojanowski, John
AU - DeCarli, Charles
AU - Saykin, Andrew
AU - Bennett, David
AU - Rosenberg, Roger
AU - Kowall, Neil
AU - Vassar, Robert
AU - LaFerla, Frank
AU - Petersen, Ronald
AU - Reiman, Eric
AU - Miller, Bruce
AU - Levey, Allan
AU - Van Eldik, Linda
AU - Asthana, Sanjay
AU - Swerdlow, Russell
AU - Golde, Todd
AU - Strittmatter, Stephen
AU - Henderson, Victor
AU - Craft, Suzanne
AU - Paulson, Henry
AU - Seshadri, Sudha
AU - Roberson, Erik
AU - Sabbagh, Marwan
AU - Rosenberg, Gary
AU - Jefferson, Angela
AU - Whitson, Heather
AU - Leverenz, James
N1 - Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - Background: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer’s disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Methods: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the “ABC score” from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed. Results: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Conclusions: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
AB - Background: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer’s disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Methods: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the “ABC score” from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed. Results: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Conclusions: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
KW - Alzheimer’s disease neuropathological changes
KW - Autopsy
KW - Cortex
KW - Cortical diffusivity
KW - Diffusion tensor imaging
KW - Minicolumns
UR - http://www.scopus.com/inward/record.url?scp=85173762842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85173762842&partnerID=8YFLogxK
U2 - 10.1186/s13195-023-01309-3
DO - 10.1186/s13195-023-01309-3
M3 - Article
C2 - 37794477
AN - SCOPUS:85173762842
SN - 1758-9193
VL - 15
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 165
ER -