In vivo cortical diffusion imaging relates to Alzheimer’s disease neuropathology
Authors: Torso Mario , Ridgway Gerard R. , Valotti Michele , Hardingham Ian , Chance Steven A. ,   for the National Alzheimer’s Coordinating Center, Brewer James , Lopez Oscar , Hyman Bradley , Grabowski Thomas , Sano Mary , Chui Helena , Albert Marilyn , Morris John , Kaye Jeffrey , Wisniewski Thomas , Small Scott , Trojanowski John , DeCarli Charles , Saykin Andrew , Bennett David , Rosenberg Roger , Kowall Neil , Vassar Robert , LaFerla Frank , Petersen Ronald , Reiman Eric , Miller Bruce , Levey Allan , Van Eldik Linda , Asthana Sanjay , Swerdlow Russell , Golde Todd , Strittmatter Stephen , Henderson Victor , Craft Suzanne , Paulson Henry , Seshadri Sudha , Roberson Erik , Sabbagh Marwan , Rosenberg Gary , Jefferson Angela , Whitson Heather , Leverenz James ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

Abstract
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.