White Matter Microstructural Changes in the Cingulum Bundle of the Hippocampus in Alzheimer's Disease

Abstract

Alzheimer’s disease (AD), the most common dementia, is the seventh leading cause of death for adults in the US. Recent FDA-approved therapeutics targeting hallmark amyloid pathology may slow but do not yet halt the disease. Thus, it is likely that other factors, such as neurodegeneration, play a role in disease development. Compromised white matter (WM) microstructural integrity may be a promising biomarker for disease progression, as it has been demonstrated in both preclinical and clinical AD. WM microstructural changes can be estimated using diffusion tensor imaging (DTI), a noninvasive imaging modality which measures the diffusion of water molecules within brain tissue. First, literature describing a biological relationship between signaling pathways involved in both insufficient myelin-repair mechanisms and AD pathology was assessed to establish a foundation for studying WM in the context of AD. Then, DTI was used to assess possible WM microstructural changes of the cingulum bundle of the hippocampus (CBH), a disease-relevant region, in the KBASE cohort of older Korean adults on the AD continuum. Similar to White cohorts of European ancestry, DTI values corresponding to worsening WM microstructure occurred in a stepwise fashion across diagnostic stages and were associated with both cognition and amyloid deposition. In a sample of older adults from the Indiana Memory and Aging Study (IMAS), CBH microstructure was a sensitive biomarker of preclinical conversion from cognitively unimpaired status to mild cognitive impairment. Finally, a novel extension of the T1/T2 weighted ratio imaging method, thought to estimate myelin- related tissue integrity, yielded values in IMAS subjects reflective of previously observed DTI patterns. The complex interplay between amyloid, tau, and neurodegeneration in AD is not yet fully characterized. This research shows decreased integrity of WM microstructure in the CBH, which may be useful as a biomarker of early disease conversion to MCI.