Quantitative susceptibility mapping as an imaging biomarker for Alzheimer's disease: The expectations and limitations

Alzheimer's disease (AD) is the most common type of dementia and a distressing diagnosis for individuals and caregivers. Researchers and clinical trials have mainly focused on beta-amyloid plaques, which are hypothesized to be one of the most important factors for neurodegeneration in AD. Meanwhile, recent clinicopathological and radiological studies have shown closer associations of tau pathology rather than beta-amyloid pathology with the onset and progression of Alzheimer's symptoms. Toward a biological definition of biomarker-based research framework for AD, the 2018 National Institute on Aging-Alzheimer's Association working group has updated the ATN classification system for stratifying disease status in accordance with relevant pathological biomarker profiles, such as cerebral beta-amyloid deposition, hyperphosphorylated tau, and neurodegeneration. In addition, altered iron metabolism has been considered to interact with abnormal proteins related to AD pathology thorough generating oxidative stress, as some prior histochemical and histopathological studies supported this iron-mediated pathomechanism. Quantitative susceptibility mapping (QSM) has recently become more popular as a non-invasive magnetic resonance technique to quantify local tissue susceptibility with high spatial resolution, which is sensitive to the presence of iron. The association of cerebral susceptibility values with other pathological biomarkers for AD has been investigated using various QSM techniques; however, direct evidence of these associations remains elusive. In this review, we first briefly describe the principles of QSM. Second, we focus on a large variety of QSM applications, ranging from common applications, such as cerebral iron deposition, to more recent applications, such as the assessment of impaired myelination, quantification of venous oxygen saturation, and measurement of blood- brain barrier function in clinical settings for AD. Third, we mention the relationships among QSM, established biomarkers, and cognitive performance in AD. Finally, we discuss the role of QSM as an imaging biomarker as well as the expectations and limitations of clinically useful diagnostic and therapeutic implications for AD.

Automated summary

This review summarizes the latest advances in the diagnosis and pathological mechanisms of Alzheimer's disease, including the closer association of tau pathology rather than beta-amyloid pathology with the onset and progression of Alzheimer's symptoms, as well as the pathomechanism of altered iron metabolism interacting with abnormal proteins related to AD pathology. The study also investigates the association of cerebral susceptibility values with other pathological biomarkers for AD.