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

Abstract

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 β-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 β-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 β-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.

Brain iron content in cerebral amyloid angiopathy using quantitative susceptibility mapping

“…Other studies of QSM in AD have had mixed findings, either finding no differences in iron content or greater iron when compared to controls in the occipital lobe (Ramos et al, 2014;Damulina et al, 2020;Rao et al, 2022). Overall, studies found increased iron in subcortical regions (globus pallidus, caudate, putamen, and hippocampus) when compared to healthy controls but comparisons of cortical regions were inconsistent (Li et al, 2020;Uchida et al, 2022).…”

Contributions of blood–brain barrier imaging to neurovascular unit pathophysiology of Alzheimer’s disease and related dementias

“…Blood-derived substances include fibrinogen, thrombin, hemoglobin, iron-containing hemosiderin, free iron, plasmin, environmental toxins and metals, and possibly, microbial pathogens, which can have toxic neuronal effects and lead to oxidative stress and activation of the proinflammatory microglial response, resulting in the pathological changes seen in AD ( Zlokovic, 2011 ). Quantitative susceptibility mapping (QSM) has been available as an auxiliary biomarker that reflects disease severity in AD to measure brain tissue iron concentration, which is partly due to the BBB leakage caused by the damaged NVU ( Cogswell et al, 2021 ; Uchida et al, 2022b ; Figure 3 ).…”

“…The homeostasis and physiological role of brain iron in AD and CSVD has been debated for decades ( Tao et al, 2014 ). QSM has been used to detect the abnormal iron deposition in each specific region as a clinical application and quantify the iron concentration for clinicoradiological research ( Acosta-Cabronero et al, 2013 ; Ayton et al, 2017 ; Kim et al, 2017 ; Tiepolt et al, 2018 ; Gong et al, 2019 ; Uchida et al, 2020 , 2022a , b ; Cogswell et al, 2021 ). Although abnormally high levels of iron are thought to induce free radicals, resulting in neuronal loss and cognitive dysfunction, whether iron deposition is a cause or a result of Alzheimer’s pathogenesis remains elusive.…”

A Perspective: Challenges in Dementia Research

“…The results of brain imaging are critical to any full patient description. Clearly, MRI and/or CT images of the brain should be obtained if possible [ 35 , 36 ]. However, a comprehensive evaluation should include the possibility of obtaining perfusion imaging [ 37 ] as well as CT angiogram and MR angiogram images [ 38 ] and metabolic PET scans [ 39 ].…”