<i>APOE ɛ4</i>dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction

Uchida, Yuto; Kan, Hirohito; Sakurai, Keita; Horimoto, Yoshihiko; Hayashi, Eiji; Iida, Akihiko; Okamura, Nobuyuki; Oishi, Keiji; Matsukawa, Noriyuki

doi:10.1136/jnnp-2021-328519

Cited by 36 publications

(45 citation statements)

References 40 publications

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“…Note that different approaches have been proposed for each post-processing step, which influences the accuracy of the magnetic susceptibility values and the edge of the brain mask (Haacke et al, 2015). Details of MRI acquisition parameters and postprocessing techniques in QSM studies for AD continuum subjects are summarized in Table 1 (Acosta-Cabronero et al, 2013;Hwang et al, 2016;Moon et al, 2016;van Bergen et al, 2016bvan Bergen et al, , 2018Ayton et al, 2017;Kim et al, 2017;Meineke et al, 2018;Tiepolt et al, 2018;Chen et al, 2020;Kagerer et al, 2020;Kan et al, 2020;Tuzzi et al, 2020;Cogswell et al, 2021;Ravanfar et al, 2021;Uchida et al, 2022b).…”

Section: Acquisition and Reconstruction Protocols For Quantitative Su...mentioning

confidence: 99%

“…On the other hand, there were indiscernible differences for QSM among the groups. BBB, blood-brain barrier; PiB, Pittsburgh compound B; QSM, quantitative susceptibility mapping; SUVR, standard uptake value ratio (adapted with permission from Uchida et al, 2022b).…”

Section: Biomarker For Neurodegenerative Diseasesmentioning

confidence: 99%

“…With current imaging techniques allowing for in vivo quantification of brain iron, Aβ, tau, and neurodegeneration, the efficacy of the disease modifying therapy on these AD pathologies could be more specifically monitored (Borlongan, 2012). An overview of QSM study design and main findings for AD continuum subjects are summarized in Table 2 (Acosta-Cabronero et al, 2013;Hwang et al, 2016;Moon et al, 2016;van Bergen et al, 2016bvan Bergen et al, , 2018Ayton et al, 2017;Kim et al, 2017;Meineke et al, 2018;Tiepolt et al, 2018;Chen et al, 2020;Kagerer et al, 2020;Kan et al, 2020;Tuzzi et al, 2020;Cogswell et al, 2021;Ravanfar et al, 2021;Uchida et al, 2022b).…”

Section: Expectationsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Acquisition and Reconstruction Protocols For Quantitative Su...mentioning

confidence: 99%

Section: Biomarker For Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Expectationsmentioning

confidence: 99%

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

et al. 2022

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“…But in ADNI we also observed that APOE ε4 carriers express elevated CSF ferritin, which was not replicated here. In other studies, APOE ε4 carriers were reported to have higher MRI-reported brain iron levels, which adversely influences the impact of iron on functional MRI21 42 and cognitive decline 3. Therefore, the association between apoE and ferritin levels appears to be robust, but an association with APOE ε4 genotype warrants additional validation.…”

Section: Discussionmentioning

confidence: 86%

CSF ferritin in the clinicopathological progression of Alzheimer’s disease and associations with APOE and inflammation biomarkers

Ayton

Bateman

Kalinowski

et al. 2022

J Neurol Neurosurg Psychiatry

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BackgroundA putative role for iron in driving Alzheimer’s disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodsFerritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort.ResultsIn both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%–40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-.ConclusionsCSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

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“…Further, the ε4 allele of APOE gene is the strongest and most validated genetic risk factor for sporadic AD ( Yamazaki et al, 2019 ). Emerging evidence suggests that APOE ɛ4 directly impairs the BBB: astrocyte-secreted ApoE4 induces the degeneration of brain capillary pericytes that maintain BBB integrity ( Bell et al, 2012 ), and individuals carrying APOE ɛ4 are closely linked to the onset and progression of AD pathogenesis, independent of pathological Alzheimer’s biomarkers ( Montagne et al, 2020 ; Uchida et al, 2022a ).…”

Section: Alzheimr’s Pathopyhsiology In Relation To Blood–brain Barrie...mentioning

confidence: 99%

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

Uchida

Kan

Sakurai

et al. 2023

Front. Aging Neurosci.

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The blood–brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as β-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer’s disease. Measurements of BBB function are essential toward a better understanding of Alzheimer’s pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer’s disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer’s disease and related dementias. First, we give an overview of the relationship between Alzheimer’s pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer’s disease continuum. Fourth, we introduce a wide range of Alzheimer’s pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer’s disease and related dementias.

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APOE ɛ4dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction

Cited by 36 publications

References 40 publications

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

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

CSF ferritin in the clinicopathological progression of Alzheimer’s disease and associations with APOE and inflammation biomarkers

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

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