MR fingerprinting and complex-valued neural network for quantification of brain amyloid burden
Shohei FujitaYujiro OtsukaKatsutoshi MurataGregor KoerzdoerferMathias NittkaYumiko MotoiMadoka NakajimaKoji MurakamiIssei FukunagaKoji KamagataOsamu AbeShigeki Aoki
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We developed a framework utilizing MR fingerprinting and a complex-valued neural network to detect brain amyloid burden. The tailored neural network was trained on real amyloid-PET imaging data and MR fingerprinting acquisitions to estimate PET-derived amyloid deposition from the MR fingerprinting signal evolutions. This complex-valued neural network architecture, designed to increase sensitivity to amyloid-related signals, showed a subject-level amyloid positivity classification with AUC = 0.87 in patients with cognitive decline. The proposed method enables non-invasive amyloid burden mapping, T1 and T2 mapping in a single scan, and is suitable not only for diagnosis but also for monitoring amyloid-reducing treatments.Keywords:
Amyloid (mycology)
β amyloid
Abstract In the present work, a new electrochemical strategy for the sensitive and specific detection of soluble β‐amyloid Aβ (1–40/1–42) peptides in a rat model of Alzheimer’s disease (AD) is described. In contrast to previous antibody‐based methods, β‐amyloid (1–40/1–42) was quantified based on its binding to gelsolin, a secretory protein present in the cerebrospinal fluid (CSF) and plasma. The level of soluble β‐amyloid peptides in the CSF and various brain regions were found with this method to be lower in rats with AD than in normal rats.
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The mechanism of neurodegeneration caused by beta-amyloid in Alzheimer disease is controversial. Neuronal toxicity is exerted mostly by various species of soluble beta-amyloid oligomers that differ in their N- and C-terminal domains. However, abundant accumulation of beta-amyloid also occurs in the brains of cognitively normal elderly people, in the absence of obvious neuronal dysfunction. We postulated that neuronal toxicity depends on the molecular composition, rather than the amount, of the soluble beta-amyloid oligomers. Here we show that soluble beta-amyloid aggregates that accumulate in Alzheimer disease are different from those of normal aging in regard to the composition as well as the aggregation and toxicity properties.
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The amplifying effect ofβ-amyloid fragment 25-35 (βA25-35) on the mitogen-induced rise of free intracellular calcium in circulating lymphocytes was strongly reduced in 24 patients with Alzheimer's disease when compared with elderly, non-demented controls. Lowβ-amyloid responses were significantly correlated with the presence of the apolipoprotein Eε4 allele, suggesting a dose effect.
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Calcium in biology
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Abstract In the present work, a new electrochemical strategy for the sensitive and specific detection of soluble β‐amyloid Aβ (1–40/1–42) peptides in a rat model of Alzheimer’s disease (AD) is described. In contrast to previous antibody‐based methods, β‐amyloid (1–40/1–42) was quantified based on its binding to gelsolin, a secretory protein present in the cerebrospinal fluid (CSF) and plasma. The level of soluble β‐amyloid peptides in the CSF and various brain regions were found with this method to be lower in rats with AD than in normal rats.
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Individuals with Alzheimer's disease (AD)-like neuronal injury but without evidence of amyloid pathology are referred to as having Suspected Non-Alzheimer's Disease Pathophysiology (SNAP). To date it is unclear what can explain this biomarker profile in individuals with mild cognitive impairment (MCI). We aimed to investigate the underlying pathophysiology of MCI-SNAP in cerebrospinal fluid (CSF). We included 709 individuals from 8 European studies. Based on CSF Aβ1- 42 (A) and tau (T) measures, individuals were classified as cognitively normal (CN) A-T-, MCI A+T-, MCI A-T+ (SNAP), MCI A+T+ and AD dementia A+T+. We centrally measured different CSF Aβ isoforms (Aβ1-38, Aβ1-40, Aβ1-42, Aβ1-42/Aβ1-40) and emerging AD CSF biomarkers, i.e. neurogranin (Ng), neurofilament-light (NFL), and YKL-40, and compared values between groups using ANOVA. K-means clustering was performed to identify MCI-SNAP subgroups based on CSF measures. MCI-SNAP showed higher CSF levels of non-aggregation-prone Aβ1-38 and Aβ1-40 species compared to all other groups. Relative to T- groups, MCI-SNAP demonstrated increased levels of NFL, Ng, and YKL-40, similar as seen in MCI A+T+ or dementia A+T+ (Figure 1). Cluster analyses showed that MCI-SNAP consisted of 3 subgroups: (A) a non-AD subgroup with increased Aβ1-42, Aβ1-40, Aβ1-38, and YKL-40 levels compared to CN and MCI A+T+ individuals; (B) a mild non-AD subgroup with moderately increased Aβ1-38 and Aβ1-40 levels compared to CN and MCI A+T+ but similar Aβ1-42 levels as CN individuals; and (C) an AD subgroup with a similar Aβ1-42/Aβ1-40 ratio as MCI A+T+ but higher Aβ1-42, Aβ1-40, Aβ1-38, YKL-40, Ng, and tau levels than MCI A+T+. CSF values by biomarker group. Results are boxplots (displaying first quartile, median and third quartile) and scatterplots for all CSF measures by each biomarker subgroup: (A) Neurofilament-light, (B) Neurogranin, (C) YKL-40, (D) amyloid-β1-38, (E) amyloid-β1-40, (F) amyloid-β1-42, (G) amyloid-β1- 42/1-40, (H) total tau, (I) phosphorylated tau. The MCI A-T+ group is presented in blue and the CN A-T-, MCI A-T-, MCI A+T-, MCI A+T+, and AD dementia A+T+ groups are presented in grey. CSF biomarker values were logtransformed. *indicates statistically significant differences compared to the MCI A-T+ group after Bonferroni correction for multiple comparisons. A=amyloid-pi-42, T=total or phosphorylated tau, CN=cognitively normal, MCI=mild cognitive impairment. We showed that MCI-SNAP is heterogeneous and characterized by increased levels of non-aggregation-prone Aβ1-38 and Aβ1-40 isoforms. These shorter forms have been shown to inhibit Aβ1-42 aggregation in vitro, which could potentially protect these individuals from developing Aβ pathology. Higher Aβ1-38 and Aβ1-40 levels in these individuals were associated with higher YKL-40 levels. The use of the Aβ1-42/Aβ1-40 ratio can help to identify individuals with MCI-SNAP and underlying AD.
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Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.
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Accumulation of amyloid-beta (Abeta) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is thought to be a later downstream event. It is now well established that Abeta exists as monomers, oligomers, and fibrils. To study the temporal profile of Abeta oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation of plaques and tangles and cognitive impairments. We show that SDS-resistant Abeta oligomers accumulate in an age-dependent fashion, and we present evidence to show that oligomerization of Abeta appears to first occur intraneuronally. Finally, we show that a single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear Abeta pathology, and more importantly, tau pathology. Therefore, Abeta oligomers may play a role in the induction of tau pathology, making the interference of Abeta oligomerization a valid therapeutic target.
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