Aβ Imaging Research Articles

Coassembled Chitosan-Hyaluronic Acid Nanoparticles as a Theranostic Agent Targeting Alzheimer's β-Amyloid.

β-Amyloid (Aβ) fibrillogenesis is closely associated with the pathogenesis of Alzheimer's disease (AD), so detection and inhibition of Aβ aggregation are of significance for the theranostics of AD. In this work, the coassembled nanoparticles of chitosan and hyaluronic acid cross-linked with glutaraldehyde (CHG NPs) were found to work as a theranostic agent for imaging/probing and inhibition of Aβ fibrillization both in vitro and in vivo. The biomass-based CHG NPs of high stability exhibited a wide range of excitation/emission wavelengths and showed binding affinity toward Aβ aggregates, especially for soluble Aβ oligomers. CHG NPs displayed weak emission in the monodispersed state, while they remarkably emitted increased red fluorescence upon interacting with Aβ oligomers and fibrils, showing high sensitivity with a detection limit of 0.1 nM. By comparing the different fluorescence responses of CHG NPs and Thioflavin T to Aβ aggregation, the Aβ oligomerization rate during nucleation can be determined. Moreover, the fluorescence recognition behavior of CHG NPs was selective. CHG NPs specifically bind to negatively charged amyloid aggregates but not to positively charged amyloids and negatively charged soluble proteins. Such enhancement in fluorescence emission is attributed to the clustering-triggered emission effect of CHG NPs after interaction with Aβ aggregates via various electronic conjugations and hydrogen bonding, electrostatic, and hydrophobic interactions. Besides fluorescent imaging/probing, CHG NPs over 360 μg/mL could almost completely inhibit the formation of Aβ fibrils, exhibiting the capability of regulating Aβ aggregation. In-vivo assays with Caenorhabditis elegans CL2006 demonstrated the potency of CHG NPs as an effective theranostic nanoagent for imaging Aβ plaques and inhibiting Aβ deposition. The findings proved the potential of CHG NPs for development as a potent agent for the diagnosis and treatment of AD.

Distinguishing Amyloid β-Protein in a Mouse Model of Alzheimer's Disease by Label-Free Vibrational Imaging.

Due to the increase in the average age of humans, Alzheimer’s disease (AD) has become one of the disorders with the highest incidence worldwide. Abnormal amyloid β protein (Aβ) accumulation is believed to be the most common cause of AD. Therefore, distinguishing the lesion areas can provide clues for AD diagnosis. Here, we present an optical spectroscopy and imaging approach based on coherent anti-Stokes Raman scattering (CARS). Label-free vibrational imaging of Aβ in a mouse model of AD was performed to distinguish the lesion areas by studying the spectra of regions with and without Aβ plaques. Raman spectra in Aβ and non-Aβ regions exhibited a specific difference in the intensity ratio of the wave peaks detected at 2850 and 2930 cm−1. In the non-Aβ region, the ratio of the peak intensity at 2850 cm−1 to that at 2930 cm−1 was approximately 1, whereas that in the Aβ region was 0.8. This label-free vibrational imaging may provide a new method for the clinical diagnosis and basic research of AD.

Women Exhibit Lower Global Left Frontal Cortex Connectivity Among Cognitively Unimpaired Elderly Individuals: A Pilot Study from SILCODE

Background: Mounting evidence suggests that sex differences exist in cognitive reserve (CR) for cognitively unimpaired (CU) elderly individuals. Global left frontal connectivity (gLFC connectivity) is a reliable neural substrate of CR. Objective: The purpose of this study was to explore sex differences in gLFC connectivity among CU elderly individuals. Methods: One hundred thirteen normal controls (NCs) (women = 66) and 132 individuals with subjective cognitive decline (SCD) (women = 92) were recruited from the Sino Longitudinal Study on Cognitive Decline (SILCODE) (data 1). Among them, 88 subjects underwent amyloid-β (Aβ) imaging, including 32 Aβ+ and 56 Aβ–subjects. Forty-six subjects underwent another rs-fMRI examination (data 2) to validate the repeatability of the calculation of gLFC connectivity, which was determined through seed-based functional connectivity between the LFC and voxels throughout the whole brain. Independent-sample t-tests were used to evaluate the sex differences in gLFC connectivity across different subgroups (NC versus SCD, Aβ+ versus Aβ–). Partial correlation analysis was used to calculate the correlations between gLFC connectivity and cognitive assessments. Results: Women exhibited lower gLFC connectivity in both the NC (p = 0.001) and SCD (p = 0.020) subgroups than men. Women also exhibited lower gLFC connectivity in both the Aβ–(p = 0.006) and Aβ+ (p = 0.025) groups. However, the significant difference disappeared in the Aβ+ group when considering the covariates of age, education, total intracranial volume, and APOE4-carrying status. In addition, gLFC connectivity values were negatively correlated with Geriatric Depression Scale scores in the SCD group (r = –0.176, p = 0.047). Conclusion: Women showed lower gLFC connectivity among CU elderly individuals.

Benzothiazolium Derivative-Capped Silica Nanocomposites for β-Amyloid Imaging In Vivo

Alzheimer’s disease (AD) is a neurodegenerative disease, and β-amyloid (Aβ) is believed to be a causative factor in AD pathology. The abnormal deposition of Aβ is believed to be responsible for progression of AD. In order to facilitate the imaging of Aβ in vivo, suitable probe molecules with a near-infrared emission wavelength that can penetrate the blood–brain barrier (BBB) were utilized. The commercial fluorescent probe thioflavin-T (ThT) is used to image Aβ; however, because of its short emission wavelength and poor BBB penetration, ThT can only be used in vitro. With this research, based on ThT, we design three fluorescent probes (SZIs) having a longer emission wavelength in order to image Aβ aggregates. SZIs with different numbers of double bonds respond to Aβ aggregates. The SZIs have a structure similar to ThT, and as such, the SZIs are also unable to penetrate the BBB. To deal with the problem, we develop nanocomposites (MSN-Lf@SZIs) to deliver SZIs into the brain of AD mouse and image Aβ successfully. These new nanocomposites are able to deliver the dyes into the brain and facilitate Aβ imaging in vivo.

Multimodal Theranostic Cyanine-Conjugated Gadolinium(III) Complex for In Vivo Imaging of Amyloid-β in an Alzheimer's Disease Mouse Model.

Despite the wide use of magnetic resonance imaging (MRI) as a clinical diagnostic tool, there are still no clinically approved MRI contrast agents that can be applied for cerebral Alzheimer's disease (AD) biomarker imaging. We report here the design and development of the first amyloid-β (Aβ)-targeted, blood-brain barrier (BBB) penetrable theranostic Gd(DOTA)-cyanine dyad, which was synthesized by the conjugation of Gd(DOTA) complex and carbazole-based cyanine dye by the copper(I)-catalyzed azide-alkyne cycloaddition click reaction for imaging of Aβ in vivo and ex vivo in AD mouse models. This dyad, as a multimodal probe, possesses desirable multifunctional properties, including good biocompatibility, low cytotoxicity, high Aβ selectivity, strong fluorescence enhancement upon binding with Aβ species, good paramagnetic properties, high stability, good BBB penetrability, and fast elimination from the mouse. The longitudinal relaxivity (r1) of the dyad was found to be 4.42 mM-1 s-1 at 3 T, suggesting it to be promising as a T1-weighted MRI contrast agent. The probe has been successfully demonstrated to be able to be applied for one- and two-photon excited fluorescence and magnetic resonance (MR) imaging of Aβ in transgenic mouse models of AD. In addition, it can inhibit Aβ aggregation, protect against toxicity induced by Aβ, and suppress Aβ-induced reactive oxygen species (ROS) production. Our results demonstrate the highly promising theranostic capability of the dyad for diagnosis and therapy of AD and extraordinary potential for MRI of Aβ in humans.

Fluorine-19 Magnetic Resonance Imaging for Detection of Amyloid β Oligomers Using a Keto Form of Curcumin Derivative in a Mouse Model of Alzheimer's Disease.

Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer’s disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.

Comprehensive review on design perspective of PET ligands based on β-amyloids, tau and neuroinflammation for diagnostic intervention of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative pathological condition that resulted from the deterioration of cholinergic neurons over time. The pathological hallmark features of AD include extracellular β-amyloids plaques, hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFT) and neuroinflammation. This article aims to provide a comprehensive review of PET tracers for Alzheimer’s disease, focusing on developments for targets (β-amyloids, hyperphosphorylated τ protein (tau), neuroinflammation and other related targets) available for clinical PET imaging. Studies involving the existing PET tracers used in the imaging of Aβ, tau, and neuroinflammation with essential features and limitations are discussed. Experimental studies with the design perspective of PET tracers, for biomarkers like Aβ, tau protein, and neuroinflammation, which are exploited clinically through PET Imaging have been described in detail. Comparative data have been generated based on the strength and weakness of PET radioligands for preclinical and clinical studies based on their binding affinity, selectivity and imaging. PET tracers for other targets like cannabinoid receptor type 2 (CB2), P2X7 receptor, cyclooxygenase-2, macrophage colony-stimulating factor 1 receptor (CSF1R), and monoamine oxidase (MAO) have also been included. We have summarized the ideal properties in terms of tracer's design for each target and based on their target selectivity and affinity, considering its potential strength and limitations. Where multiple tracers were present for a target, we provide a comparison of their properties. A critical assessment of both the preclinical and clinical PET tracers is carried out where sufficient data are available. This can help in designing better and highly selective PET tracers. Our comprehensive review will provide comparison and help in the design perspective of the futuristic PET tracers for Alzheimer's disease by improving their affinity towards biomarkers with higher selectivity Aβ/tau for delineation of AD at an early stage.

Relationship between amyloid and tau levels and its impact on tau spreading

PurposePrevious studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear.MethodsFour hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [18F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined.ResultsThe plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL.ConclusionOutside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.

Quantitative imaging of amyloid beta peptide (Aβ) in Alzheimer’s brain tissue by laser ablation ICP-MS using gold nanoparticles as labels

Quantitative imaging of amyloid beta (Aβ) in brain is of great significance for pathological study and follow-up drug development of Alzheimer’s disease (AD). In this work, a method using antibody-conjugated gold nanoparticles (AuNPs) was established for quantitative imaging of Aβ peptide in the brain of AD mouse by Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Aβ antibody (Anti-Aβ) was labeled with AuNPs to form the conjugate AuNPs-Anti-Aβ which was immunoreactive with Aβ in the brain slice of mouse. Quantitative imaging of Au was acquired with homogenized brain slice matrix-matched standards as external calibrants which were made by immersing in gold standard solution with different concentrations. Furthermore, the stoichiometric ratios between metal conjugates and Aβ were optimized, and the immunoreaction efficiency after labeling was also investigated. According to the molar relationship between AuNPs and Anti-Aβ (1:4.3) and the ratio of Anti-Aβ to Aβ (1:1), quantitative imaging of Aβ in brain was accomplished. The method intuitively displayed the location and concentration of Aβ aggregation, which was consistent with traditional immunohistochemical staining. Since the numerous gold atoms contained in AuNPs can enhance the signal of Aβ, the method is more intuitive and sensitive. The proposed methodology is potential in investigating the quantitative imaging of biomarker heterogeneity, and is useful to understand such complex brain mechanisms in the future.

A tau PET study of primary age‐related tauopathy in healthy volunteers

AbstractBackgroundThe term “primary age‐related tauopathy” (PART) was recently introduced to describe a pathology that is commonly observed in the brain of aged individuals. Symptoms in persons with PART usually range from normal cognition to amnesia. The aim of the study is to explore the tau aggregates accumulation in the brain of healthy volunteers by PET with [18F]PM‐PBB3 ( [18F]APN‐1607).MethodFifty‐three healthy individuals (28 men and 25 women ranging in age from 23 to 79 years with a mean of 60) without any history of psychiatric and neurological diseases participated in this study. All subjects underwent neurological examination, cognitive tests, brain MRI, [11C]PiB PET (Aβ imaging), and [18F]PM‐PBB3 PET. [11C]PiB PET images (50‐70 min) was visually assessed. An automated analysis of the volumes of interest in [18F]PM‐PBB3 images (90‐110 min) was performed using the PNEURO module in the PMOD software. Standardized uptake value ratio (SUVR) values were obtained using the cerebellar cortex as a reference region. Pearson correlation analysis was performed between [18F]PM‐PBB3 SUVR and age.ResultNeurological examination revealed no significant finding except for hand tremors in one subject. Cognitive tests were normal in all subjects. Two men were Aβ positive and excluded from the following analysis. There was a positive correlation between age and tau PET signal in the parahippocampus (r = 0.30, P < 0.03), fusiform gyrus (r = 0.41, P < 0.003), and middle and inferior temporal cortex (r = 0.28, P < 0.05) of 51 subjects. No positive correlation between age and [18F]PM‐PBB3 SUVR was found in any other brain regions.ConclusionThe present result supports the concept of PART and the detectability of PART‐type tau deposits by PET with [18F]PM‐PBB3.

Impact of APOE‐ε4 on cerebral amyloid deposition in participants with abnormal soluble amyloid levels

AbstractBackgroundAmyloid pathology can be detected using cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging, even though they measure two distinct beta‐amyloid (Aβ) pools. While CSF Aβ concentrations reflect the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques in the brain tissue. Many studies have shown the concordance between the two measures in individuals along the Alzheimer’s continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for Alzheimer’s disease (AD), affects the pattern of cerebral Aβ load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR = 0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ40 and Aβ42 concentrations were determined with the Roche NeuroToolKit (Roche Diagnostics) and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxel‐wise regression was performed to predict FTM uptake, with the following independent variables: age, sex, APOE‐ε4, and CSF Aβ42/40 ratio. Statistical threshold was set to p < 0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ42/40 ratio was negatively associated with cerebral FTM uptake (Figure 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM‐binding across the whole sample (Figure 2b‐2c). Importantly, we found a significant interaction between CSF Aβ42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Figure 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers showed higher cerebral Ab load for any given level of CSF Aβ42/40 in areas that are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the Alzheimer’s continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

Impact of the APOE gene on amyloid deposition in participants with abnormal soluble amyloid levels

AbstractBackgroundAmyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer’s disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.

18F-labeled 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid imaging probes

This study reported the design, synthesis and bio-evaluation of 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid (Aβ) imaging probes. This strategy of introducing two hydroxyls offered a simplified method for effectively reducing the lipophilicity. The probes (R, S)/(S, R)-14–15 with benzothiazole scaffold displayed good binding affinities toward Aβ1-42 aggregates with Ki values ranging from 47.63 to 56.28 nM. Further biological studies shown that (R, S)/(S, R)-[18F]14 have no obvious chirality-related discrepancy in binding ability and mice bio-distribution, while (S, R)-enantiomer exhibited slightly faster brain washout rate than (R, S)-enantiomer. Compared to the FDA approved [18F]Florbetapir and the fluoro-peglated 2-phenylbenzothiazole derivatives, (S, R)-[18F]14 displayed improved brain kinetics (6.40% ID/g at 2 min, brain2 min/brain60 min = 7.80) that is favorable for further application. In vitro autoradiography studies validated its high affinity and specificity to Aβ plaques. Overall, (S, R)-[18F]14 deserved further detailed study as a potential PET imaging probe for AD early diagnosis.

Amyloid-β oligomer targeted theranostic probes for in vivo NIR imaging and inhibition of self-aggregation and amyloid-β induced ROS generation

To enable the early detection and intervention of Alzheimer's disease (AD), it is highly desirable to develop novel theranostic agents for simultaneous detection of toxic and pathogenic amyloid-β (Aβ) oligomers in vivo and attenuation of Aβ-induced toxicity. Herein, we report a new series of oligomeric Aβ targeted near infrared (NIR) emissive dibutylnaphthylamine-based cyanine probes for in vivo and ex vivo imaging of Aβ in AD mouse model. These new fluorophores exhibited strong solvatochromism and a large bathochromic shift of the emission spectrum upon binding with Aβ species, giving rise to advantageous NIR emission. Besides, they showed an intriguingly stronger fluorescence enhancement upon interacting with Aβ oligomers and monomers, and binding affinity toward Aβ oligomers and monomers than Aβ fibrils, suggesting they were selective to Aβ oligomers and monomers. In addition to low toxicity, one of the fluorophores, DBAN-SLM, showed remarkably effective inhibitory effect on Aβ aggregation, significant neuroprotection effect against the Aβ-induced toxicities, and suppression on Aβ-induced reactive oxygen species (ROS) generation. Because of excellent blood-brain barrier (BBB) permeability, good biocompatibility and stability, high specificity towards Aβ oligomers as well as strong turn-on fluorescence upon Aβ binding, DBAN-SLM was successfully applied for in vivo and ex vivo imaging of Aβ in AD mouse model, signifying its great promise as a useful theranostic agent for the early diagnosis and therapy of AD. Our results also demonstrated for the first time that the dibutyl-2-naphthylamine moiety is a useful and effective structural building block to promote the targeting capability of oligomeric Aβ.

The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease

As Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer's disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

Discovery of Diphenoxy Derivatives with Flexible Linkers as Ligands for β-Amyloid Plaques.

The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity (Ki < 100 nM) for Aβ1-42 aggregates, and some ligands even showed values of Ki less than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for Aβ binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of Aβ imaging agents.

Dual-functional AIE fluorescent probes for imaging β-amyloid plaques and lipid droplets

Alzheimer’s disease (AD) is a chronic neurodegenerative disease. Better imaging and early diagnosis of biomarkers of AD is extremely important for therapeutic interventions. The amyloid cascade hypothesis and its revised version identify insoluble β-amyloid deposition as a good diagnostic biomarker for AD. Moreover, lipid droplets may also act as an auxiliary biomarker related to AD pathology based on recent studies. Herein, two quinoline-based AIE probes were designed and synthesized for the imaging of Aβ plaques and lipid droplets. The probes exhibited remarkable turn-on fluorescence enhancements with the Aβ aggregates. The lipid droplets-targeting probe FB exhibited high selectivity and binding affinity towards the Aβ aggregates with a detection limit as low as 26.9 nM. Furthermore, FB was capable of readily imaging Aβ plaques and lipid droplets at the cellular level and in brain sections of transgenic AD mice. The probe FB can serve as a promising tool for developing early diagnosis and innovative therapeutics of AD.

PyrPeg, a Blood-Brain-Barrier-Penetrating Two-Photon Imaging Probe, Selectively Detects Neuritic Plaques, Not Tau Aggregates.

Amyloid-β (Aβ) tracers have made a significant contribution to the treatment of Alzheimer's disease (AD) by allowing a definitive diagnosis in living patients. Unfortunately, they also detect tau and other protein aggregates that compromise test accuracy. In AD research, there has been a growing need for in vivo Aβ imaging by two-photon microscopy, which enables deep-brain-fluorescence imaging. There is no suitable neuritic Aβ probe for two-photon microscopy. Here we report PyrPeg, a novel two-photon fluorescent probe that can selectively target insoluble Aβ rather than tau and α-synuclein aggregates in the AD model brain and postmortem brain. When injected intravenously, PyrPeg detects the neuritic plaques in the brain and olfactory bulb of the AD model. PyrPeg may serve as a useful blood-brain-barrier-penetrating diagnostic tool for optical and functional monitoring of insoluble forms of Aβ aggregates in the living AD brain.

Flexible multidentate benzyldiamine derivatives with high affinity for β-amyloid in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) commonly found in the aged is pathologically characterized by β-amyloid (Aβ) deposition in the walls of arteries and capillaries of brain. In this study, four flexible multidentate benzyldiamine derivatives as potential probes for cerebrovascular Aβ deposition were designed and synthesized. In in vitro inhibition assays, the ligands 18-21 displayed high affinities for Aβ aggregates with Ki values of 1.45 ± 0.53nM, 1.68 ± 0.35nM, 1.16 ± 0.23nM and 1.72 ± 0.19nM, respectively. A significant improvement in the binding affinity over the monomer, compounds 9-12 or benzyldiamine derivatives, demonstrated the applicability of the multidentate approach. The underlying mechanism of these novel Aβ agents was explored by molecular docking technique, which theoretically verified the high affinities of the multidentate benzyldiamine derivatives for Aβ aggregates. Moreover, the molecular masses of the ligands 18-21 are more than 700 Dalton, which are believed to be hardly capable of penetrating blood brain barrier. In this regard, these ligands could be used to distinguish CAA from Alzheimer's disease which is another Aβ-related disorder disease. To convert these ligands to positron emission tomography imaging agents, we attempted to radiosynthesize [18F]18. Though the radiolabeling was not very successful, the preliminary results suggested that these newly proposed multidentate benzyldiamine derivatives may be used as potential Aβ imaging agents in cerebral amyloid angiopathy.

Design of Multifunctional Agent Based on Basified Serum Albumin for Efficient In Vivo β-Amyloid Inhibition and Imaging.

Theranostics, the combination of therapeutics and diagnostics, has emerged as a sophisticated, integrated, and advanced tool in the prevention and treatment of serious diseases, such as Alzheimer's disease (AD). However, the preclinical research of an AD theranostic molecule is in its infancy and needs to be explored in depth. Herein, a multifunctional theranostic agent is designed and fabricated by conjugating an Aβ-specific near-infrared (NIR) fluorescence probe (F) and by coupling a BBB penetrable peptide (Penetratin, Pen) onto the basified human serum albumin (HSA-B) that has been recently proven as an effective amyloid-β (Aβ) inhibitor. Such an elaborately constructed HSA-B-based molecule (HSA-BFP) possesses high potency on inhibiting Aβ fibrillogenesis, for example, increasing SH-SY5Y cell viability from 66.5 to 93%.In addition, HSA-BFPexhibits favorable stability in the "off-on" NIR imaging of Aβ plaques and achieves a 2-fold increase of BBB permeability after the Pen modification. More importantly,in vivo assays with the AD model C. elegans CL2006 indicate that HSA-BFP can specifically image Aβ deposits, decrease amyloid accumulation, and attenuate Aβ-triggered paralysis. Thus, HSA-B has been proven as a potent and versatile platform for the development of AD theranostic agents.