Aβ Imaging Research Articles

Solvent and media effects on the photophysics of cranad-2 and cranad-58

Alzheimer’s disease (AD) represents the most widespread form of age-related cognitive degeneration, characterized by long-term degenerative damage, cognitive dysfunction, and profound deficits in logical thinking, knowledge acquisition, and interpersonal communication. A principal biomarker of AD involves the emergence and aggregation of β-amyloid (Aβ). Cranad derivatives are fluorescent probes capable of detecting, quantifying, and imaging Aβ aggregates. In this work, the effect of solvent and microheterogeneous environments on the photophysical behavior of CRANAD-2 and CRANAD-58 was investigated employing a large solvent set and several microorganized systems. Both the absorption and fluorescence spectra exhibit a substantial solvatochromic effect, resulting in significant Stokes shifts. Application of linear solvation energy relationships to correlate the fluorescence spectra maxima and the Stokes shift with microscopic solvent parameters suggests significant intramolecular charge transfer during the excitation, as corroborated by the increased dipole moment in the excited state. Generally, fluorescence quantum yields determined for CRANAD-2 exceed those of CRANAD-58 in most solvents, with low values in polar solvents and bigger values in non-polar solvents. Introduction of CRANAD-2 and CRANAD-58 into micellar and vesicular solutions notably augments the fluorescence emission intensity, accompanied by a blue shift in the fluorescence maxima. The fluorescence maxima values observed within microheterogeneous systems closely parallel those reported for interactions between CRANAD derivatives and soluble or aggregated Aβ amyloids which potentially constrains the efficacy of “in vivo” Aβ detection trials, because localization of CRANAD derivatives in non-polar microenvironments present in biological media could interfere with the detection of amyloid fibers.

Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer’s disease

BackgroundIt is not fully established whether plasma β-amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer’s disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.MethodsWe recruited 470 older adults and analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ42/Aβ40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ42/Aβ40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.ResultsPlasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.DiscussionThis study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.

18F]Flotaza for Aβ Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Design and synthesis of hemicyanine-based NIRF probe for detecting Aβ aggregates in Alzheimer’s disease

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, has garnered increased attention due to its substantial economic burden and the escalating global aging phenomenon. Amyloid-β deposition is a key pathogenic marker observed in the brains of Alzheimer’s sufferers. Based on real-time, safe, low-cost, and commonly used, near-infrared fluorescence (NIRF) imaging technology have become an essential technique for the detection of AD in recent years. In this work, NIRF probes with hemicyanine structure were designed, synthesized and evaluated for imaging Aβ aggregates in the brain. We use the hemicyanine structure as the parent nucleus to enhance the probe’s optical properties. The introduction of PEG chain is to improve the probe’s brain dynamice properties, and the alkyl chain on the N atom is to enhance the fluorescence intensity of the probe after binding to the Aβ aggregates as much as possible. Among these probes, Z2, Z3, Z6, X3, X6 and T1 showed excellent optical properties and high affinity to Aβ aggregates (Kd = 24.31 ∼ 59.60 nM). In vitro brain section staining and in vivo NIRF imaging demonstrated that X6 exhibited superior discrimination between Tg mice and WT mice, and X6 has the best brain clearance rate. As a result, X6 was identified as the optimal probe. Furthermore, the docking theory calculation results aided in describing X6′s binding behavior with Aβ aggregates. As a high-affinity, high-selectivity, safe and effective probe of targeting Aβ aggregates, X6 is a promising NIRF probe for in vivo detection of Aβ aggregates in the AD brain.

N-methylbenzothiazolium based theranostics as fluorescence imaging and photo-oxidation agents for Amyloid-β

Alzheimer's disease is a progressive neurodegenerative disorder with an insidious onset of symptoms. At present, there are no treatments that can effectively stop or reverse the disease from progressing. The development of effective methods for early diagnosis and treatment of Alzheimer's disease is therefore still urgently needed. In this article, we designed a family of Q-series probes (Q16∼Q21) that bind to Aβ aggregates by introducing different electron donors to bind to benzothiazole salts electron acceptors with different substituents to achieve imaging and photooxidation of aggregated Aβ proteins. The structure of the six probes was composed of N, N-dimethylaminophenyl and triphenylamine (donor groups), benzothiazole salts (acceptor groups), and π-conjugated double bonds. Among them, the probe Q17 with triphenylamine as the electron donor had a good singlet oxygen production efficiency, which can effectively carry out photooxidation after combining with Aβ aggregates, effectively reducing the degree of aggregation, and the cytotoxicity of Aβ aggregates was significantly reduced after bright light oxidation through cell experiments, which has great potentials in the treatment of Aβ photooxidation. On the other hand, probes Q16 and Q18 with N, N-dimethylaminophenyl as donors had excellent imaging abilities, good affinities for Aβ (Kd-Q16 = 26.95 nM, Kd-Q18 = 21.56 nM), can effectively image Aβ plaques in AD mouse brain slices and monitor the change of cell viscosity, and have a good application prospect in fluorescence imaging.

A novel BODIPY-based theranostic agent for in vivo fluorescence imaging of cerebral Aβ and ameliorating Aβ-associated disorders in Alzheimer's disease transgenic mice.

β-Amyloid (Aβ) aggregation is increasingly recognized as both a biomarker and an inducer of the progression of Alzheimer's disease (AD). Here, we describe a novel fluorescent probe P14, developed based on the BODIPY structure, capable of simultaneous visualization and inhibition of Aβ aggregation in vivo. P14 shows high binding affinity to Aβ aggregates and selectively labels Aβ plaques in the brain slices of APP/PS1 mice. Moreover, P14 is able to visualize overloaded Aβ in both APP/PS1 and 5 × FAD transgenic mice in vivo. From the aspect of potential therapeutic effects, P14 administration inhibits Aβ aggregation and alleviates Aβ-induced neuronal damage in vitro, as well as reduces central Aβ deposition and ameliorates cognitive impairment in APP/PS1 transgenic mice in vivo. Finally, P14 is applied to monitor the progression of Aβ aggregation in the brain of 5 × FAD transgenic mice and the intervention effect itself by fluorescence imaging. In summary, the discovery of this fluorescent agent might provide important clues for the future development of theranostic drug candidates targeting Aβ aggregation in AD.

Modulation of intramolecular freedom for tuning fluorescence imaging and photooxidation of amyloid-β aggregates.

Alzheimer's disease (AD) is distinguished by amyloid-β (Aβ) deposition and plaque formation, prompting significant interest in fluorescence imaging and photooxidation of Aβ aggregates for diagnostic and intervention purposes. However, the molecular engineering required to modulate fluorescence imaging and photooxidation of Aβ presents notable challenges. Here, we present the design of four small molecules (BTD-SZ, BTD-YD, BTD-TA-SZ, and BTD-TA-YD) aimed at investigating the influence of intramolecular freedom of movement on imaging and photooxidation. Notably, BTD-SZ exhibits exceptional fluorescence properties, offering promising potential for non-invasive detection of Aβ plaques in vivo. Furthermore, by converting dimethylamine into triphenylamine to restrict intramolecular freedom of movement in the aggregate state, we synthesized a photosensitizer denoted as BTD-TA-SZ. This compound demonstrates aggregation-induced photooxidation (AIP), effectively impeding Aβ aggregation under light irradiation in vivo. Thus, the modulation of intramolecular freedom of movement emerges as a pivotal molecular engineering strategy for developing photosensitizers for the diagnosis and intervention of AD, offering insights into innovative approaches for combating this debilitating condition.

Association of Tooth Loss with Alzheimer's Disease Tau Pathologies Assessed by Positron Emission Tomography.

Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC). To elucidate the relevance of oral conditions and amyloid-β (Aβ) and tau pathologies in human participants. We examined the number of remaining teeth and the biofilm-gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aβ and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aβ-positive, and all HCs were Aβ-negative. We analyzed the correlation between the oral parameters and radiotracer retention. No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status. Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.

Recent Research Progress in Fluorescent Probes for Detection of Amyloid-β In Vivo.

Alzheimer's disease (AD) is a neurodegenerative disease. Due to its complex pathological mechanism, its etiology is not yet clear. As one of the main pathological markers of AD, amyloid-β (Aβ) plays an important role in the development of AD. The deposition of Aβ is not only related to the degeneration of neurons, but also can activate a series of pathological events, including the activation of astrocytes and microglia, the breakdown of the blood-brain barrier, and the change in microcirculation, which is the main cause of brain lesions and death in AD patients. Therefore, the development of efficient and reliable Aβ-specific probes is crucial for the early diagnosis and treatment of AD. This paper focuses on reviewing the application of small-molecule fluorescent probes in Aβ imaging in vivo in recent years. These probes efficiently map the presence of Aβ in vivo, providing a pathway for the early diagnosis of AD and providing enlightenment for the design of Aβ-specific probes in the future.

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults.

Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau. We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aβ imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

Rational construction and evaluation of a dual-functional near-infrared fluorescent probe for the imaging of Amyloid-β and mitochondrial viscosity

Alzheimer's disease is a fatal, incurable, chronic neurodegenerative disease. Diagnosis in its early and even preclinical stages will be beneficial for its prevention and treatment. In the accepted pathological theory, abnormal accumulation of Aβ protein and abnormal mitochondrial function, including changes in mitochondrial viscosity, is closely related to Alzheimer's disease. To date, rare fluorescent probes have been reported that can simultaneously image Aβ plaques and mitochondrial viscosity. Therefore, the development of a dual-functional fluorescent probe for real-time fluorescence imaging of Aβ plaques and mitochondrial viscosity is crucial to discover a novel approach and strategy for the treatment of Alzheimer's disease, and to understand the pathological process and crosstalk between different biomarkers of Alzheimer's disease. Herein, we rationally designed and synthesized a series of fluorescent probes QM-SF-1∼5 with dimethylamino-quinolinium as the skeleton and thiophene as the π bridge to connect the groups with different electron-push/pull capacities. Among them, QM-SF-2 exhibited excellent properties such as large Stokes shift (168 nm), near-infrared emission (689 nm), and high selectivity and sensitivity (limit of detection was 1.07 μM) to Aβ aggregate and mitochondrial viscosity changes, indicating its promising prospects as a dual-functional imaging tool in the pathological study of Alzheimer's disease.

Rational design synthesis and evaluation of a novel near-infrared fluorescent probe for selective imaging of amyloid-β aggregates in Alzheimer's disease

Alzheimer's disease (AD) is a degenerative neurological disorder that remains incurable to date, seriously affecting the quality of life and health of those affected. One of the key neuropathological hallmarks of AD is the formation of amyloid-β (Aβ) plaques. Near-infrared (NIR) probes that possess a large Stokes shift show great potential for imaging of Aβ plaques in vivo and in vitro. Herein, we proposed a rational strategy for design and synthesis of a series of NIR fluorescent probes that incorporate a tricarbonitrile group as a strong electron-withdrawing group (EWG) to enable NIR emission and large Stokes shift for optimal imaging of Aβ plaques. The probe TCM-UM exhibited remarkable in vitro performance, including strong NIR emission (λem = 670 nm), large Stokes shift (120–245 nm), and its affinity for Aβ42 aggregates (Kd = 43.78 ± 4.09 nM) was superior to the commercially available probe Thioflavin T (ThT, Kd = 896.04 ± 33.43 nM). Further, TCM-UM was selected for imaging Aβ plaques in brain tissue slices and APP/PS1 transgenic (AD) mice, the results indicated that TCM-UM had an excellent ability to penetrate the blood-brain barrier (BBB) compared with ThT, and it could effectively distinguish wild-type (Wt) mice and APP/PS1 transgenic (AD) mice.

Nonfluent Variant Primary Progressive Aphasia on FDG, 11 C-PIB, and 18 F-APN-1607 PET Imaging.

A 61-year-old right-handed man presented with decreased cognitive function, short-term memory, fluent speech disorders, and grammatical errors for 1 year. The patient underwent PET imaging with 11 C-PIB, 18 F-FDG, and 18 F-APN-1607. The 11 C-PIB PET showed no amyloid accumulation; the 18 F-FDG PET showed hypometabolism in the bilateral frontal lobe, temporal lobe, and midbrain; and the 18 F-APN-1607 PET showed tau accumulation in the brainstem, basal ganglia, and left inferior frontal gyrus. These findings suggested a diagnosis of nonfluent variant primary progressive aphasia. This case emphasizes the value of combined imaging of glucose metabolism, Aβ, and tau PET in the diagnosis of nonfluent variant primary progressive aphasia.

A dual-functional fluorescence probe for detection of Aβ aggregates and hydroxyl radicals

Synchronous detection of Aβ aggregates and reactive oxygen species (ROS) would provide direct insight to reveal the complicated correlations between the two crucial Alzheimer’s disease (AD) hallmarks. Herein, the first fluorescence probe (Quin-HCy) for dual-functional detection of Aβ aggregates and the highly destructive ROS hydroxyl radicals (•OH) is developed. Quin-HCy is designed with a blood-brain barrier (BBB) permeable quinoline fluorophore and a •OH-responsive hydrocyanine moiety. Quin-HCy shows obvious fluorescence increases in response to Aβ aggregates and •OH at 450 nm and 770 nm, respectively. The large spectral shift (∼ 320 nm) is advantageous for the independent detection of these two analytes in two distant channels. Quin-HCy has been used to image •OH in cells through the addition of Fenton reagents, stimulation with PMA and induction of ferroptosis. Most importantly, fluorescence imaging with Quin-HCy shows that significant •OH is generated in Aβ aggregate-treated neuron cells, which provides direct evidence for the high dependence between Aβ aggregates and •OH in the etiology of AD. Besides, Quin-HCy has favorable BBB permeability, and is able to image Aβ plaques and •OH in AD mice brain slices.

Design of Self-Assembled Nanoparticles as a Potent Inhibitor and Fluorescent Probe for β-Amyloid Fibrillization.

Alzheimer's disease (AD) remains incurable due to its complex pathogenesis. The deposition of β-amyloid (Aβ) in the brain appears much earlier than any clinical symptoms and plays an essential role in the occurrence and development of AD neuropathology, which implies the importance of early theranostics. Herein, we designed a self-assembled bifunctional nanoparticle (LC8-pCG-fLC8) for Aβ fluorescent diagnosis and inhibition. The nanoparticle was synthesized by click chemistry from Aβ-targeting peptide Ac-LVFFARKC-NH2 (LC8) and an Aβ fluorescent probe f with the zwitterionic copolymer poly(carboxybetaine methacrylate-glycidyl methacrylate) (p(CBMA-GMA), pCG). Owing to the high reactivity of epoxy groups, the peptide concentration of LC8-pCG-fLC8 nanoparticles reached about 4 times higher than that of the existing inhibitor LVFFARK@poly(carboxybetaine) (LK7@pCB). LC8-pCG-fLC8 exhibited remarkable inhibitory capability (suppression efficiency of 83.0% at 20 μM), altered the aggregation pathway of Aβ, and increased the survival rate of amyloid-induced cultured cells from 76.5% to 98.0% at 20 μM. Notably, LC8-pCG-fLC8 possessed excellent binding affinity, good biostability, and high fluorescence responsivity to β-sheet-rich Aβ oligomers and fibrils, which could be used for the early diagnosis of Aβ aggregation. More importantly, in vivo tests using transgenic C. elegans CL2006 stain showed that LC8-pCG-fLC8 could specifically image Aβ plaques, prolong the lifespan (from 13 to 17 days), and attenuate the AD-like symptoms (reducing paralysis and Aβ deposition). Therefore, self-assembled nanoparticles hold great potential in AD theranostics.

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span.

White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF β-amyloid (Aβ) 42, Aβ40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aβ with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span. We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models. A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers. Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.

Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes.

Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)-related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFRβ was associated with different AD-associated and age-associated pathologic changes leading to dementia. PDGFRβ was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with β-amyloid (Aβ)-PET and tau-PET standardized uptake value ratio, APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb), and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes). The cohort had a mean age of 67 years (CU = 62.8, MCI = 69.9, dementia = 70.4), and 50.1% were male (CU = 46.6%, MCI = 53.7%, dementia = 54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b = 19.1, β = 0.5, 95% CI 16-22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, β = 0.5, 95% CI 2.8-3.9, p < 0.001), GFAP (b = 27.4, β = 0.4, 95% CI 20.9-33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, β = 0.2, 95% CI 24.9-49.9, p < 0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16%-33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05). In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.

Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.

[18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694. We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups. Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex. Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

High-Affinity Fluorescent Probes for the Detection of Soluble and Insoluble Aβ Deposits in Alzheimer's Disease.

The overproduction and deposition of the amyloid-β (Aβ) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aβ aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aβ species with (iii) emission maxima in the 500-750 nm region. Thioflavin-T (ThT) is the most used fluorescent probe for imaging Aβ fibril aggregates. However, because of the poor BBB crossing (log P = -0.14) and short emission wavelength (482 nm) after binding with Aβ fibrils, ThT can be limited to in vitro use only. Herein, we have developed Aβ deposit-recognizing fluorescent probes (ARs) with a D-π-A architecture and a longer emission wavelength after binding with Aβ species. Among the newly designed probes, AR-14 showed an admirable fluorescence emission (>600 nm) change after binding with soluble Aβ oligomers (2.3-fold) and insoluble Aβ fibril aggregates (4.5-fold) with high affinities Kd = 24.25 ± 4.10 nM; Ka = (4.123 ± 0.69) × 107 M-1 for fibrils; Kd = 32.58 ± 4.89 nM; and Ka = (3.069 ± 0.46) × 107 M-1 for oligomers with high quantum yield, molecular weight of <500 Da, reasonable log P = 1.77, stability in serum, and nontoxicity, and it can cross the BBB efficiently. The binding affinity of AR-14 toward Aβ species is proved by fluorescence binding studies and fluorescent staining of 18-month-old triple-transgenic (3xTg) mouse brain sections. In summary, the fluorescent probe AR-14 is efficient and has an admirable quality for the detection of soluble and insoluble Aβ deposits in vitro and in vivo.