Search

Background: Auditory event-related potentials (AERPs) have been suggested as possible biomarkers for the early diagnosis of Alzheimer's disease (AD). However, no study has investigated AERP measures in individuals with subjective memory complaints (SMCs), who have been suggested to be at a pre-clinical stage of AD. Objective: This study investigated whether AERPs in older adults with SMC can be used to objectively identify those at high risk of developing AD. Methods: AERPs were measured in older adults. Presence of SMC was determined using the Memory Assessment Clinics Questionnaire (MAC-Q). Hearing thresholds using pure-tone audiometry, neuropsychological data, levels of amyloid-β burden and Apolipoprotein E (APOE)ɛ genotype were also obtained A classic two-tone discrimination (oddball) paradigm was used to elicit AERPs (i.e., P50, N100, P200, N200, and P300). Results: Sixty-two individuals (14 male, mean age 71.9±5.2 years) participated in this study, of which, 43 (11 male, mean age 72.4±5.5 years) were SMC and 19 (3 male, mean age 70.8±4.3 years) were non-SMC (controls). P50 latency was weakly but significantly correlated with MAC-Q scores. In addition, P50 latencies were significantly longer in Aβ+ individuals compared to Aβ– individuals. Conclusion: Results suggest that P50 latencies may be a useful tool to identify individuals at higher risk (i.e., participants with high Aβ burden) of developing measurable cognitive decline. Further longitudinal and cross-sectional studies in a larger cohort on SMC individuals are warranted to determine if AERP measures could be of significance for the detection of pre-clinical AD. [ABSTRACT FROM AUTHOR]

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78–0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93–0.99) and overall accuracy (93.0%). Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. Objective: This study aimed to examine the heritability of SCCs, correlations between SCCs and memory ability, and the influence of personality and mood on these relationships. Methods: Participants were 306 twin pairs. The heritability of SCCs and the genetic correlations between SCCs and memory performance, personality, and mood scores were determined using structural equation modelling. Results: SCCs were low to moderately heritable. Memory performance, personality and mood were genetically, environmentally, and phenotypically correlated with SCCs in bivariate analysis. However, in multivariate analysis, only mood and memory performance had significant correlations with SCCs. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. The link between personality and SCCs was mediated by mood. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. Conclusion: Our results suggest that SCCs are influenced both by a person's mood and their memory performance, and that these determinants are not mutually exclusive. While SCCs had genetic overlap with memory performance and environmental association with mood, much of the genetic and environmental components that comprised SCCs were specific to SCCs, though these specific factors are yet to be determined. [ABSTRACT FROM AUTHOR]

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; P diff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; P diff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886–0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835–0.872; P diff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642–0.813; P diff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; P diff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320–0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD) has prolonged asymptomatic or mild symptomatic periods. Given that there is an increase in treatment options and that early intervention could modify the disease course, it is desirable to devise biological indices that may differentiate AD and nonAD at mild cognitive impairment (MCI) stage. Methods: Based on two well-acknowledged observations of background slowing (attenuation in alpha power and enhancement in theta and delta powers) and early involvement of posterior cingulate cortex (PCC, a neural hub of default-mode network), this study devised novel neural markers, namely, spectral ratios of alpha1 to delta and alpha1 to theta in the PCC. Results: We analysed 46 MCI patients, with 22 ADMCI and 24 nonADMCI who were matched in age, education, and global cognitive capability. Concordant with the prediction, the regional spectral ratios were lower in the ADMCI group, suggesting its clinical application potential. Conclusion: Previous research has verified that neural markers derived from clinical electroencephalography may be informative in differentiating AD from other neurological conditions. We believe that the spectral ratios in the neural hubs that show early pathological changes can enrich the instrumental assessment of brain dysfunctions at the MCI (or pre-clinical) stage. [ABSTRACT FROM AUTHOR]

High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC–autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aβ for Aβ plaques and autoradiography with [18F]flotaza and [125I]IBETA for Aβ plaques. For Tau, [124I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [125I]IPPI and [124I]IPPI. Annotations for Aβ plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aβ plaques and Tau in each slice. The binding of [124I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [124I]IPPI with MK-6240. Percent positivity for Aβ plaques was 4–15%, and for Tau, it was 1.3 to 35%. All IHC Aβ plaque-positive subjects showed [18F]flotaza and [125I]IBETA binding with a positive linear correlation (r2 > 0.45). Tau-positive subjects showed [124/125I]IPPI binding with a stronger positive linear correlation (r2 > 0.80). This quantitative IHC–autoradiography approach provides an accurate measurement of Aβ plaques and Tau within and across subjects. [ABSTRACT FROM AUTHOR]

Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr−/−.Leiden mice. Baseline measurements were performed in chow-fed Ldlr−/−.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed. [ABSTRACT FROM AUTHOR]

A sensitive and selective molecularly imprinted polymer (MIP) sensor was developed for the determination of amyloid-β (1–42) (Aβ42). The glassy carbon electrode (GCE) was successively modified with electrochemical reduction graphene oxide (ERG) and poly(thionine-methylene blue) (PTH-MB). The MIPs were synthesized by electropolymerization with Aβ42 as a template and o-phenylenediamine (o–PD) and hydroquinone (HQ) as functional monomers. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CC), and differential pulse voltammetry (DPV) were used to study the preparation process of the MIP sensor. The preparation conditions of the sensor were investigated in detail. In optimal experimental conditions, the response current of the sensor was linear in the range of 0.12–10 μg mL−1 with a detection limit of 0.018 ng mL−1. The MIP-based sensor successfully detected Aβ42 in commercial fetal bovine serum (cFBS) and artificial cerebrospinal fluid (aCSF). [ABSTRACT FROM AUTHOR]

Background: Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. Methods: CSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. Results: In AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time. Conclusions: Our findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum. [ABSTRACT FROM AUTHOR]

Background: The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear. Objective: To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points. Methods: We examined multivariate multimodal neuroimaging relationships between MRI and 18FDG-PET among suspected non-Alzheimer's disease pathology (SNAP) (A–T/N+; n = 14), Amyloid Only (A+T–N–; n = 24) and Probable AD (A+T+N+; n = 77) groups. Sparse canonical correlation analyses were employed to model spatially disjointed regions of association between MRI and 18FDG-PET data. These relationships were assessed at three combinations of time points –cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. Results: In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. Conclusion: These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ and 41 Aβ–PET–), 11 mild cognitively impaired (3 Aβ–PET+ and 8 Aβ–PET–) and 6 probable AD (5 Aβ–PET+ and 1 Aβ–PET–) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ–PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load. [ABSTRACT FROM AUTHOR]

Background: Several blood-based biomarkers are promising to be used in the diagnosis of Alzheimer's disease (AD) including A_42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results. Methods: This study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma A_42/40 was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (A_-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of A_-PET positivity was defined as =1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels. Results: A total of 645 participants were included in this study. The levels and diagnostic performance of A_42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in A_-PET negetive sample (_ = -0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and A_-PET stratified groups (_ = -0.27, p < 0.001 in whole sample; _ = -0.28, p = 0.004 in A-; _ = -0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR. Conclusion: Plasma A_42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages. [ABSTRACT FROM AUTHOR]

Glycinal (HCOCH2NH2) and acetamide (CH3CONH2) are simple molecular building blocks of biomolecules in prebiotic chemistry, though their origin on early Earth and formation in interstellar media remain a mystery. These molecules are formed with their tautomers in low temperature interstellar model ices upon interaction with simulated galactic cosmic rays. Glycinal and acetamide are accessed via barrierless radical‐radical reactions of vinoxy (⋅CH2CHO) and acetyl (⋅C(O)CH3), and then undergo keto‐enol tautomerization. Exploiting tunable photoionization reflectron time‐of‐flight mass spectroscopy and photoionization efficiency (PIE) curves, these results demonstrate fundamental reaction pathways for the formation of complex organics through non‐equilibrium ice reactions in cold molecular cloud environments. These molecules demonstrate an unconventional starting point for abiotic synthesis of organics relevant to contemporary biomolecules like polypeptides and cell membranes in deep space. [ABSTRACT FROM AUTHOR]

Background: Early detection of ß-amyloid (Aß) accumulation, a major biomarker for Alzheimer's disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aß for predicting Aß deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aß is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aß and CSF Aß levels for Aß PET positivity. Methods: We recruited 488 participants who underwent both plasma Aß and Aß PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aß and Aß PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aß and CSF Aß, respectively, logistic regression and receiver operating characteristic analyses were performed. Results: When predicting Aß PET status, both plasma Aß42/40 ratio and CSF Aß42 showed high accuracy (plasma Aß area under the curve (AUC) 0.814; CSF Aß AUC 0.848). In the plasma Aß models, the AUC values were higher than plasma Aß alone model, when the models were combined with either cognitive stage (p < 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aß models, when these variables were added. Conclusion: Plasma Aß might be a useful predictor of Aß deposition on PET status as much as CSF Aß, particularly when considered with clinical information such as APOE genotype and cognitive stage. [ABSTRACT FROM AUTHOR]

Glycinal (HCOCH2NH2) and acetamide (CH3CONH2) are simple molecular building blocks of biomolecules in prebiotic chemistry, though their origin on early Earth and formation in interstellar media remain a mystery. These molecules are formed with their tautomers in low temperature interstellar model ices upon interaction with simulated galactic cosmic rays. Glycinal and acetamide are accessed via barrierless radical‐radical reactions of vinoxy (⋅CH2CHO) and acetyl (⋅C(O)CH3), and then undergo keto‐enol tautomerization. Exploiting tunable photoionization reflectron time‐of‐flight mass spectroscopy and photoionization efficiency (PIE) curves, these results demonstrate fundamental reaction pathways for the formation of complex organics through non‐equilibrium ice reactions in cold molecular cloud environments. These molecules demonstrate an unconventional starting point for abiotic synthesis of organics relevant to contemporary biomolecules like polypeptides and cell membranes in deep space. [ABSTRACT FROM AUTHOR]

Objectives: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer's disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. Conclusions: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases. [ABSTRACT FROM AUTHOR]

1,2-Ethenediols are deemed key intermediates in prebiotic and interstellar syntheses of carbohydrates. Here we present the gas-phase synthesis of these enediols, the high-energy tautomers of glycolaldehyde, trapped in cryogenic argon matrices. Importantly, upon photolysis at λ = 180–254 nm, the enols rearrange to the simplest sugar glycolaldehyde. [ABSTRACT FROM AUTHOR]

With the growth of technology and the need to integrate optical devices, photonic crystals (PhCs) will have great potential in designing and fabricating programmable photonic integrated circuits (PICs). This paper proposes two all-optical majority gates using the fluid infiltration approach in a PhC slab, which aims to design logic functions. Numerical results using the well-known plane wave expansion method show that the proposed fundamental PhC slab has three photonic band gaps (PBGs) in TE mode. The most important is in the wavelength range of 1.516 μm ≤ λ ≤ 1.743 μm, located in the attractive telecom C-band range. The results of light propagation inside the proposed gates using the finite-difference time-domain (FDTD) method reveal that both gates have a standard threshold of less than 0.28 for the logic zero and more than 0.35 for the logic one. The first and second proposed majority gates also have delays of 680 fs and 610 fs, respectively. One of the advantages of using the fluid infiltration approach is that there is no need to change the geometric dimensions of the structure for the desired application. That goal can be achieved only by replacing the fluid with another one. The proposed designs can be used as basic logic gates in the design of PICs. [ABSTRACT FROM AUTHOR]

Simple Summary: The central nervous system is extremely sensitive to cosmic rays – an ionizing radiation that astronauts encounter during interplanetary missions, particularly to Mars. There are still disputes about how dangerous cosmic rays are to brain health. Our review aimed to analyze the studies on the influence of cosmic rays at flight-related doses on physical development, well-being, emotional state, depressive-like behavior, cognition, neurogenesis and the course of neurodegenerative process. The combined effects of cosmic rays and hypogravity were also the focus of our review. Thus, for the first time a comprehensive picture of radiation-induced changes in the central nervous system is presented: from functional to neurochemical and molecular. Relying on the literature data we conclude that cosmic rays are relatively safe for the central nervous system functions. Moreover, under some irradiation scenarios, it has been shown that cosmic rays enhance cognitive abilities of rodents and nonhuman primates. This effect is often accompanied by hyperactivity, increased orientational-exploratory behavior and, simultaneously, state anxiety. Interestingly, the results of several studies strongly suggest that cosmic rays reverse negative effects of antiorthostatic suspension (a ground-based model of hypogravity). Taken together, these data allow us to be optimistic about the prospects for humanity's cosmic expansion. Galactic cosmic rays (GCR) pose a serious threat to astronauts' health during deep space missions. The possible functional alterations of the central nervous system (CNS) under GCR exposure can be critical for mission success. Despite the obvious negative effects of ionizing radiation, a number of neutral or even positive effects of GCR irradiation on CNS functions were revealed in ground-based experiments with rodents and primates. This review is focused on the GCR exposure effects on emotional state and cognition, emphasizing positive effects and their potential mechanisms. We integrate these data with GCR effects on adult neurogenesis and pathological protein aggregation, forming a complete picture. We conclude that GCR exposure causes multidirectional effects on cognition, which may be associated with emotional state alterations. However, the irradiation in space-related doses either has no effect or has performance enhancing effects in solving high-level cognition tasks and tasks with a high level of motivation. We suppose the model of neurotransmission changes after irradiation, although the molecular mechanisms of this phenomenon are not fully understood. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) infections in cattle are a major cause of economic loss and mortality. Machine learning (ML) techniques are gaining widespread application in solving predictive tasks in both human and veterinary medicine. Objectives: Our primary aim was to develop and compare ML models that could predict the likelihood of a CNS disorder of infectious or inflammatory origin in neurologically‐impaired cattle. Our secondary aim was to create a user‐friendly web application based on the ML model for the diagnosis of infection and inflammation of the CNS. Animals: Ninety‐eight cattle with CNS infection and 86 with CNS disorders of other origin. Methods: Retrospective observational study. Six different ML methods (logistic regression [LR]; support vector machine [SVM]; random forest [RF]; multilayer perceptron [MLP]; K‐nearest neighbors [KNN]; gradient boosting [GB]) were compared for their ability to predict whether an infectious or inflammatory disease was present based on demographics, neurological examination findings, and cerebrospinal fluid (CSF) analysis. Results: All 6 methods had high prediction accuracy (≥80%). The accuracy of the LR model was significantly higher (0.843 ± 0.005; receiver operating characteristic [ROC] curve 0.907±0.005) than the other models and was selected for implementation in a web application. Conclusion and Clinical Importance: Our findings support the use of ML algorithms as promising tools for veterinarians to improve diagnosis. The open‐access web application may aid clinicians in achieving correct diagnosis of infectious and inflammatory neurological disorders in livestock, with the added benefit of promoting appropriate use of antimicrobials. [ABSTRACT FROM AUTHOR]

Zinc (Zn) is an essential micronutrient involved in biochemical processes for growth and development of plants. Here, we investigated the variability in response of 15 rice genotypes for number of roots, shoot and root length, metal tolerance score under zinc sufficient (ZS) and zinc deficient (ZD) conditions using hydroponics system. Significant variation was observed among genotypes for four traits under ZS and ZD conditions. Five genotypes were identified with promising performance under ZD, which could be deployed in rice breeding program for zinc deficiency. Expression analysis of OsHMA2 and OsHMA3 in root tissues of five selected zinc efficient genotypes has shown up-regulation of OsHMA3 in three genotypes with high grain zinc. Root length was highly correlated with OsHMA2 and OsHMA3 under ZD condition. [ABSTRACT FROM AUTHOR]

Background: Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased β-amyloid (Aβ) uptake and global Aβ status. Methods: We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach. Results: A total of 62 (6.4%) subjects showed increased focal Aβ uptake with subthreshold global Aβ status [global (-) and focal (+) Aβ group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment (p < 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(-)F(-). Participants with widespread Aβ involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aβ involvement G(-)F(+). Conclusion: Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aβ uptake and global Aβ status. Thus, researchers and clinicians should pay more attention to focal increased Aβ uptake in addition to global Aβ status. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by brain parenchymal abundance of amyloid-beta (Aβ) and the accumulation of lipofuscin material that is rich in neutral lipids. However, the mechanisms for aetiology of AD are presently not established. There is increasing evidence that metabolism of lipoprotein-Aβ in blood is associated with AD risk, via a microvascular axis that features breakdown of the blood-brain barrier, extravasation of lipoprotein-Aβ to brain parenchyme and thereafter heightened inflammation. A peripheral lipoprotein-Aβ/capillary axis for AD reconciles alternate hypotheses for a vascular, or amyloid origin of disease, with amyloidosis being probably consequential. Dietary fats may markedly influence the plasma abundance of lipoprotein-Aβ and by extension AD risk. Similarly, apolipoprotein E (Apo E) serves as the primary ligand by which lipoproteins are cleared from plasma via high-affinity receptors, for binding to extracellular matrices and thereafter for uptake of lipoprotein-Aβ via resident inflammatory cells. The epsilon APOE ε4 isoform, a major risk factor for AD, is associated with delayed catabolism of lipoproteins and by extension may increase AD risk due to increased exposure to circulating lipoprotein-Aβ and microvascular corruption. [ABSTRACT FROM AUTHOR]

There is increasing evidence of a positive association of type 2 diabetes with Alzheimer's disease (AD), the most prevalent form of dementia. Suggested pathways include cerebral vascular dysfunction; central insulin resistance, or exaggerated brain abundance of potentially cytotoxic amyloid-b (Ab), a hallmark feature of AD. However, contemporary studies find that Ab is secreted in the periphery by lipogenic organs and secreted as nascent triglyceride-rich lipoproteins (TRL's). Pre-clinical models show that exaggerated abundance in blood of TRL-Ab compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Ab moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Ab by peripheral lipogenic organs attenuates the early-AD phenotype indicated in animal models, consistent with causality. Poorly controlled type 2 diabetes commonly features hypertriglyceridemia because of exaggerated TRL secretion and reduced rates of catabolism. Alzheimer's in diabetes may therefore be a consequence of heightened abundance in blood of lipoprotein-Ab and accelerated breakdown of the BBB. This review reconciles the prevailing dogma of amyloid associated cytotoxicity as a primary risk factor in lateonset AD, with substantial evidence of a microvascular axis for dementia-indiabetes. Consideration of potentially relevant pharmacotherapies to treat insulin resistance, dyslipidaemia and by extension plasma amyloidemia in type 2 diabetes are discussed. [ABSTRACT FROM AUTHOR]

Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer's disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, which obtained regional specificity through the differing distributions of amyloid β and tau in AD brains. A concerted search for more selective and affine tau PET tracers yielded compounds belonging to at least eight structural categories; 18F-flortaucipir, known variously as [18F]-T807, AV-1451, and Tauvid®, emerged as the first tau tracer approved by the American Food and Drug Administration. The various tau tracers differ concerning their selectivity over amyloid β, off-target binding at sites such as monoamine oxidase and neuromelanin, and degree of uptake in white matter. While there have been many reviews of molecular imaging of tau in AD and other conditions, there has been no systematic comparison of the fitness of the various tracers for discriminating between AD patient and healthy control (HC) groups. In this narrative review, we endeavored to compare the binding properties of the various tau tracers in vitro and the effect size (Cohen's d) for the contrast by PET between AD patients and age-matched HC groups. The available tracers all gave good discrimination, with Cohen's d generally in the range of two–three in culprit brain regions. Overall, Cohen's d was higher for AD patient groups with more severe illness. Second-generation tracers, while superior concerning off-target binding, do not have conspicuously higher sensitivity for the discrimination of AD and HC groups. We suppose that available pharmacophores may have converged on a maximal affinity for tau fibrils, which may limit the specific signal imparted in PET studies. [ABSTRACT FROM AUTHOR]

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non‐invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15O]H2O and [18F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine‐enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine‐enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non‐monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2X7 receptor, type 1 cannabinoid receptor (CB1), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed. [ABSTRACT FROM AUTHOR]

With the advances in modern medicine and the adaptation towards healthier lifestyles, the average life expectancy has doubled since the 1930s, with individuals born in the millennium years now carrying an estimated life expectancy of around 100 years. And even though many individuals around the globe manage to age successfully, the prevalence of aging‐associated neurodegenerative diseases such as sporadic Alzheimer's disease has never been as high as nowadays. The prevalence of Alzheimer's disease is anticipated to triple by 2050, increasing the societal and economic burden tremendously. Despite all efforts, there is still no available treatment defeating the accelerated aging process as seen in this disease. Yet, given the advances in neuroimaging techniques that are discussed in the current Review article, such as in positron emission tomography (PET) or magnetic resonance imaging (MRI), pivotal insights into the heterogenous effects of aging‐associated processes and the contribution of distinct lifestyle and risk factors already have and are still being gathered. In particular, the concepts of resilience (i.e. coping with brain pathology) and resistance (i.e. avoiding brain pathology) have more recently been discussed as they relate to mechanisms that are associated with the prolongation and/or even stop of the progressive brain aging process. Better understanding of the underlying mechanisms of resilience and resistance may one day, hopefully, support the identification of defeating mechanism against accelerating aging. [ABSTRACT FROM AUTHOR]

Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated 'a first and second wave' of reactive astrogliosis in AD with distinct close‐loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET‐tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide further invaluable mechanistic insights into AD and other non‐AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinical value of new fluid astrocytes biomarkers in the context of existing biomarkers, are the latest avenue that needs further exploration. [ABSTRACT FROM AUTHOR]

Background Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration. Methods Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression. Results Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change −0.003 mm [95% confidence interval (CI) −0.005 to −0.001], p =.002), but not amyloid accumulation (0.003 [95% CI −0.001 to 0.006], p =.107), or WMH increase (0.011 cm3 [95% CI −0.001 to 0.023], p =.062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (−0.004 mm [95% CI −0.008 to −0.001, p =.014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p =.011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p =.006). Hospitalization was not associated with developing abnormal cortical thinning (p =.407), amyloid accumulation (p =.596), or WMH/infarctions score (p =.565). Conclusions Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold. [ABSTRACT FROM AUTHOR]

Early cognitive decline in patients with Alzheimer's (AD) is associated with quantifiable structural and functional connectivity changes in the brain. AD dysregulation of Aβ and tau metabolism progressively disrupt normal synaptic function, leading to loss of synapses, decreased hippocampal synaptic density and early hippocampal atrophy. Advances in brain imaging techniques in living patients have enabled the transition from clinical signs and symptoms-based AD diagnosis to biomarkers-based diagnosis, with functional brain imaging techniques, quantitative EEG, and body fluids sampling. The hippocampus has a central role in semantic and episodic memory processing. This cognitive function is critically dependent on normal intrahippocampal connections and normal hippocampal functional connectivity with many cortical regions, including the perirhinal and the entorhinal cortex, parahippocampal cortex, association regions in the temporal and parietal lobes, and prefrontal cortex. Therefore, decreased hippocampal synaptic density is reflected in the altered functional connectivity of intrinsic brain networks (aka large-scale networks), including the parietal memory, default mode, and salience networks. This narrative review discusses recent critical issues related to detecting AD-associated early cognitive decline with brain synaptic structural and functional markers in high-risk or neuropsychologically diagnosed patients with subjective cognitive impairment or mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Relationship agreements are important for HIV prevention among gay and bisexual men (GBM) in relationships, with research earlier in the HIV epidemic often finding that agreements specified monogamy or condom use with casual partners. There is evidence that HIV pre-exposure prophylaxis (PrEP) has shifted sexual practices among some men in relationships, such as allowing condomless sex with casual partners, but there has been little attention paid to relationship agreements among GBM who use PrEP. In this paper, we analyzed national, Australian, cross-sectional data from an online survey completed by non-HIV-positive GBM in 2021 (N = 1,185). Using logistic regression, we identified demographic characteristics, sexual practices and the types of relationship agreement that were associated with PrEP use among GBM in relationships. Using Pearson's chi-squared tests, we explored whether PrEP users in relationships reported similar sexual practices to PrEP users not in relationships. PrEP use among GBM in relationships was independently associated with older age, identifying as gay, being in a non-monogamous relationship, having a spoken (explicit) relationship agreement, having a primary HIV-negative partner taking PrEP or a primary partner living with HIV, reporting recent condomless casual sex, reporting an STI diagnosis in the past year, and knowing at least one other PrEP user. We found that PrEP users in relationships had similar sexual practices to PrEP users not in relationships. GBM in relationships who have casual sex and who meet PrEP suitability criteria may be good candidates for PrEP. Our findings suggest that explicit relationship agreements remain important for HIV prevention, and they support PrEP use among GBM in relationships. [ABSTRACT FROM AUTHOR]

Background: Wide evidence suggests that physical activity (PA) confers protection against Alzheimer's disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε4 allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε4. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε4 carriage might be dependent on the specific outcome measure utilised. Main body. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model on the interactive effects of PA and APOE ε4 carriage on well-established mechanisms underlying AD. Available literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response and glucose metabolism. Finally, combining all this information, we have built an integrative model, which includes evidence-based and theoretical synergistic interactions across mechanisms. Moreover, we have identified key knowledge gaps in the literature, providing a list of testable hypotheses that future studies need to address. Conclusions: We conclude that PA influences a wide array of molecular targets involved in AD neuropathology. A deeper understanding of where, when and, most importantly, how PA decreases AD risk even in the presence of the APOE ε4 allele will enable the creation of new protocols using exercise along pharmaceuticals in combined therapeutic approaches. [ABSTRACT FROM AUTHOR]

We unravel, for the very first time, the formation pathways of hydroxyacetone (CH3COCH2OH), methyl acetate (CH3COOCH3), and 3-hydroxypropanal (HCOCH2CH2OH), as well as their enol tautomers within mixed ices of methanol (CH3OH) and acetaldehyde (CH3CHO) analogous to interstellar ices in the ISM exposed to ionizing radiation at ultralow temperatures of 5 K. Exploiting photoionization reflectron time-of-flight mass spectrometry (PI-ReToF-MS) and isotopically labeled ices, the reaction products were selectively photoionized allowing for isomer discrimination during the temperature-programmed desorption phase. Based on the distinct mass-to-charge ratios and ionization energies of the identified species, we reveal the formation pathways of hydroxyacetone (CH3COCH2OH), methyl acetate (CH3COOCH3), and 3-hydroxypropanal (HCOCH2CH2OH) via radical–radical recombination reactions and of their enol tautomers (prop-1-ene-1,2-diol (CH3C(OH)CHOH), prop-2-ene-1,2-diol (CH2C(OH)CH2OH), 1-methoxyethen-1-ol (CH3OC(OH)CH2) and prop-1-ene-1,3-diol (HOCH2CHCHOH)) via keto-enol tautomerization. To the best of our knowledge, 1-methoxyethen-1-ol (CH3OC(OH)CH2) and prop-1-ene-1,3-diol (HOCH2CHCHOH) are experimentally identified for the first time. Our findings help to constrain the formation mechanism of hydroxyacetone and methyl acetate detected within star-forming regions and suggest that the hitherto astronomically unobserved isomer 3-hydroxypropanal and its enol tautomers represent promising candidates for future astronomical searches. These enol tautomers may contribute to the molecular synthesis of biologically relevant molecules in deep space due to their nucleophilic character and high reactivity. [ABSTRACT FROM AUTHOR]

Purpose: The role of cerebral blood flow (CBF) in the early stages of Alzheimer's disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD). Methods: We included 187 cognitively normal individuals with SCD from the SCIENCe project (65 ± 8 years, 39% F, MMSE 29 ± 1). Each underwent a dynamic (0–70 min) [18F]florbetapir PET and T1-weighted MRI scan, enabling calculation of mean binding potential (BPND; specific amyloid binding) and R1 (measure of relative (r)CBF). Eighty-three individuals underwent a second [18F]florbetapir PET (2.6 ± 0.7 years). Participants annually underwent neuropsychological assessment (follow-up time 3.8 ± 3.1 years; number of observations n = 774). Results: A low baseline R1 was associated with steeper decline on tests addressing memory, attention, and global cognition (range betas 0.01 to 0.27, p < 0.05). High BPND was associated with steeper decline on tests covering all domains (range betas − 0.004 to − 0.70, p < 0.05). When both predictors were simultaneously added to the model, associations remained essentially unchanged. Additionally, we found longitudinal associations between R1 and BPND. High baseline BPND predicted decline over time in R1 (all regions, range betasBP×time − 0.09 to − 0.14, p < 0.05). Vice versa, low baseline R1 predicted increase in BPND in frontal, temporal, and composite ROIs over time (range betasR1×time − 0.03 to − 0.08, p < 0.05). Conclusion: Our results suggest that amyloid accumulation and decrease in rCBF are two parallel disease processes without a fixed order, both providing unique predictive information for cognitive decline and each process enhancing the other longitudinally. [ABSTRACT FROM AUTHOR]

Purpose: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. Methods: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). Results: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. Conclusions: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed. [ABSTRACT FROM AUTHOR]

Objective: We determined the interactive associations of apolipoprotein e4 (APOE-e4), and obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease and examined for racial/ethnic differences of this association. Methods: We used data from the National Alzheimer's Coordinating Center Uniform Dataset (NACC UDS). All participants undergo annual observations, including demographic survey, battery of neuropsychological tests, blood draw (with genotyping), and a clinical evaluation with medical and cognitive/ dementia status assessment, while a subset of participants have cerebrospinal fluid (CSF) biomarkers and neuroimaging data. Biomarkers of AD were characterized as the presence of abnormally low amyloid in CSF, via validated Aβ42 cut off protocols, and total segmented hippocampal volume, and volume of white matter hyper intensities (WMH). While clinical markers (to preview cognitive relationships) were characterized via the Montreal Cognitive Assessment (MOCA). Results: Biomarker and clinical marker data were derived from 1,387 participants at baseline (mean age=69.73+8.32; 58.6% female; 13.7% Black/ African American), 18.4% of the sample had sleep apnea, and 37.9% were APOE-e4 carriers. Our results confirmed previous reports that OSA and APOE-e4 were independently associated with AD through abnormal levels of amyloid (F(1,306)=4.27; p = 0.040; F(1,285)=60.88; p<0.000, respectively), WMH volume (F(1,306)=4.27; p = 0.040; F(1,285)=60.88; p<0.000, respectively), and MOCA scores (F(1,306)=4.27; p = 0.040; F(1,285)=60.88; p<0.000, respectively). No significant interaction between OSA and APOE-e4 relative to amyloid emerged, however, race stratified analyses indicated the interaction of OSA and APOE-e4 and was significantly associated with WMH and hippocampal volume in Black/African American, but not white participants. Conclusion: OSA and APOE-e4 are interactively associated with WHM in Black/African Americans. This interaction may partially explicate increased levels of risk in this population. [ABSTRACT FROM AUTHOR]

Background: The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter‐rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. [ABSTRACT FROM AUTHOR]

(1) Background and aims: Amyloidosis due to aggregation of amyloid-β (Aβ42) is a key pathogenic event in Alzheimer's disease (AD), whereas aggregation of mature islet amyloid polypeptide (IAPP37) in human islets leads to β-cell dysfunction. The aim of this study is to uncover potential biomarkers that might additionally point to therapy for early AD patients. (2) Methods: We used bioinformatic approach to uncover novel IAPP isoforms and developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their peptide levels in human plasma and CSF from individuals with early AD and controls, as well as postmortem cerebrum of clinical confirmed AD and controls. We used Thioflavin T amyloid reporter assay to measure the IAPP isoform fibrillation propensity and anti-amyloid potential against aggregation of Aβ42 and IAPP37. (3) Results: We uncovered hominid-specific IAPP isoforms: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is processed to mature IAPP25 instead of IAPP37. We found that hIAPPβ was significantly reduced in the plasma of AD patients with the accuracy of 89%. We uncovered that IAPP25 and a GDNF derived DNSP11 were nonaggregating peptides that inhibited the aggregation of IAPP37 and Aβ42. (4) Conclusions: The novel peptides derived from hIAPP isoforms have potential to serve as blood-derived biomarkers for early AD and be developed as peptide based anti-amyloid medicine. [ABSTRACT FROM AUTHOR]

Cerebral blood flow (CBF) changes are closely related to Alzheimer's disease (AD). Arterial spin labeling (ASL) uses water proton in blood as an endogenous contrast agent to obtain CBF, which has attracted must attention in AD studies due to its advantages of non - invasiveness and safety. However, there is still a lack of uniformity in the implementation of ASL in clinical settings, and limited by sample size and different population cohorts, research results may be different or lack of universality, which lead to the fact that this technology has not yet been widely applied in AD. This article reviews the new research progress on the correlation between CBF measured by ASL and AD disease process, pathologic biomarkers, vascular pathological burden, apolipoprotein E ε4 (ApoEε4) gene, and cognitive impairment development, in order to provide guidance for the clinical application of ASL in AD. [ABSTRACT FROM AUTHOR]