Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS) to Assess Effects of Age, Sex, and Head Size on Interstitial Fluid Dynamics in Healthy Subjects.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer's disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET.

INTRODUCTION: Mapping of microscopic changes in the perivascular space (PVS) of the cerebral cortex, beyond magnetic resonance-visible PVS in white matter, may enhance our ability to diagnose Alzheimer's disease (AD) early. METHODS: We used the cerebrospinal fluid (CSF) water fraction (CSFF), a magnetic resonance imaging-based biomarker, to characterize brain parenchymal CSF water, reflecting microscopic PVS in parenchyma. We measured CSFF and amyloid beta (Aß) using 11 C Pittsburgh compound B positron emission tomography to investigate their relationship at both the subject and voxel levels. RESULTS: Our research has demonstrated a positive correlation between the parenchymal CSFF, a non-invasive imaging biomarker indicative of parenchymal glymphatic clearance, and Aß deposition, observed at both individual and voxel-based assessments in the posterior cingulate cortex. DISCUSSION: This study shows that an increased parenchymal CSFF is associated with Aß deposition, suggesting that CSFF could serve as a biomarker for brain glymphatic clearance, which can be used to detect early fluid changes in PVS predisposing individuals to the development of AD. HIGHLIGHTS: Cerebrospinal fluid fraction (CSFF) could be a biomarker of parenchymal perivascular space. CSFF is positively associated with amyloid beta (Aß) deposition at subject level. CSFF in an Aß+ region is higher than in an Aß- region in the posterior cingulate cortex. Correspondence is found between Aß deposition and glymphatic clearance deficits measured by CSFF.

Multimodal assessment of brain fluid clearance is associated with amyloid-beta deposition in humans.

PURPOSE: The present study investigates a multimodal imaging assessment of glymphatic function and its association with brain amyloid-beta deposition. METHODS: Two brain CSF clearance measures (vCSF and DTI-ALPS) were derived from dynamic PET and MR diffusion tensor imaging (DTI) for 50 subjects, 24/50 were Aß positive (Aß+). T1W, T2W, DTI, T2FLAIR, and 11C-PiB and 18F-MK-6240 PET were acquired. Multivariate linear regression models were assessed with both vCSF and DTI-ALPS as independent variables and brain Aß as the dependent variable. Three types of models were evaluated, including the vCSF-only model, the ALPS-only model and the vCSF+ALPS combined model. Models were applied to the whole group, and Aß subgroups. All analyses were controlled for age, gender, and intracranial volume. RESULTS: Sample demographics (N=50) include 20 males and 30 females with a mean age of 69.30 (sd=8.55). Our results show that the combination of vCSF and ALPS associates with Aß deposition (p < 0.05, R2 = 0.575) better than either vCSF (p < 0.05, R2 = 0.431) or ALPS (p < 0.05, R2 = 0.372) alone in the Aß+ group. We observed similar results in whole-group analyses (combined model: p < 0.05, R2 = 0.287; vCSF model: p <0.05, R2 = 0.175; ALPS model: p < 0.05, R2 = 0.196) with less significance. Our data also showed that vCSF has higher correlation (r = -0.548) in subjects with mild Aß deposition and DTI-ALPS has higher correlation (r=-0.451) with severe Aß deposition subjects. CONCLUSION: The regression model with both vCSF and DTI-ALPS is better associated with brain Aß deposition. These two independent brain clearance measures may better explain the variation in Aß deposition than either term individually. Our results suggest that vCSF and DTI-ALPS reflect complementary aspects of brain clearance functions.

A Multi-Criteria Decision Aid Tool for Radiopharmaceutical Selection in Tau PET Imaging.

The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer's disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)-tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [18F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations.

Distinct and joint effects of low and high levels of Aß and tau deposition on cortical thickness.

Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

BACKGROUND: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER: NCT03053908.

An investigation to choose the proper therapy technique in the management of autism spectrum disorder.

Aim: Autism spectrum disorder is a class of neurological disorders that affect the development of brain functions. This study aims to evaluate, compare and rank the therapy techniques used in the management of autism spectrum disorder using multicriteria decision-making approaches. Materials & methods: Fuzzy PROMETHEE and fuzzy TOPSIS approaches were used. Fuzzy PROMETHEE utilizes a pair-wise comparison of alternatives under the fuzzy environment while fuzzy TOPSIS utilizes geometric distance from the positive ideal solution under the fuzzy environment for the evaluation of the effectiveness of the alternatives.The techniques selected for evaluation are applied behavioral analysis, cognitive behavioral therapy, speech therapy and pharmacological therapy such as Risperidone and Aripiprazole. Criteria used in this study include efficacy, cost and side effects, and their weights are assigned based on specific patient conditions. Results: The results indicate that applied behavioral analysis, cognitive behavioral therapy and speech therapy are the most preferred techniques, followed by Aripiprazole and Risperidone. Conclusion: More criteria could be considered and the weights could be assigned according to the patient profile.

Lay abstract Autism spectrum disorder is a neurodevelopmental disorder (affecting the development of the brain) that usually presents during childhood. Because autism spectrum disorder has no cure, selecting the best therapy to manage the disorder is important for therapists, parents, health institutions and researchers with an interest in these types of disorders. This study focuses on comparing specific therapy techniques by using multicriteria decision-making methods. The result obtained by a decision-maker is not always the same, as different decision-makers may come up with different solutions depending on things like the cost and how well a therapy works on different aspects of the disorder. The outcome of the study indicates that applied behavioral analysis, cognitive behavioral therapy and speech therapy are preferred treatment alternatives, followed by treatment with Risperidone and Aripiprazole. Further analyses are needed to obtain more accurate patient-specific results that will incorporate specific patient demographics and data, as well as looking at the combination of two or three techniques.