Departed Pleasures

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Abnormalities of iron homeostasis and the dopaminergic system in Tourette syndrome revealed by 7T MRI and PET

While the implication of a dysfunctional dopaminergic system in Tourette syndrome (TS) is well established, the underlying pathophysiological mechanisms remain unclear. Apart from neurotransmitters, disturbed iron homeostasis and iron regulatory mechanisms are also suspected. Iron is a trace element of fundamental biological importance and is involved in the synthesis and metabolism of dopamine and its receptors and transporters. The goal of the current pre-registered, multi-modal, cross-sectional study was to investigate the relationship between potential iron homeostasis imbalances and dopaminergic system disturbances in patients with TS. Susceptibility-sensitive MRI at 7 Tesla was used to obtain surrogate measures for local brain iron in 25 patients with TS (age 30 ± 9 years, 6 female) and 40 matched control subjects. Additionally, dopamine D1 receptor availability was investigated with [11C]SCH23390 PET in a subgroup of 20 patients and 20 controls. Significantly reduced sub-cortical magnetic susceptibility, indicating reduced iron levels, was observed in TS patients in the caudate, pallidum, sub-thalamic nucleus, thalamus, red nucleus and substantia nigra. These reductions were accompanied by significant reductions of the [11C]SCH23390 binding potential indicating reduced availability of D1 receptors in the dorsal striatum. The D1 receptor abnormality correlated with tic severity. These results point to alterations of intra-synaptic dopamine release and reduced striatal D1 receptor binding, supporting the notion of disruption in multiple functional elements of the dopaminergic system. Such dopaminergic abnormalities appear to be associated with disturbances in iron homeostasis

Epileptiform Activity in Alcohol Dependent Patients and Possibilities of Its Indirect Measurement

Background: Alcohol dependence during withdrawal and also in abstinent period in many cases is related to reduced inhibitory functions and kindling that may appear in the form of psychosensory symptoms similar to temporal lobe epilepsy frequently in conditions of normal EEG and without seizures. Because temporal lobe epileptic activity tend to spread between hemispheres, it is possible to suppose that measures reflecting interhemispheric information transfer such as electrodermal activity (EDA) might be related to the psychosensory symptoms. Methods and Findings: We have performed measurement of bilateral EDA, psychosensory symptoms (LSCL-33) and alcohol craving (ACQ) in 34 alcohol dependent patients and 32 healthy controls. The results in alcohol dependent patients show that during rest conditions the psychosensory symptoms (LSCL-33) are related to EDA transinformation (PTI) between left and right EDA records (Spearman r = 0.44, p,0.01). Conclusions: The result may present potentially useful clinical finding suggesting a possibility to indirectly assess epileptiform changes in alcohol dependent patients

Variable Anisotropic Brain Electrical Conductivities in Epileptogenic Foci

Source localization models assume brain electrical conductivities are isotropic at about 0.33 S/m. These assumptions have not been confirmed ex vivo in humans. This study determined bidirectional electrical conductivities from pediatric epilepsy surgery patients. Electrical conductivities perpendicular and parallel to the pial surface of neocortex and subcortical white matter (n = 15) were measured using the 4-electrode technique and compared with clinical variables. Mean (±SD) electrical conductivities were 0.10 ± 0.01 S/m, and varied by 243% from patient to patient. Perpendicular and parallel conductivities differed by 45%, and the larger values were perpendicular to the pial surface in 47% and parallel in 40% of patients. A perpendicular principal axis was associated with normal, while isotropy and parallel principal axes were linked with epileptogenic lesions by MRI. Electrical conductivities were decreased in patients with cortical dysplasia compared with non-dysplasia etiologies. The electrical conductivity values of freshly excised human brain tissues were approximately 30% of assumed values, varied by over 200% from patient to patient, and had erratic anisotropic and isotropic shapes if the MRI showed a lesion. Understanding brain electrical conductivity and ways to non-invasively measure them are probably necessary to enhance the ability to localize EEG sources from epilepsy surgery patients

Connectivity as a universal predictor of tau spreading in typical and atypical Alzheimer's disease

BackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid-β-positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA-AD; 83 logopenic variant primary progressive aphasia, lvPPA-AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS-AD) and 68 with typical AD from 12 international cohorts, who underwent tau-PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid-β-negative controls, cross-sectional tau-PET standardized uptake value ratios within Schaefer-200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity-based distance (using the 30% strongest positive region-to-region connections of a group-average connectivity matrix from ADNI elderly controls) and tau-PET covariance (group-average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1-4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA-AD, left-hemispheric dominant pattern in lvPPA-AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS-AD, and temporo-parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau-PET covariance was associated with shorter functional connectivity-based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (pConclusionThis multi-center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant-specific endpoints in clinical trials

Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex

The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTase) which sequentially methylate the RNA cap at guanosine-N7 and ribose 2′-O positions, catalyzed by nsp14 N7-MTase and nsp16 2′-O-MTase, respectively. A unique feature for SARS-CoV is that nsp16 requires non-structural protein nsp10 as a stimulatory factor to execute its MTase activity. Here we report the biochemical characterization of SARS-CoV 2′-O-MTase and the crystal structure of nsp16/nsp10 complex bound with methyl donor SAM. We found that SARS-CoV nsp16 MTase methylated m7GpppA-RNA but not m7GpppG-RNA, which is in contrast with nsp14 MTase that functions in a sequence-independent manner. We demonstrated that nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and SAM cofactor. Structural analysis revealed that nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1∶1 ratio. The structure of the nsp16/nsp10 interaction interface shows that nsp10 may stabilize the SAM-binding pocket and extend the substrate RNA-binding groove of nsp16, consistent with the findings in biochemical assays. These results suggest that nsp16/nsp10 interface may represent a better drug target than the viral MTase active site for developing highly specific anti-coronavirus drugs

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia. We found that from age 60 years to 80 years, tau PET positivity in a temporal composite region increased from 1.1% to 4.4% among CU amyloid-β (Aβ)-negative participants and from 17.4% to 22.2% among CU Aβ-positive participants. Across the same age span, tau PET positivity decreased from 68.0% to 52.9% in participants with MCI and from 91.5% to 74.6% in participants with dementia. Age, Aβ status, APOE ε4 carriership and female sex were all associated with a higher prevalence of tau PET positivity across groups. APOE ε4 carriership in CU individuals lowered the age at onset of both Aβ positivity and tau positivity by decades. Finally, we replicated these associations in an independent autopsy dataset (N = 5,072 from 3 cohorts)

Nutritional Systems Biology Modeling: From Molecular Mechanisms to Physiology

The use of computational modeling and simulation has increased in many biological fields, but despite their potential these techniques are only marginally applied in nutritional sciences. Nevertheless, recent applications of modeling have been instrumental in answering important nutritional questions from the cellular up to the physiological levels. Capturing the complexity of today's important nutritional research questions poses a challenge for modeling to become truly integrative in the consideration and interpretation of experimental data at widely differing scales of space and time. In this review, we discuss a selection of available modeling approaches and applications relevant for nutrition. We then put these models into perspective by categorizing them according to their space and time domain. Through this categorization process, we identified a dearth of models that consider processes occurring between the microscopic and macroscopic scale. We propose a “middle-out” strategy to develop the required full-scale, multilevel computational models. Exhaustive and accurate phenotyping, the use of the virtual patient concept, and the development of biomarkers from “-omics” signatures are identified as key elements of a successful systems biology modeling approach in nutrition research—one that integrates physiological mechanisms and data at multiple space and time scales

Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicenter study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n=139 posterior cortical atrophy/PCA-AD; n=103 logopenic variant primary progressive aphasia/lvPPA-AD; n=35 behavioural variant AD/bvAD; n=43 corticobasal syndrome/CBS-AD), with a subset of individuals (n=78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n=19 PCA-AD, n=32 lvPPA-AD, n=23 bvAD, n=19 CBS-AD). Gaussian mixture modeling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state fMRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicenters (i.e., the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicenters (i.e., the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicenters aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicenters and accumulation epicenters corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific endpoints in clinical trials

Presupposed ignorance and exhaustification: how scalar implicatures and presuppositions interact

International audienceWe investigate the interactions between scalar implicatures and presuppositions in sentences containing both a scalar item and presupposition trigger. We first critically discuss Gajewski and Sharvit’s previous approach.We then closely examine two ways of integrating an exhaustivity-based theory of scalar implicatures with a trivalent approach to presuppositions. The empirical side of our discussion focuses on two novel observations: (i) the interactions between prosody and monotonicity, and (ii) what we call presupposed ignorance. In order to account for these observations, our final proposal relies on two mechanisms of scalar strengthening, the Presupposed Ignorance Principle and an exhaustivity operator which lets the presuppositions of negated alternatives project