Comparisons of global topographic/isostatic models to the Earth's observed gravity field

The Earth's gravitational potential, as described by a spherical harmonic expansion to degree 180, was compared to the potential implied by the topography and its isostatic compensation using five different hypothesis. Initially, series expressions for the Airy/Heiskanen topographic isostatic model were developed to the third order in terms of (h/R), where h is equivalent rock topography and R is a mean Earth radius. Using actual topographic developments for the Earth, it was found that the second and third terms of the expansion contributed 30 and 3 percents, of the first of the expansion. With these new equations it is possible to compute depths (D) of compensation, by degree, using 3 different criteria. The results show that the average depth implied by criterion I is 60 km while it is about 33 km for criteria 2 and 3 with smaller compensation depths at the higher degrees. Another model examined was related to the Vening-Meinesz regional hypothesis implemented in the spectral domain. Finally, oceanic and continental response functions were derived for the global data sets and comparisons made to locally determined values

A highly conserved circular RNA is required to keep neural cells in a progenitor state in the mammalian brain

circSLC45A4 is the main RNA splice isoform produced from its genetic locus and one of the highest expressed circRNAs in the developing human frontal cortex. Knockdown of this highly conserved circRNA in a human neuroblastoma cell line is sufficient to induce spontaneous neuronal differentiation, measurable by increased expression of neuronal marker genes. Depletion of circSlc45a4 in the developing mouse cortex causes a significant reduction of the basal progenitor pool and increases the expression of neurogenic regulators. Furthermore, knockdown of circSlc45a4a induces a significant depletion of cells in the cortical plate. In addition, deconvolution of the bulk RNA-seq data with the help of single-cell RNA-seq data validates the depletion of basal progenitors and reveals an increase in Cajal-Retzius cells. In summary, we present a detailed study of a highly conserved circular RNA that is necessary to maintain the pool of neural progenitors in vitro and in vivo

A blind spot in mental healthcare? Psychotherapists lack education and expertise for the support of adults on the autism spectrum

Most adults on the autism spectrum have co-occurring mental health conditions, creating a high demand for mental health services – including psychotherapy – in autistic adults. However, autistic adults have difficulties accessing mental health services. The most-reported barriers to accessing treatment are therapists’ lack of knowledge and expertise surrounding autism, as well as unwillingness to treat autistic individuals. This study was conducted by a participatory autism research group and examined 498 adult-patient psychotherapists on knowledge about autism and self-perceived competency to diagnose and treat autistic patients without intellectual disability compared to patients with other diagnoses. Psychotherapists rated their education about autism in formal training, and competency in the diagnosis and treatment of patients with autism, lowest compared to patients with all other diagnoses surveyed in the study, including those with comparable prevalence rates. Many therapists had misconceptions and outdated beliefs about autism. Few had completed additional training on autism, but the majority were interested in receiving it. Greater knowledge about autism was positively linked to openness to accept autistic patients. The results point to an alarming gap in knowledge necessary for adequate mental health care for individuals with autism. Lay abstract Most autistic adults experience mental health problems. There is a great demand for psychotherapeutic support that addresses the specific needs of autistic individuals. However, people with autism encounter difficulties trying to access diagnostic and therapeutic services. This study was conducted by a participatory autism research group: a group in which autistic individuals and scientists collaborate. The group developed a questionnaire for psychotherapists in Germany to assess their knowledge about autism. Psychotherapists also rated their ability to diagnose and treat autistic patients without intellectual disability, and patients with other psychological diagnoses. Many of the 498 psychotherapists that responded reported little knowledge and outdated beliefs about autism, as well as little training on treating patients with autism. Their expertise about other psychological conditions was more comprehensive. However, many psychotherapists were interested in professional training on autism. Those with more knowledge were also more open to treating autistic patients. In conclusion, psychotherapists’ lack of knowledge and expertise seem to be a major barrier for adults with autism to receiving helpful psychotherapeutic support. The results demonstrate the need for an advancement in autism education during psychotherapists’ training and in continuous education.Peer Reviewe

Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease

Objective Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. Methods Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial alpha-/beta-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. Results Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with alpha-diversity. Physical activity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with beta-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with alpha- and beta-diversity. Physical inactivity and constipation were highest in individuals with theFirmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with thePrevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. Interpretation Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2020Peer reviewe

Machine Learning to Detect Alzheimer's Disease from Circulating Non-coding RNAs

Blood-borne small non-coding (sncRNAs) are among the prominent candidates for blood-based diagnostic tests. Often, high-throughput approaches are applied to discover biomarker signatures. These have to be validated in larger cohorts and evaluated by adequate statistical learning approaches. Previously, we published high-throughput sequencing based microRNA (miRNA) signatures in Alzheimer’s disease (AD) patients in the United States (US) and Germany. Here, we determined abundance levels of 21 known circulating miRNAs in 465 individuals encompassing AD patients and controls by RT-qPCR. We computed models to assess the relation between miRNA expression and phenotypes, gender, age, or disease severity (Mini-Mental State Examination; MMSE). Of the 21 miRNAs, expression levels of 20 miRNAs were consistently de-regulated in the US and German cohorts. 18 miRNAs were significantly correlated with neurodegeneration (Benjamini-Hochberg adjusted P < 0.05) with highest significance for miR-532-5p (Benjamini-Hochberg adjusted P = 4.8 × 10−30). Machine learning models reached an area under the curve (AUC) value of 87.6% in differentiating AD patients from controls. Further, ten miRNAs were significantly correlated with MMSE, in particular miR-26a/26b-5p (adjusted P = 0.0002). Interestingly, the miRNAs with lower abundance in AD were enriched in monocytes and T-helper cells, while those up-regulated in AD were enriched in serum, exosomes, cytotoxic t-cells, and B-cells. Our study represents the next important step in translational research for a miRNA-based AD test

Gait Is Associated with Cognitive Flexibility: A Dual-Tasking Study in Healthy Older People

Objectives: To analyze which gait parameters are primarily influenced by cognitive flexibility, and whether such an effect depends on the walking condition used. Design: Cross-sectional analysis. Setting: Tübingen evaluation of Risk factors for Early detection of Neurodegenerative Disorders. Participants: A total of 661 non-demented individuals (49-80 years). Measurements: A gait assessment with four conditions was performed: a 20 m walk at convenient speed (C), at fast speed (F), at fast speed while checking boxes (FB), and while subtracting serial 7s (FS). Seven gait parameters from a wearable sensor-unit (McRoberts, Netherlands) were compared with delta Trail-Making-Test (dTMT) values, which is a measure of cognitive flexibility. Walking strategies of good and poor dTMT performers were compared by evaluating the patterns of gait parameters across conditions. Results: Five parameters correlated significantly with the dTMT in the FS condition, two parameters in the F and FB condition, and none in the C condition. Overall correlations were relatively weak. Gait speed was the gait parameter that most strongly correlated with the dTMT (r(2) = 7.4%). In good, but not poor, dTMT performers differences between FB and FS were significantly different in variability-associated gait parameters. Conclusion: Older individuals need cognitive flexibility to perform difficult walking conditions. This association is best seen in gait speed. New and particularly relevant for recognition and training of deficits is that older individuals with poor cognitive flexibility have obviously fewer resources to adapt to challenging walking conditions. Our findings partially explain gait deficits in older adults with poor cognitive flexibility

Prodromal Markers in Parkinson's Disease:Limitations in Longitudinal Studies and Lessons Learned

A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson's disease (PD). Studies have identified several different prodromal markers that may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies

Older adults’ coping strategies during the COVID-19 pandemic – a longitudinal mixed-methods study

IntroductionOlder age is a main risk factor for severe COVID-19. In 2020, a broad political debate was initiated as to what extent older adults need special protection and isolation to minimize their risk for SARS-CoV-2 infection. However, isolation might also have indirect negative psychological (e.g., loneliness, stress, fear, anxiety, depression) or physical (e.g., lack of exercise, missing medical visits) consequences depending on individual strategies and personality traits to cope longitudinally with this crisis.MethodsTo examine the impact of individuals’ coping with the pandemic on mental health, a large sample of 880 older adults of the prospective longitudinal cohort TREND study were surveyed six times about their individual coping strategies in the COVID-19 pandemic between May 2020 (05/2020: Mage = 72.1, SDage = 6.4, Range: 58–91 years) and November 2022 in an open response format. The relevant survey question was: “What was helpful for you to get through the last months despite the COVID-19 pandemic? E.g., phone calls, going for a walk, or others.”Results and DiscussionIn total, we obtained 4,561 records containing 20,578 text passages that were coded and assigned to 427 distinct categories on seven levels based on qualitative content analysis using MAXQDA. The results allow new insights into the impact of personal prerequisites (e.g., value beliefs, living conditions), the general evaluation of the pandemic (e.g., positive, irrelevant, stressful) as well as the applied coping strategies (e.g., cognitive, emotional- or problem-focused) to deal with the COVID-19 pandemic by using an adapted Lazarus stress model. Throughout the pandemic emotional-focused as well as problem-focused strategies were the main coping strategies, whereas general beliefs, general living conditions and the evaluation were mentioned less frequently

A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer's disease

BACKGROUND: Alzheimer's disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aβ aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously. METHODS: We quantified progressive Aβ aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs. RESULTS: Experiments revealed faster accumulation of Aβ42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aβ42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aβ aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aβ42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aβ plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients. CONCLUSIONS: We report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker