Self-determined motivational health coaching ('SAMI') during outpatient treatment to promote physical activity of people with serious mental illness: a pilot controlled trial.

BACKGROUND: Brief motivational coaching, integrated into health care; seems promising to address physical inactivity of people with serious mental illness (SMI). AIMS: To test the impact of a self-determined health coaching approach (the "SAMI" intervention) during outpatient mental health treatment on moderate-to-vigorous physical activity (MVPA) of people with SMI. METHODS: Adults (mean age = 41.9, SD = 10.9) with an ICD-10 diagnosis of mental illness were semi-randomized to the SAMI-intervention group (IG) or control group (CG). The IG received 30 minutes of health coaching based on the self-determination theory (SDT). MVPA and sedentary time (ST) were measured with the International Physical Activity Questionnaire - short form (IPAQ-SF) and symptoms of mental illness with the Brief Symptom Inventory (BSI-18), each at baseline and follow-up (3-4 months). Differences in primary (MVPA) and secondary (ST, BSI-18) outcomes were evaluated using negative binomial regressions and general linear models. RESULTS: In the IG (n = 30), MVPA increased from 278 (interquartile range [IQR] = 175-551) to 435 (IQR = 161-675) min/week compared to a decrease from 250 (IQR = 180-518) to 155 (IQR = 0-383) min/week in the CG (n = 26; adjusted relative difference at follow-up: Incidence Rate Ratio [IRR] = 2.14, 95% CI: 1.17-3.93, p = 0.014). There were no statistically significant differences in ST and BSI-18. CONCLUSIONS: Brief self-determined health coaching during outpatient treatment could increase post-treatment MVPA in people with SMI, potentially up to a clinically relevant level. However, great uncertainty (for all outcomes) weakens the assessment of clinical relevance.

A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Mitochondrial genome study in blood of maternally inherited ALS cases.

BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer's and Parkinson's diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells.

ALS is a fatal motor neuron disease that displays a broad variety of phenotypes ranging from early fatal courses to slowly progressing and rather benign courses. Such divergence can also be seen in genetic ALS cases with varying phenotypes bearing specific mutations, suggesting epigenetic mechanisms like DNA methylation act as disease modifiers. However, the epigenotype dictated by, in addition to other mechanisms, DNA methylation is also strongly influenced by the individual's genotype. Hence, we performed a DNA methylation study using EPIC arrays on 7 monozygotic (MZ) twin pairs discordant for ALS in whole blood, which serves as an ideal model for eliminating the effects of the genetic-epigenetic interplay to a large extent. We found one CpG site showing intra-pair hypermethylation in the affected co-twins, which maps to the Glutamate Ionotropic Receptor Kainate Type Subunit 1 gene (GRIK1). Additionally, we found 4 DMPs which were subsequently confirmed using 2 different statistical approaches. Differentially methylated regions or blocks could not be detected within the scope of this work. In conclusion, we revealed that despite a low sample size, monozygotic twin studies discordant for the disease can bring new insights into epigenetic processes in ALS, pointing to new target loci for further investigations.

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Recommending Physical Activity for People with Intellectual Disabilities: The Relevance of Public Health Guidelines, Physical Activity Behaviour and Type of Contact.

People with an intellectual disability (ID) often exhibit more sedentary behaviour and are less physically active than the general population. While previous public health guidelines on physical activity (PA) did not specifically address the needs of people with an ID, the recent updates now include this population, with recommendations similar to those for the general population. However, it is unclear whether the information about these guidelines has reached the broader public and what factors may influence their implementation. To investigate these issues, an online survey was conducted in Austria, Germany and Switzerland, which examined the (a) PA recommendation for people with an ID, (b) awareness of current guidelines, (c) participants' own PA behaviour (IPAQ-SF) and (d) specific contact with people with an ID. Participants (n = 585) recommended similar levels of PA for people with an ID as for the general population, but knowledge of the guidelines did not affect their recommendation. However, participants' own PA behaviour and context-specific contact (e.g., in family or at work) were associated with the recommended PA levels. Therefore, promoting the relevance of PA and fostering contact with people with an ID might be suitable ways to increase PA in people with an ID.

ALS is imprinted in the chromatin accessibility of blood cells.

Amyotrophic Lateral Sclerosis (ALS) is a complex and incurable neurodegenerative disorder in which genetic and epigenetic factors contribute to the pathogenesis of all forms of ALS. The interplay of genetic predisposition and environmental footprints generates epigenetic signatures in the cells of affected tissues, which then alter transcriptional programs. Epigenetic modifications that arise from genetic predisposition and systemic environmental footprints should in theory be detectable not only in affected CNS tissue but also in the periphery. Here, we identify an ALS-associated epigenetic signature ('epiChromALS') by chromatin accessibility analysis of blood cells of ALS patients. In contrast to the blood transcriptome signature, epiChromALS includes also genes that are not expressed in blood cells; it is enriched in CNS neuronal pathways and it is present in the ALS motor cortex. By combining simultaneous ATAC-seq and RNA-seq with single-cell sequencing in PBMCs and motor cortex from ALS patients, we demonstrate that epigenetic changes associated with the neurodegenerative disease can be found in the periphery, thus strongly suggesting a mechanistic link between the epigenetic regulation and disease pathogenesis.

Spreading of alpha-synuclein between different cell types.

Aggregation of alpha-synuclein (α-syn) is central in Parkinson's disease as well as in other synucleinopathies. Recent evidence suggests that not only intracellular aggregation of α-syn plays an important role for disease pathogenesis but also cell-to-cell propagation of α-syn seems to significantly contribute to pathological changes in synucleinopathies. In this mini-review we summarize current aspects of spreading of α-syn between brain cell types and its role in pathology.

Thoracic trauma promotes alpha-Synuclein oligomerization in murine Parkinson's disease.

BACKGROUND: Systemic and neuroinflammatory processes play key roles in neurodegenerative diseases such as Parkinson's disease (PD). Physical trauma which induces considerable systemic inflammatory responses, represents an evident environmental factor in aging. However, little is known about the impact of physical trauma, on the immuno-pathophysiology of PD. Especially blunt chest trauma which is associated with a high morbidity and mortality rate in the elderly population, can induce a strong pulmonary and systemic inflammatory reaction. Hence, we sought out to combine a well-established thoracic trauma mouse model with a well-established PD mouse model to characterize the influence of physical trauma to neurodegenerative processes in PD. METHODS: To study the influence of peripheral trauma in a PD mouse model we performed a highly standardized blunt thorax trauma in a well-established PD mouse model and determined the subsequent local and systemic response. RESULTS: We could show that blunt chest trauma leads to a systemic inflammatory response which is quantifiable with increased inflammatory markers in bronchoalveolar fluids (BALF) and plasma regardless of the presence of a PD phenotype. A difference of the local inflammatory response in the brain between the PD group and non-PD group could be detected, as well as an increase in the formation of oligomeric pathological alpha-Synuclein (asyn) suggesting an interplay between peripheral thoracic trauma and asyn pathology in PD. CONCLUSION: Taken together this study provides evidence that physical trauma is associated with increased asyn oligomerization in a PD mouse model underlining the relevance of PD pathogenesis under traumatic settings.

Methylome analysis of ALS patients and presymptomatic mutation carriers in blood cells.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with a monogenic cause in approximately 10% of cases. However, familial clustering of disease without inheritance in a Mendelian manner and the broad range of phenotypes suggest the presence of epigenetic mechanisms. Hence, we performed an epigenome-wide association study on sporadic, symptomatic and presymptomatic familial ALS cases with mutations in C9ORF72 and FUS and healthy controls studying DNA methylation in blood cells. We found differentially methylated DNA positions (DMPs) and regions embedding DMPs associated with either disease status, C9ORF72 or FUS mutation status. One DMP reached methylome-wide significance and is attributed to a region encoding a long non-coding RNA (LOC389247). Furthermore, we could demonstrate co-localization of DMPs with an ALS-associated GWAS region near the SCN7A/SCN9A and XIRP2 genes. Finally, a classifier model that predicts disease status (ALS, healthy) classified all but one presymptomatic mutation carrier as healthy, suggesting that the presence of ALS symptoms rather than the presence of ALS-associated genetic mutations is associated with blood cell DNA methylation.

T-cell dysregulation is associated with disease severity in Parkinson's Disease.

The dysregulation of peripheral immunity in Parkinson's Disease (PD) includes changes in both the relative numbers and gene expression of T cells. The presence of peripheral T-cell abnormalities in PD is well-documented, but less is known about their association to clinical parameters, such as age, age of onset, progression rate or severity of the disease. We took a detailed look at T-cell numbers, gene expression and activation in cross-sectional cohorts of PD patients and age-matched healthy controls by means of flow cytometry and NanoString gene expression assay. We show that the well-pronounced decrease in relative T-cell numbers in PD blood is mostly driven by a decrease of CD8+ cytotoxic T cells and is primarily associated with the severity of the disease. In addition, we demonstrate that the expression of inflammatory genes in T cells from PD patients is also associated with disease severity. PD T cells presented with increased activation upon stimulation with phytohemagglutinin that also correlated with disease severity. In summary, our data suggest that the consequences of disease severity account for the changes in PD T cells, rather than age, age of onset, duration or the disease progression rate.

Protein Binding Partners of Dysregulated miRNAs in Parkinson's Disease Serum.

Accumulating evidence suggests that microRNAs (miRNAs) are a contributing factor to neurodegenerative diseases. Although altered miRNA profiles in serum or plasma have been reported for several neurodegenerative diseases, little is known about the interaction between dysregulated miRNAs and their protein binding partners. We found significant alterations of the miRNA abundance pattern in serum and in isolated serum-derived extracellular vesicles of Parkinson's disease (PD) patients. The differential expression of miRNA in PD patients was more robust in serum than in isolated extracellular vesicles and could separate PD patients from healthy controls in an unsupervised approach to a high degree. We identified a novel protein interaction partner for the strongly dysregulated hsa-mir-4745-5p. Our study provides further evidence for the involvement of miRNAs and HNF4a in PD. The demonstration that miRNA-protein binding might mediate the pathologic effects of HNF4a both by direct binding to it and by binding to proteins regulated by it suggests a complex role for miRNAs in pathology beyond the dysregulation of transcription.

Short-and Long-Term Effectiveness of a Physical Activity Intervention with Coordinated Action between the Health Care Sector and Local Sports Clubs. A Pragmatic Trial in Austrian Adults.

(1) Background: Collaboration between the health care sector and the sports sector to increase physical activity (PA) behaviour among inactive adults is still rare. The objective of the study was to evaluate the short- and long-term effectiveness of a mixed PA intervention on the PA behaviour in an adult population. (2) Methods: In a quasi-experimental study with two follow-up measurements (four and 12 months), adults were contacted by post before their stay in a health resort. During the health resort stay, the intervention group (IG) received PA counselling and a coupon for 12 standardised free-of-charge sessions in a sports club. The participants in the comparator group (CG) received PA counselling and written material. PA was measured with an accelerometer (GENEActive). Linear mixed-effects models were applied to examine the change in PA behaviour, both within and between groups in moderate- to vigorous-intensity PA over time. (3) Results: We obtained at least one follow-up measurement from 217 participants (IG = 167, CG = 50), who were 50% female, with an average age of 53 (±6) years. PA significantly increased from the baseline to the four-month measurement by 58 min./wk (95% CI 36, 80) and to the 12-month measurement by 24 min./wk (95% CI 2, 46) within the IG. No change in PA occurred in the CG. We also found a short-term between-group (IG vs. CG) difference in change over time, but not a long-term difference. (4) Conclusions: The study confirms that a collaboration between the health care sector and local sports clubs is a feasible method of recruiting people into a standardised PA programme and to increase their PA over the long term.

A Qualitative Examination of the Physical Activity Needs of People with Severe Mental Illness.

It is recognised that physical activity has a positive impact on quality of life, social well-being and overall health of people with severe mental illness. However, there is a lack of theory informed programmes that support people with mental illness to adopt regular physical activity behaviour. The aim of this case study was to identify determinants of long-term physical activity among people with severe mental illness that may then inform the development of more suitable physical activity programmes. Semi-structured interviews were conducted with 15 people (13 men and 2 women) with a mean age of 36.7 [standard deviation (SD)=11.8] who had a diagnosed mental illness and were attending a physical activity programme run by a mental health non-governmental organisation. Interview data was analysed using the documentary method to emphasise the perspective of people with severe mental illness. Three participation types were generated in the context of individuals' physical activity orientation and social background-first 'rehabilitative orientated' (physical activity as a supportive measure to re-enter the labour market and develop a daily routine); second 'social-orientated' (social well-being within the group as the primary motive); finally, 'trust-orientated' (a sense of trust that encourages participation). Based on these type-specific categories, it is suggested that different settings (mental health care centres and sport clubs) might be needed to attract and maintain the physical activity engagement of people with severe mental illness. In the context of sport clubs, it is recommended that coaches undergo training in mental health literacy.

How Does Counselling in a Stationary Health Care Setting Affect the Attendance in a Standardised Sports Club Programme? Process Evaluation of a Quasi-Experimental Study.

Actions in partnership across sectors is one principle for the promotion of health behaviours. The objective of this study was to describe the participation in a sports club-based exercise programme-named JACKPOT-following an intervention in a health care setting. Focus was given to the recruitment into JACKPOT, the attendance level, and whether the different programme elements were implemented as intented. The practicability of the project was also retrospectively rated. Participants were 238 inactive people (50% women) between 30 and 65 years of age who attended a health resort. Of these, 77% were assigned to the intervention group (IG). The recruitment into the 12 JACKPOT sessions and the attendance levels were recorded via attendance lists. The implementation of the intervention standards was assessed with structured interviews and participatory observation. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS)-2 tool served to rate the practicability of the project. Almost 50% of the IG subjects attended JACKPOT sessions at least once and 54% of the attenders visited ≥75% of the 12 sessions. Some of the programme elements were not delivered fully. The process evaluation results showed that the project worked in a real-world setting, and also uncovered potential reasons such as incomplete information delivery for the moderate recruitment and attendance level.