Comparative analysis of neurofilaments and biomarkers of muscular damage in amyotrophic lateral sclerosis.

Diagnosis of the fatal neurodegenerative disease amyotrophic lateral sclerosis is challenging. Neurofilaments, indicative of neuronal damage, along with creatine kinase, creatinine, myoglobin, and troponin T, representing muscular damage, have been identified as promising fluid biomarkers. This study aims to comprehensively assess and compare their diagnostic and prognostic potential in a 'real-world' cohort of patients with amyotrophic lateral sclerosis. About 77 patients with amyotrophic lateral sclerosis and its clinical variants, and 26 age- and sex-matched controls with various neuromuscular and neurodegenerative diseases, were retrospectively included in this monocentric, cross-sectional study. Neurofilaments in cerebrospinal fluid and biomarkers of muscular damage in serum were measured and correlated with demographic features, motor function, survival time, clinical phenotypes, and the extent of upper and lower motor neuron involvement. Neurofilament, myoglobin, and troponin T concentrations were higher in patients with amyotrophic lateral sclerosis compared to disease controls. Higher neurofilament levels correlated with lower motor function and faster disease progression rate, while higher creatine kinase and creatinine concentrations were linked to preserved motor function. In contrast, troponin T elevation indicated poorer fine and gross motor functions. Increased neurofilament levels were associated with shorter survival, whereas biomarkers of muscular damage lacked survival correlation. Neurofilament concentrations were higher in classical amyotrophic lateral sclerosis than in progressive muscular atrophy, while myoglobin and troponin T levels were elevated in progressive muscular atrophy compared to primary lateral sclerosis. Neurofilaments were predominantly linked to upper motor neuron involvement. Our findings confirmed the robust diagnostic and prognostic value of neurofilaments in amyotrophic lateral sclerosis. Elevated neurofilament concentrations were associated with higher disease severity, faster disease progression, shorter survival, and predominant upper motor neuron degeneration. Biomarkers of muscular damage were inferior in distinguishing amyotrophic lateral sclerosis from other neuromuscular and neurodegenerative diseases. However, they may serve as complementary biomarkers and support in discriminating clinical variants of amyotrophic lateral sclerosis.

Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.

Introduction: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases. Methods: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics. Results: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width). Discussion: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.

Risk willingness in multiple system atrophy and Parkinson's disease understanding patient preferences.

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson's Disease (PD) are in early phases of clinical testing. Involving patients' preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001-25%] of sudden death for a 99% [interquartile range: 99.999-75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001-5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients' risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients' risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.

Diagnostic accuracy and confounders of vagus nerve ultrasound in amyotrophic lateral sclerosis-a single-center case series and pooled individual patient data meta-analysis.

BACKGROUND: Several single-center studies proposed utility of vagus nerve (VN) ultrasound for detecting disease severity, autonomic dysfunction, and bulbar phenotype in amyotrophic lateral sclerosis (ALS). However, the resulting body of literature shows opposing results, leaving considerable uncertainty on the clinical benefits of VN ultrasound in ALS. METHODS: Relevant studies were identified up to 04/2024 and individual patient data (IPD) obtained from the respective authors were pooled with a so far unpublished cohort (from Munich). An IPD meta-analysis of 109 patients with probable or definite ALS (El Escorial criteria) and available VN cross-sectional area (CSA) was performed, with age, sex, ALS Functional Rating Scale-revised (ALSFRS-R), disease duration, and bulbar phenotype as independent variables. RESULTS: Mean age was 65 years (± 12) and 47% of patients (± 12) had bulbar ALS. Mean ALSFRS-R was 38 (± 7), and mean duration was 18 months (± 18). VN atrophy was highly prevalent [left: 67% (± 5), mean CSA 1.6mm2 (± 0.6); right: 78% (± 21), mean CSA 1.8 mm2 (± 0.7)]. VN CSA correlated with disease duration (mean slope: left - 0.01; right - 0.01), but not with ALSFRS-R (mean slope: left 0.004; mean slope: right - 0.002). Test accuracy for phenotyping bulbar vs. non-bulbar ALS was poor (summary receiver operating characteristic area under the curve: left 0.496; right 0.572). CONCLUSION: VN atrophy in ALS is highly prevalent and correlates with disease duration, but not with ALSFRS-R. VN CSA is insufficient to differentiate bulbar from non-bulbar ALS phenotypes. Further studies are warranted to analyze the link between VN atrophy, autonomic impairment, and survival in ALS.

Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them. METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment. PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed. TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.

Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.

OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results. METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans. RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC. INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.

Predicted hot superconductivity in LaSc2H24 under pressure.

The recent theory-driven discovery of a class of clathrate hydrides (e.g., CaH6, YH6, YH9, and LaH10) with superconducting critical temperatures (Tc) well above 200 K has opened the prospects for "hot" superconductivity above room temperature under pressure. Recent efforts focus on the search for superconductors among ternary hydrides that accommodate more diverse material types and configurations compared to binary hydrides. Through extensive computational searches, we report the prediction of a unique class of thermodynamically stable clathrate hydrides structures consisting of two previously unreported H24 and H30 hydrogen clathrate cages at megabar pressures. Among these phases, LaSc2H24 shows potential hot superconductivity at the thermodynamically stable pressure range of 167 to 300 GPa, with calculated Tcs up to 331 K at 250 GPa and 316 K at 167 GPa when the important effects of anharmonicity are included. The very high critical temperatures are attributed to an unusually large hydrogen-derived density of states at the Fermi level arising from the newly reported peculiar H30 as well as H24 cages in the structure. Our predicted introduction of Sc in the La-H system is expected to facilitate future design and realization of hot superconductors in ternary clathrate superhydrides.

Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.

OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS). METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival. RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001). CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.

Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1G37R mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients.

Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

Increased Vulnerability to Ferroptosis in FUS-ALS.

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson's disease or Alzheimer's disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc- and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.

An integrative miRNA-mRNA expression analysis identifies miRNA signatures associated with SOD1 and TARDBP patient-derived motor neurons.

MicroRNAs (miRNAs) are a subset of small non-coding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression of a variety of transcript targets. Therefore altered miRNA expression may result in the dysregulation of key genes and biological pathways that has been reported with the onset and progression of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS). ALS is marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Although the pathomechanism underlying molecular interactions of ALS remains poorly understood, alterations in RNA metabolism, including dysregulation of miRNA expression in familial as well as sporadic forms are still scarcely studied. In this study, we performed combined transcriptomic data and miRNA profiling in MN samples of the same samples of iPSC-derived MNs from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls. We report a global upregulation of mature miRNAs, and suggest that differentially expressed (DE) miRNAs have a significant impact on mRNA-level in SOD1-, but not in TARDBP-linked ALS. Furthermore, in SOD1-ALS we identified dysregulated miRNAs such as miR-124-3p, miR-19b-3p and miR-218 and their potential targets previously implicated in important functional process and pathogenic pathways underlying ALS. These miRNAs may play key roles in the neuronal development and cell survival related functions in SOD1-ALS. Altogether, we provide evidence of miRNA regulated genes expression mainly in SOD1 rather than TDP43-ALS.

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5-20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.

Cell-Type-Dependent Recruitment Dynamics of FUS Protein at Laser-Induced DNA Damage Sites.

Increased signs of DNA damage have been associated to aging and neurodegenerative diseases. DNA damage repair mechanisms are tightly regulated and involve different pathways depending on cell types and proliferative vs. postmitotic states. Amongst them, fused in sarcoma (FUS) was reported to be involved in different pathways of single- and double-strand break repair, including an early recruitment to DNA damage. FUS is a ubiquitously expressed protein, but if mutated, leads to a more or less selective motor neurodegeneration, causing amyotrophic lateral sclerosis (ALS). Of note, ALS-causing mutation leads to impaired DNA damage repair. We thus asked whether FUS recruitment dynamics differ across different cell types putatively contributing to such cell-type-specific vulnerability. For this, we generated engineered human induced pluripotent stem cells carrying wild-type FUS-eGFP and analyzed different derivatives from these, combining a laser micro-irradiation technique and a workflow to analyze the real-time process of FUS at DNA damage sites. All cells showed FUS recruitment to DNA damage sites except for hiPSC, with only 70% of cells recruiting FUS. In-depth analysis of the kinetics of FUS recruitment at DNA damage sites revealed differences among cellular types in response to laser-irradiation-induced DNA damage. Our work suggests a cell-type-dependent recruitment behavior of FUS during the DNA damage response and repair procedure. The presented workflow might be a valuable tool for studying the proteins recruited at the DNA damage site in a real-time course.

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.

Revisiting Solid-Solid Phase Transitions in Sodium and Potassium Tetrafluoroborate for Thermal Energy Storage.

In situ synchrotron powder X-ray diffraction (PXRD) study was conducted on sodium and potassium tetrafluoroborate (NaBF4 and KBF4) to elucidate structural changes across solid-solid phase transitions over multiple heating-cooling cycles. The phase transition temperatures from diffraction measurements are consistent with the differential scanning calorimetry data (∼240 °C for NaBF4 and ∼290 °C for KBF4). The crystal structure of the high-temperature (HT) NaBF4 phase was determined from synchrotron PXRD data. The HT disordered phase of NaBF4 crystallizes in the hexagonal, space group P63/mmc (no. 194) with a = 4.98936(2) Å, c = 7.73464(4) Å, V = 166.748(2) Å3, and Z = 2 at 250 °C. Density functional theory molecular dynamics (MD) calculations imply that the P63/mmc is indeed a stable structure for rotational NaBF4. MD simulations reproduce the experimental phase sequence upon heating and indicate that F atoms are markedly more mobile than K and B atoms in the disordered state. Thermal expansion coefficients for both phases were determined from high-precision lattice parameters at elevated temperatures, as obtained from Rietveld refinement of the PXRD data. Interestingly, for the HT-phase of NaBF4, the structure (upon heating) contracts slightly in the a-b plane but expands in the c direction such that overall thermal expansion is positive. Thermal conductivities at room temperature were measured, and the values are 0.8-1.0 W m-1 K-1 for NaBF4 and 0.55-0.65 W m-1 K-1 for KBF4. The thermal conductivity and diffusivity showed a gradual decrease up to the transition temperature and then rose slightly. Both materials show good thermal and structural stabilities over multiple heating/cooling cycles.

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis.

Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC).Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ.Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor.Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.

In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.

Tuning Reactivities of tert-Butyllithium by the Addition of Stoichiometric Amounts of Tetrahydrofuran.

In alkyllithium chemistry the highest reactivity has historically been linked to the smallest degree of aggregation possible. Since tert-butyllithium is known to form a monomer in tetrahydrofuran solution, using just stoichiometric amounts of the lewis base to selectively form a dimeric species seemed irrational. In this study, we showed a considerable increase of the reactivity of t-BuLi when using stoichiometric amounts of THF in the non-polar solvent n-pentane in order to enable the deprotonation of simple methyl silanes and other low C-H-acidic substrates. In this context, we were able to obtain the corresponding aggregates of t-BuLi with the ligand THF in suspension and as crystalline solids and investigate them by single crystal X-ray structural analysis, in situ FTIR spectroscopy and quantum chemical calculations. Furthermore, we were able to explain the enhanced reactivity of t-BuLi with stoichiometric amounts of THF on the basis of structural features of the bridged dimer obtained under these conditions. With these findings, we present a new target in the aggregation of alkyllithium reagents: the selectively formed "frustrated" aggregates!