Physiological shedding and C-terminal proteolytic processing of TMEM106B.

Genetic variants in TMEM106B, coding for a transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a strong effect in patients with frontotemporal degeneration. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis. Whether this luminal domain is generated under physiological conditions and which protease(s) are involved in shedding remain unclear.

Hypothalamic volume is associated with age, sex and cognitive function across lifespan: a comparative analysis of two large population-based cohort studies.

Background: Emerging findings indicate that the hypothalamus, the body's principal homeostatic centre, plays a crucial role in modulating cognition, but comprehensive population-based studies are lacking.

Methods: We used cross-sectional data from the Rhineland Study (N = 5812, 55.2 ± 13.

Subtypes of cognitive impairment in cerebellar disease identified by cross-diagnostic cluster-analysis: results from a German multicenter study.

Background: Cognitive and neuropsychiatric impairment, known as cerebellar cognitive affective syndrome (CCAS), may be present in cerebellar disorders. This study identified distinct CCAS subtypes in cerebellar patients using cluster analysis.

Methods: The German CCAS-Scale (G-CCAS-S), a brief screening test for CCAS, was assessed in 205 cerebellar patients and 200 healthy controls.

CSF synaptic biomarkers and cognitive impairment in multiple sclerosis.

Background: People with multiple sclerosis (PwMS) experience various degrees of cognitive impairment (CI). Synaptic dysfunction may contribute to CI in PwMS but cerebrospinal fluid (CSF) synaptic biomarkers are unexplored in MS.

Objective: To assess the role of CSF synaptosomal-associated protein 25 (SNAP-25), β-synuclein, neurogranin and neurofilament light chain protein (NfL) in patients with early relapsing MS with and without CI.

Effect of IV Thrombolysis With Alteplase in Patients With Vessel Occlusion in the WAKE-UP Trial.

Background And Objectives: Data from randomized trials on the treatment effect of pure thrombolysis in patients with vessel occlusion are lacking. We examined data from a corresponding subsample of patients from the multicenter, randomized, placebo-controlled WAKE-UP trial to determine whether MRI-guided IV thrombolysis with alteplase in unknown-onset ischemic stroke benefits patients presenting with vessel occlusion.

Methods: Patients with an acute ischemic lesion visible on MRI diffusion-weighted imaging but no marked parenchymal hyperintensity on fluid-attenuated inversion recovery images were randomized to treatment with IV alteplase or placebo.

Non-motor fluctuations in Parkinson's disease: underdiagnosed, yet important.

Non-motor fluctuations (NMF) in Parkinson's disease (PD) significantly affect patients' well-being. Despite being identified over two decades ago, NMF remain largely under-recognized, under-treated, and poorly understood. While they are often temporally associated with motor fluctuations (MF) and can share common risk factors and pathophysiologic mechanisms, NMF and MF are currently considered distinct entities.

Unveiling the power of high-dimensional cytometry data with cyCONDOR.

High-dimensional cytometry (HDC) is a powerful technology for studying single-cell phenotypes in complex biological systems. Although technological developments and affordability have made HDC broadly available in recent years, technological advances were not coupled with an adequate development of analytical methods that can take full advantage of the complex data generated. While several analytical platforms and bioinformatics tools have become available for the analysis of HDC data, these are either web-hosted with limited scalability or designed for expert computational biologists, making their use unapproachable for wet lab scientists.

Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.

The Parkinson's disease (PD)-linked protein Leucine-Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis-Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a K value of LRRK2 that lies within the range of the physiological GTP concentrations within the cell.

Craving induction through virtual reality cue-exposure for patients with alcohol dependence in rehabilitation treatment.

New therapeutic approaches for alcohol dependence (AD) include virtual reality (VR)-based treatments offering scalable options for cue exposure (CE), a well-established strategy in cognitive behavioral therapy. This study aimed to evaluate the feasibility and tolerability of a new VR-CE paradigm. On an explorative basis, factors influencing the induction of craving were examined.

A dataset profiling the multiomic landscape of the prefrontal cortex in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, which still lacks effective disease-modifying therapies. Similar to other neurodegenerative disorders, such as Alzheimer and Parkinson disease, ALS pathology is presumed to propagate over time, originating from the motor cortex and spreading to other cortical regions. Exploring early disease stages is crucial to understand the causative molecular changes underlying the pathology.

Metastasis Detection Using True and Artificial T1-Weighted Postcontrast Images in Brain MRI.

Objectives: Small lesions are the limiting factor for reducing gadolinium-based contrast agents in brain magnetic resonance imaging (MRI). The purpose of this study was to compare the sensitivity and precision in metastasis detection on true contrast-enhanced T1-weighted (T1w) images and artificial images synthesized by a deep learning method using low-dose images.

Materials And Methods: In this prospective, multicenter study (5 centers, 12 scanners), 917 participants underwent brain MRI between October 2021 and March 2023 including T1w low-dose (0.

Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli.

Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene SORL1 (sortilin-related receptor 1). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some SORL1 gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli.

Low income, being without employment, and living alone: how they are associated with cognitive functioning-Results from the German national cohort (NAKO).

Aim was to investigate to what extent cognitive functioning differs by three socioeconomic conditions: low income, being without employment, and living alone. A total of N = 158,144 participants of the population-based German National Cohort (NAKO) provided data on socioeconomic conditions and completed cognitive tests. Multivariable confounder-adjusted regression analyses indicated that cognitive functioning was lower in those with low income (b = -0.

The impact of proton pump inhibitors on brain health based on cross-sectional findings from the Rhineland Study.

Reports linking proton pump inhibitors (PPIs) with cognition and dementia show conflicting results, with limited evidence on underlying biological mechanisms. However, existing studies did not investigate brain microstructure, which could provide valuable insights into early structural changes indicative of cognitive decline. Analyses were based on cross-sectional baseline data from the Rhineland Study (n = 7,465; mean age 55.

Comparing Different Implementation Strategies for Collaborative Dementia Care Management in Terms of Patients' Characteristics, Unmet Needs, and the Impact on Quality of Life and Costs in Germany.

Objective: To compare the implementation of collaborative dementia care management (cDCM) across two settings regarding patients' characteristics, unmet needs, and the impact on health-related quality of life (HRQoL) and costs.

Methods: This analysis was based on data from the DCM:IMPact study, implementing cDCM in a physician network (n = 22 practices) and two day care centers (DCC) for community-dwelling persons with dementia over 6 months in Germany. Participants completed comprehensive assessments at baseline and 6 months after, soliciting sociodemographic and clinical characteristics, unmet needs, HRQoL and healthcare resource utilization.

Versatile MRI acquisition and processing protocol for population-based neuroimaging.

Neuroimaging has an essential role in studies of brain health and of cerebrovascular and neurodegenerative diseases, requiring the availability of versatile magnetic resonance imaging (MRI) acquisition and processing protocols. We designed and developed a multipurpose high-resolution MRI protocol for large-scale and long-term population neuroimaging studies that includes structural, diffusion-weighted and functional MRI modalities. This modular protocol takes almost 1 h of scan time and is, apart from a concluding abdominal scan, entirely dedicated to the brain.

Patient-Reported Outcome Measures in NMDA Receptor Encephalitis.

Background And Objectives: The characteristics of persistent long-term symptoms and their contribution to subjective quality of life remain unclear in patients with NMDAR encephalitis. In this study, we aimed to evaluate postacute neuropsychiatric symptoms, subjective cognitive complaints, and disease coping mechanisms and identify predictors of health-related quality of life (HRQoL) after N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Methods: This cross-sectional observational study investigated patients with NMDAR encephalitis in the postacute phase.

Regional distribution of polymorphisms associated to the disease-causing gene of spinocerebellar ataxia type 3.

Introduction: Knowledge about the distribution and frequency of the respective haplotypes on the wildtype and mutant allele is highly relevant in the context of future gene therapy clinical studies in Spinocerebellar Ataxia Type 3, the most common autosomal dominantly inherited ataxia. Single nucleotide polymorphisms associated to the disease-causing gene, ATXN3, have been determined. We wanted to investigate the frequency and regional distribution of two intragenic single nucleotide polymorphisms (SNPs) in a large European SCA3 cohort and their relation to the clinical phenotype.

Diagnosing primary lateral sclerosis: a clinico-pathological study.

Background:  Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

Methods: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results.

Myelin basic protein and TREM2 quantification in the CSF of patients with Multiple System Atrophy and other Parkinsonian conditions.

Background: It is well known that myelin disruption and neuroinflammation are early and distinct pathological hallmarks in multiple system atrophy (MSA) as well as in idiopathic Parkinson's disease and in other atypical Parkinsonian syndromes. The objective of this study was to assess the value of non-neuronal biomarker candidates that reflect myelin disruption and neuroinflammation.

Methods: Myelin basic protein (MBP) and the soluble form of TREM2 were quantified in a comprehensive movement disorder cohort from two different neurological centers, comprising a total of 171 CSF samples.