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Background: Patients with Progressive Supranuclear Palsy (PSP) suffer from several neuropsychological impairments. These mainly affect the frontal lobe and subcortical brain structures. However, a scale for the assessment of cognitive and neuropsychiatric disability in PSP is still missing., Objectives: To create and validate a new scale for cognitive and neuropsychiatric impairment in PSP., Methods: The Short Cognitive and Neuropsychiatric (ShoCo) scale was developed containing five items (bradyphrenia, apathy, aphasia, dysexecution and disinhibition). Each item can be categorized into 0 = no deficit, 1 = mild deficit, 2 = moderate deficit and 3 = severe deficit. The total score includes 15 points, 0 meaning no deficit and 15 severe deficits. Cross-sectional and longitudinal data from 201 baseline and 71 follow up patients were analyzed., Results: Baseline ShoCo scale results were 5.9 ± 2.9. No significant differences between patients with Richardson syndrome (PSP-RS) and variants (vPSP) could be detected in the PSP-ShoCo scale scores (PSP-RS 6.1 ± 3.0, n = 160, vPSP 5.1 ± 2.6, n = 41, P = 0.057). The scale showed good correlation with established scores (eg, Montreal cognitive assessment r = -0.535, P = 0.001). The ShoCo scale showed significant annualized change within the PSP-RS patients (baseline 6.2 ± 2.9, follow up 6.9 ± 3.1, annualized diff. 1.0 ± 3.1, n = 57, P = 0.022)., Conclusions: The ShoCo scale seems a promising and valid tool to measure specific neuropsychological disabilities of PSP patients in clinical routine and research., (© 2025 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The recent Movement Disorders Society (MDS)-progressive supranuclear palsy (PSP) diagnostic criteria conceptualized three clinical diagnostic certainty levels: "suggestive of PSP" for sensitive early diagnosis based on subtle clinical signs, "possible PSP" balancing sensitivity and specificity, and "probable PSP" highly specific for PSP pathology., Objective: The aim of this study was to prospectively validate the criteria against long-term clinical follow-up and characterize the diagnostic certainty increase over time., Methods: Patients with "possible PSP" or "suggestive of PSP" diagnosis and clinical follow-up were recruited in two German multicenter longitudinal observational studies (ProPSP and DescribePSP). The cumulative percentage of patients longitudinally increasing diagnostic certainty was assessed over up to 2.5 years of follow-up. The sample size per arm required to detect 30% attenuated rate in diagnostic certainty increase in trials was estimated over multiple time intervals., Results: Of 254 patients with available longitudinal data, 61 patients had low diagnostic certainty at baseline (48 suggestive of PSP, 13 possible PSP) and multiple clinical visits (median: 3, range: 2-4). The cumulative percentage of patients increasing diagnostic certainty progressed with follow-up duration (30.4% at 6 months, 51.7% at 1 year, 80.4% at 2.5 years). The sample size required to detect 30% reduction in diagnostic certainty increase rate within 1 year was 163, slightly smaller than that required using the PSP rating scale., Conclusions: Most "suggestive of PSP" patients increased diagnostic certainty upon longitudinal follow-up, providing the first prospective multicenter validation of MDS-PSP diagnostic criteria. Our data support the design of trials tailored for these early-stage patients, suggesting the PSP rating scale and the diagnostic certainty increase rate as potential endpoint measures. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer's disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins-neurofilament medium and myelin basic protein-showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers., Competing Interests: Declarations. Competing interests: Johannes Levin reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve and Roche, consulting fees from Axon Neuroscience, EISAI and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH,is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. Jens Wiltfang has been an honorary speaker for Actelion, Amgen, Beeijing Yibai Science and Technology Ltd., Gloryren, Janssen Cilag, Med Update GmbH, Pfizer, Roche Pharma, and has been a member of the advisory boards of Abbott, Biogen, Boehringer Ingelheim, Lilly, MSD Sharp & Dohme, and Roche Pharma and receives fees as a consultant for Immungenetics, Noselab and Roboscreen and holds the following patents: PCT/EP 2011 001724 and PCT/EP 2015 052945., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Objective: Interhemispheric neurons in the motor section of the corpus callosum have an inhibitory effect on neurons of the contralateral motor cortex. Three quarters of patients with amyotrophic laterals sclerosis (ALS) show impaired transcallosal inhibition. We aimed to investigate whether structural changes co-occur with this functional impairment and to explore its phenotypic correlates., Methods: The demographic, clinical, and neuropsychological data of 127 ALS patients were analysed. Transcallosal inhibition was assessed with an ipsilateral silent period (iSP) protocol using transcranial magnetic stimulation. Patients were categorised based on an iSP response or its loss, and the groups were characterised by demographic, clinical, and neuropsychological variables. Diffusion-weighted images from a subset of 63 patients were analysed using tractography, and white matter (WM) structural integrity metrics were compared across groups., Results: 54 % of patients displayed iSP loss. The average free-water-corrected fractional anisotropy values within the callosal tract between the primary motor cortices were lower for patients with iSP loss compared to patients with an iSP response. There were no group differences based on other diffusivity metrics. The groups did not differ regarding any of the demographic, clinical, or neuropsychological variables., Interpretation: We found reduced WM integrity in the motor section of the corpus callosum that differentiated ALS patients with iSP loss from patients with an iSP response, but with a small effect size. Nevertheless, the underlying pathological substrate and potential genetic drivers for these structural and functional changes in a subset of ALS patients remain to be satisfactorily investigated., Competing Interests: Declaration of competing interest S.T. served on advisory boards of Lilly, Eisai, and Biogen, and is member of the independent data safety and monitoring board of the ENVISION study (Biogen)., (Copyright © 2024. Published by Elsevier B.V.)

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing., (© 2024. The Author(s).)

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., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18 F-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., (© 2024. The Author(s).)

Introduction: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging., Methods: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry., Results: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta 1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects., Discussion: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy., Highlights: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials., (© 2024. The Author(s).)

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.

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 DRD2 CC 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., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7 T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: In amyotrophic lateral sclerosis (ALS), phrenic nerve (PN) atrophy has been found, whereas there is controversy regarding vagus nerve (VN) atrophy. Here, we aimed to find out whether PN atrophy is related to respiratory function and 12-month survival. Moreover, we investigated the relevance of VN and spinal accessory nerve (AN) atrophy in ALS., Methods: This prospective observational monocentric study included 80 adult participants (40 ALS patients, 40 age- and sex-matched controls). The cross-sectional area (CSA) of bilateral cervical VN, AN, and PN was measured on high-resolution ultrasonography. Clinical assessments included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), the Non-Motor Symptoms Questionnaire, and handheld spirometry of forced vital capacity (FVC). One-year survival was documented., Results: The CSA of each nerve, VN, AN, and PN, was smaller in ALS patients compared to controls. VN atrophy was unrelated to nonmotor symptom scores. PN CSA correlated with the respiratory subscore of the ALSFRS-R (Spearman test, r = 0.59, p < 0.001), the supine FVC (r = 0.71, p < 0.001), and the relative change of sitting-supine FVC (r = -0.64, p = 0.001). Respiratory impairment was predicted by bilateral mean PN CSA (p = 0.046, optimum cutoff value of ≤0.37 mm 2 , sensitivity = 92%, specificity = 56%) and by the sum of PN and AN CSA (p = 0.036). The combination of ALSFRS-R score with PN and AN CSA measures predicted 1-year survival with similar accuracy as the combination of ALSFRS-R score and FVC., Conclusions: Ultrasonography detects degeneration of cranial nerve motor fibers. PN and AN calibers are tightly related to respiratory function and 1-year survival in ALS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients., Objectives: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease., Methods: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®., Results: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions., Conclusions: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients., (© 2023. The Author(s).)

Background: Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels., Methods: Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms., Results: Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD., Conclusions: Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD., Funding: This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A)., Competing Interests: LH, SE, KM, LS, KF, KF, JK, JP, MS No competing interests declared, HB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Life Molecular Imaging and Novartis/AAA. The author has no other competing interests to declare, MS has received consulting fees from, and currently act as a consultant for Aviado Bio, Prevail, Servier, Reata and Orphazyme. They have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GenOrph. The author has no other competing interests to declare, JW has received consulting fees from Boehringer-Ingelheim, F. Hoffmann-La Roche, Biogen, Immungenetics, Roboscreen and Abbott. They currently act as a consultant for Boehringer-Ingelheim, F. Hoffmann-La Roche, Biogen and Immungenetics, and hold a Leadership or fiduciary role at CSF Society, AGNP and DGLN. The author has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Janssen, MSD SHARP & DOHME, Amgen, Roche Pharma, Actelion Pharmaceutical, Guangzhou Glorylen Medicial Technology Co. (China), Bejing Yibai Science and Technology Ltd. The author has been issued the following patents; EP2095128B1 and EP3105589A1. The author has no other competing interests to declare, JD has received a speaker fee from Jansen and Roche. The author has no other competing interests to declare, MO has received grants from BMBF - FTLD consortium, moodmarker, ALS association and EU - MIRIADE. The author has received consulting fees from, and currently acts as a consultant for, BIOGEN, Axon and Roche. The author has been issued a patent for Foundation state Baden-Wuerttemberg, Beta Syn as Biomarker for neurodegenerative diseases. The author holds an unpaid leadership or fiduciary role at the German Society for CSF diagnostics and neurochemistry and the Society for CSF diagnostics and neurochemistry, and as a speaker at the FTLD consortium. The author is co-inventor of a patent application (PCT/EP2020/072559) for using beta-synuclein measurement in blood.The author has no other competing interests to declare, JD former employee of and current consultant for F.Hoffmann-La Roche, (© 2024, Hahn et al.)

Amyotrophic lateral sclerosis (ALS) can result into an incomplete locked in state (iLIS), in which communication depends on eye tracking computer devices. Oculomotor function impairments in ALS have been reported, but there is little research, particularly with respect to patients in iLIS. In the present study, we compared reflexive and executive oculomotor function by means of an eye tracking test battery between three groups: advanced ALS patients in iLIS (n = 22), patients in early to middle ALS stages (n = 44) and healthy subjects (n = 32). Patients with ALS showed significant deteriorations in oculomotor functions, with stronger impairments in iLIS. More specifically, ALS patients produced visually guided prosaccades with longer latencies and more frequent hypometria compared to healthy subjects. Longest latencies were obtained in iLIS patients, with a stronger prolongation for vertical than for horizontal prosaccades. ALS patients made more antisaccade errors and generated antisaccades with longer latencies. Smooth pursuit was also impaired in ALS. In the earlier ALS stages, bulbar onset patients presented stronger antisaccade and smooth pursuit deficits than spinal onset patients. Our findings reveal a relevant deterioration of important oculomotor functions in ALS, which increases in iLIS. It includes impairments of reflexive eye movements to loss of executive inhibitory control, indicating a progressing pathological involvement of prefrontal, midbrain and brainstem areas. The assessment of oculomotor functions may therefore provide clinically relevant bio- and progression marker, particularly in advanced ALS., (© 2023. The Author(s).)

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

Background and Purpose: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV)., Methods: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale., Results: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001)., Conclusions: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The emergence of potentially effective new therapies for genetic forms of amyotrophic lateral sclerosis (ALS) necessitates the identification of biomarkers to facilitate early treatment, prior to the onset of motor symptoms. Here, we sought to investigate whether metabolic alterations are detectable in presymptomatic ALS gene mutation carriers, and whether such alterations precede neurofilament light chain (NfL) changes in serum., Methods: Between 02/2014 and 11/2021, we prospectively studied 60 presymptomatic ALS gene mutation carriers (40% male, age 48.7 ± 14.9; 28 C9orf72, 22 SOD1, 10 other) compared to 73 individuals from the same families (47% male, age 47.4 ± 12.9) without pathogenic mutations as controls. Bioimpedance analysis (BIA) and indirect calorimetry were performed, and Body Mass Index (BMI), Fat Mass (FM), Body Fat Percentage, Body Water (BW), Lean Body Mass (LBM), Extracellular Mass (ECM), Body Cell Mass (BCM), ECM/BCM ratio, Cells Percentage, Phase Angle, Resting Metabolic Rate (RMR), Metabolic Ratio (MR), and NfL were measured. Participants and evaluators were blinded regarding gene carrier status., Findings: Presymptomatic ALS gene carriers showed reduced LBM (p = 0.02), BCM (p = 0.004), Cells Percentage (p = 0.04), BW (p = 0.02), Phase Angle (p = 0.04), and increased ECM/BCM ratio (p = 0.04), consistently indicating a loss of metabolically active body cells. While in C9orf72 mutation carriers all tissue masses were reduced, only metabolically active tissue was affected in SOD1 mutation carriers. Unexpectedly, RMR (p = 0.009) and MR (p = 0.01) were lower in presymptomatic ALS gene carriers compared to non-carriers. NfL serum levels were similar in mutation carriers and non-carriers (p = 0.60)., Interpretation: The observed metabolic phenomena might reflect reduced physical activity and/or preemptive, insufficient compensatory mechanisms to prepare for the later hypermetabolic state. As pre-symptomatic biomarkers we propose ECM/BCM ratio and Phase Angle for SOD1, and a 4-compartment affection in BIA for C9orf72 mutation carriers., Funding: This work was an investigator-initiated trial. On the German side, there was no institutional or industrial funding. On the Swedish side, this work was supported by grants from the Swedish Brain Foundation (grants nr. 2013-0279, 2016-0303, 2018-0310, 2020-0353), the Swedish Research Council (grants nr. 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305, 2020.0232), the Ulla-Carin Lindquist Foundation, Umeå University (223-2808-12, 223-1881-13, 2.1.12-1605-14) and the Västerbotten County Council (grants nr 56103-7002829), King Gustaf V:s and Queen Victoria's Freemason's Foundation., Competing Interests: Declaration of interests JD reports honoraria for presentations from Biogen and ITF Pharma. PW reports grants or contracts from Alle Lieben Schmidt e.V., Boris Canessa Stiftung, and EHDN; consulting fees from Biogen, ITF Pharma, and Novartis. DB reports stocks from Ionis pharmaceuticals. PMA reports consultancies or advisory boards for Biogen, Roche, Avrion, Regeneron, uniQure and Orphazyme; clinical trial site investigator for Biogen, Alexion, Sanofi, Lilly AL-S Pharma, Amylyx, PTC Pharmaceuticals, Orion Pharma and Orphazyme; since 1993 Director of the ALS-genetic laboratory at Umeå University Hospital that performs clinical and research genetic testing; member of the ClinGen ALS Gene Curation Expert panel. LD reports grants from Cytokinetics and Lecture Fees from Cytokinetics. ACL reports grants or contracts from European Union (Horizon), BMBF, Deutsche Forschungsgemeinschaft (DFG), and Deutscher Akademischer Austauschdienst (DAAD) as well as sponsored trials by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, Biogen, and Orphazyme; payment for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx, and Streamed Up! GmbH; support for attending meetings and/or travel from Biogen; participation on advisory boards from Roche Pharme, Biogen, Alextor, and Amylyx; President of Deutsche Neurowissenschaftliche Gesellschaft (NWG). All other authors report no conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD)., Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores., Results: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy., Discussion: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations., Highlights: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL)., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Understanding the relationships between brain structure and language behaviour in primary progressive aphasia provides crucial information about these diseases' pathomechanisms. However, previous investigations have been limited from providing a statistically reliable view of broad language abilities by sample size, variant focus and task focus. In this study, the authors aimed to determine the relationship between brain structure and language behaviour in primary progressive aphasia, to determine the degree to which task-associated regions were atrophied across disease variants and to determine the degree to which task-related atrophy overlaps across disease variants. Participants were 118 primary progressive aphasia patients and 61 healthy, age-matched controls tested from 2011 to 2018 in the German Consortium for Frontotemporal Lobar Degeneration cohort. Diagnosis of primary progressive aphasia required progressive deterioration of mainly speech and language for ≥ 2 years, and variant was diagnosed by the criteria of Gorno-Tempini et al . (Classification of primary progressive aphasia and its variants. Neurology . 2011;76(11):1006-1014). Twenty-one participants not fulfilling a specific subtype were classified as mixed-variant and excluded. Language tasks of interest included the Boston naming test, a German adaptation of the Repeat and Point task, phonemic and category fluency tasks and the reading/writing subtest of the Aachen Aphasia Test. Brain structure was measured by cortical thickness. We observed networks of language task-associated temporal, frontal and parietal cortex. Overlapping task-associated atrophy was observed in the left lateral, ventral and medial temporal lobes, middle and superior frontal gyri, supramarginal gyrus and insula. Some regions, primarily in the perisylvian region, were associated with language behaviour despite showing no significant atrophy. The results crucially extend less powerful studies associating brain and language measures in primary progressive aphasia. Cross-variant atrophy in task-associated regions suggests partially shared underlying deficits, whereas unique atrophy reinforces variant-specific deficits. Language task-related regions that are not obviously atrophied suggest regions of future network disruption and encourage understanding of task deficits beyond clearly atrophied cortex. These results may pave the way for new treatment approaches., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Dementia syndromes can be difficult to diagnose. We aimed at building a classifier for multiple dementia syndromes using magnetic resonance imaging (MRI)., Methods: Atlas-based volumetry was performed on T1-weighted MRI data of 426 patients and 51 controls from the multi-centric German Research Consortium of Frontotemporal Lobar Degeneration including patients with behavioral variant frontotemporal dementia, Alzheimer's disease, the three subtypes of primary progressive aphasia, i.e., semantic, logopenic and nonfluent-agrammatic variant, and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal syndrome. Support vector machine classification was used to classify each patient group against controls (binary classification) and all seven diagnostic groups against each other in a multi-syndrome classifier (multiclass classification)., Results: The binary classification models reached high prediction accuracies between 71 and 95% with a chance level of 50%. Feature importance reflected disease-specific atrophy patterns. The multi-syndrome model reached accuracies of more than three times higher than chance level but was far from 100%. Multi-syndrome model performance was not homogenous across dementia syndromes, with better performance in syndromes characterized by regionally specific atrophy patterns. Whereas diseases generally could be classified vs controls more correctly with increasing severity and duration, differentiation between diseases was optimal in disease-specific windows of severity and duration., Discussion: Results suggest that automated methods applied to MR imaging data can support physicians in diagnosis of dementia syndromes. It is particularly relevant for orphan diseases beside frequent syndromes such as Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objective markers for the neurodegenerative disorder progressive supranuclear palsy (PSP) are needed to provide a timely diagnosis with greater certainty. Non-coding RNA (ncRNA), including microRNA, piwi-interacting RNA, and transfer RNA, are good candidate markers in other neurodegenerative diseases, but have not been investigated in PSP. Therefore, as proof of principle, we sought to identify whether they were dysregulated in matched serum and cerebrospinal fluid (CSF) samples of patients with PSP. Small RNA-seq was undertaken on serum and CSF samples from healthy controls (n = 20) and patients with PSP (n = 31) in two cohorts, with reverse transcription-quantitative PCR (RT-qPCR) to confirm their dysregulation. Using RT-qPCR, we found in serum significant down-regulation in hsa-miR-92a-3p, hsa-miR-626, hsa-piR-31068, and tRNA-ValCAC. In CSF, both hsa-let-7a-5p and hsa-piR-31068 showed significant up-regulation, consistent with their changes observed in the RNA-seq results. Interestingly, we saw no correlation in the expression of hsa-piR-31068 within our matched serum and CSF samples, suggesting there is no common dysregulatory mechanism between the two biofluids. While these changes were in a small cohort of samples, we have provided novel evidence that ncRNA in biofluids could be possible diagnostic biomarkers for PSP and further work will help to expand this potential.

Patients suffering from immune-mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis-specific auto-antibodies anti-SRP54 or -HMGCR, while about one third of them do not. Activation of chaperone-assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR)-stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER/SR-stress may be part of the molecular etiology of IMNM. To address this assumption, ER/SR-stress related key players covering the three known branches (PERK-mediated, IRE1-mediated, and ATF6-mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM-patients. Our results demonstrate an activation of all three UPR-branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well-documented characteristics for the activation of the UPR. Further, we identified increased general XBP1-level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased ATF6-expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6-form toward the forced transcription of UPR-related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER/SR co-chaperones and chaperones (e.g., SIL1) indicating an UPR-activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR-activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER-stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)