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Background: Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq)., Methods: We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions., Results: We identified the expansion of CD56 dim natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56 dim NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10 - 11 ) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10 - 6 ). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10 - 8 ) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56 bright NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels., Conclusion: Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56 dim NK subpopulation (NK_2), as well as a possible role of CD56 bright NK cells in neurodegeneration., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the ethics committee of Hospital Sant Pau and adhered to the standards for medical research involving humans as recommended by the Declaration of Helsinki. All participants and/or their legal representatives signed the written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Objective: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing., Methods: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region., Results: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 ( ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes., Conclusions: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown., Methods: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ 1-42 /Aβ 1-40 ratio. Plasma pTau 217 , pTau 181 , Aβ 1-42 and Aβ 1-40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ 1-42 /Aβ 1-40 ratio. We analyzed the concordance of pTau 217 with CSF amyloidosis., Results: Plasma pTau 217 and pTau 181 concentration were higher in A + than A- while the plasma Aβ 1-42 /Aβ 1-40 ratio was lower in A + compared to A-. pTau 181 and the Aβ 1-42 /Aβ 1-40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92-0.97) for pTau 217 , and 0.88 (95% CI 0.84-0.92) for both pTau 181 and Aβ 1-42 /Aβ 1-40 . Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau 217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4-7% misclassification rate. The global accuracy of plasma pTau 217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%., Conclusion: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau 217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit., (© 2024. The Author(s).)

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).)

It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown., Methods: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A+) or negative (A-) according to CSF Aβ 1-42 /Aβ 1-40 ratio. Plasma pTau 217 , pTau 181 , Aβ 1-42 and Aβ 1-40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ 1-42 /Aβ 1-40 ratio. We analyzed the potential of pTau 217 to predict amyloidosis in CSF., Results: Plasma pTau 217 and pTau 181 concentration were higher in A + than A- while the plasma Aβ 1-42 /Aβ 1-40 ratio was lower in A + compared to A-. pTau 181 and the Aβ 1-42 /Aβ 1-40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92-0.97) for pTau 217 , and 0.88 (95% CI 0.84-0.92) for both pTau 181 and Aβ 1-42 /Aβ 1-40 . Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau 217 had the highest fold change (x4.2) and showed high predictive capability in discriminating A + from A-, having 4-7% misclassification rate. The global accuracy of plasma pTau 217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%., Conclusion: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau 217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit., Competing Interests: Competing interests Daniel Alcolea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Pla Estratègic de Recerca i Innovació en Salut (PERIS SLT006/17/125), and from Instituto de Salud Carlos III (PI18/00435 and INT19/00016). He participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Zambon S.A.U., Esteve, and from Krka Farmacéutica S.L. Javier Arranz is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none Nuole Zhu is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none Sara Rubio-Guerra is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none Iñigo Rodríguez-Baz is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none. Rosa Ferrer is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none María Carmona-Iragui is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Isabel Barroeta is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Dr. Illán-Gala is a senior Atlantic Fellows for Equity in Brain Health at the Global Brain Health Institute (GBHI), and is supported with funding from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-21-720973 and AACSF-21-850193). Dr Illán-Gala was also supported by the Juan Rodés Contract (JR20/0018) and Fondo de Investigaciones Sanitario, (PI21/00791) from Instituto de Salud Carlos III. Ignacio Illán-Gala reported receiving personal fees from Nutricia, Esteve, UCB, and Neuraxpharm Spain outside the submitted work. Miguel Santos-Santos is employed by Hospital de la Santa Creu i Sant Pau. His research is supported by funding from the Spanish Institute of Health Carlos III (Juan Rodés contract JR18-00018; Fondo de investigación sanitaria grant PI19/00882), the Alzheimer’s Association clinician scientist fellowship (AACSF-22-972945), and the National Institutes of Health (R01AG080470). Juan Fortea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, National Institutes of Health, Fundació La Marató de TV3, and Pla Estratègic de Recerca i Innovació en Salut (PERIS). Dr. Fortea has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, NovoNordisk, Esteve and Biogen and served at advisory boards for AC Immune, Zambon and Lundbeck. Alberto Lleó is employed by Hospital de la Santa Creu i Sant Pau and received research grants from CIBERNED, Institute of Health Carlos III, Generalitat de Catalunya (PERIS and AGAUR) and Fundación Tatiana and BBVA. He participated in advisory boards from Biogen, Eisai, Fujirebio-Europe, Novartis, NovoNordisk, Nutricia, Otsuka Pharmaceutical, and Zambón, and received speaker honoraria from Lilly, Biogen, KRKA and Zambon. Mireia Tondo is employed by Hospital de la Santa Creu i Sant Pau and has received research grants from Instituto de Salud Carlos III (PI18/00164; PI21/00140) and has served as consultant in Araclon. Additional Declarations: Competing interest reported. Daniel Alcolea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Pla Estratègic de Recerca i Innovació en Salut (PERIS SLT006/17/125), and from Instituto de Salud Carlos III (PI18/00435 and INT19/00016). He participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Zambon S.A.U., Esteve, and from Krka Farmacéutica S.L. Javier Arranz is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none Nuole Zhu is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none Sara Rubio-Guerra is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none Iñigo Rodríguez-Baz is employed by Biomedical Research Institute Sant Pau. He is funded by a “Rio Hortega” research grant from the Institute of Health Carlos III. Declarations of interest: none. Rosa Ferrer is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none María Carmona-Iragui is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Isabel Barroeta is employed by Hospital de la Santa Creu i Sant Pau. Declarations of interest: none. Dr. Illán-Gala is a senior Atlantic Fellows for Equity in Brain Health at the Global Brain Health Institute (GBHI), and is supported with funding from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-21-720973 and AACSF-21-850193). Dr Illán-Gala was also supported by the Juan Rodés Contract (JR20/0018) and Fondo de Investigaciones Sanitario, (PI21/00791) from Instituto de Salud Carlos III. Ignacio Illán-Gala reported receiving personal fees from Nutricia, Esteve, UCB, and Neuraxpharm Spain outside the submitted work. Miguel Santos-Santos is employed by Hospital de la Santa Creu i Sant Pau. His research is supported by funding from the Spanish Institute of Health Carlos III (Juan Rodés contract JR18-00018; Fondo de investigación sanitaria grant PI19/00882), the Alzheimer’s Association clinician scientist fellowship (AACSF-22-972945), and the National Institutes of Health (R01AG080470). Juan Fortea is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, National Institutes of Health, Fundació La Marató de TV3, and Pla Estratègic de Recerca i Innovació en Salut (PERIS). Dr. Fortea has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, NovoNordisk, Esteve and Biogen and served at advisory boards for AC Immune, Zambon and Lundbeck. Alberto Lleó is employed by Hospital de la Santa Creu i Sant Pau and received research grants from CIBERNED, Institute of Health Carlos III, Generalitat de Catalunya (PERIS and AGAUR) and Fundación Tatiana and BBVA. He participated in advisory boards from Biogen, Eisai, Fujirebio-Europe, Novartis, NovoNordisk, Nutricia, Otsuka Pharmaceutical, and Zambón, and received speaker honoraria from Lilly, Biogen, KRKA and Zambon. Mireia Tondo is employed by Hospital de la Santa Creu i Sant Pau and has received research grants from Instituto de Salud Carlos III (PI18/00164; PI21/00140) and has served as consultant in Araclon.

Objectives: Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Recently, blood-based markers (BBM) Aβ1-42, Aβ1-40, and phospho Tau181 (p-Tau181) have demonstrated the potential to transform the diagnosis and prognostic assessment of AD. Our aim was to investigate the effect of different storage conditions on the quantification of these BBM and to evaluate the interchangeability of plasma and serum samples., Methods: Forty-two individuals with some degree of cognitive impairment were studied. Thirty further patients were retrospectively selected. Aβ1-42, Aβ1-40, and p-Tau181 were quantified using the LUMIPULSE-G600II automated platform. To assess interchangeability between conditions, correction factors for magnitudes that showed strong correlations were calculated, followed by classification consistency studies., Results: Storing samples at 4 °C for 8-9 days was associated with a decrease in Aβ fractions but not when stored for 1-2 days. Using the ratio partially attenuated the pre-analytical effects. For p-Tau181, samples stored at 4 °C presented lower concentrations, whereas frozen samples presented higher ones. Concerning classification consistency in comparisons that revealed strong correlations (p-Tau181), the percentage of total agreement was greater than 90 % in a large number of the tested cut-offs values., Conclusions: Our findings provide relevant information for the standardization of sample collection and storage in the analysis of AD BBM in an automated platform. This knowledge is crucial to ensure their introduction into clinical settings., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Purpose: Hypoechogenicity of the raphe nuclei (hR) has been related to major depression. Comorbidity between migraine and depression is bidirectional postulating a common mechanism of serotonergic dysfunction. We aimed to investigate the association between migraine and hR and its role as biomarker of migraine-associated depression and disease severity., Methods: This is a single-center cross-sectional descriptive study. We included consecutive patients with episodic (EM) and chronic migraine (CM). We collected their comorbidities, analgesic consumption, hospital anxiety and depression scale (HADS), disability, and impact on quality of life associated with migraine. We also included a group of control subjects, matched for age and sex with the patients. In both groups, hR was assessed by means of transcranial sonography. We performed a meta-analysis of the studies investigating the association between migraine and hR., Results: A total of 107 subjects were included (57 cases and 50 controls). hR rate was lower in controls than in migraine patients (22.2% vs. 42.9%, p = .02) with a progressive increase in EM and CM groups respect to the control group (33.3% and 50% vs. 22.2%, respectively; p = .03). Among patients, hR was not associated with depression, higher HADS score, greater migraine-related disability, or higher consumption of analgesic medication. The meta-analysis showed a significant association between migraine and hR (odds ratio = 2.16; 95% confidence interval: 1.42-3.29)., Conclusion: hR is more prevalent in migraine patients than in controls and, in our population, its prevalence increases in a stepwise manner in patients with EM and CM. These findings support the role of raphe nuclei in migraine pathophysiology., (© 2022 American Society of Neuroimaging.)

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers., Methods: We performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit., Results: Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs ( p < 0.05). NOD2 and Spp1 levels were significantly higher in sera from patients with ALS than in HCs ( p < 0.001). Receiver operating characteristic analysis showed an area under the curve of 0.63 for NOD2 and 0.81 for Spp1. NOD2 levels were significantly lower in patients with AD and FTD than in patients with ALS ( p < 0.0001), but we found no significant differences in Spp1 levels between patients with ALS, AD ( p = 0.51), and FTD ( p = 0.42). We found a negative correlation between Spp1 levels and ALS functional rating scale ( r = -0.24, p = 0.009)., Discussion: Our discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies., Competing Interests: Teresa Gómez-Isla participated as speaker in an Eli Lilly and Company-sponsored educational symposium and serves in an Eli Lilly Data Monitoring Committee. All other authors declare no competing interests., (© 2021 The Authors.)