bims-barned 2026-04-12 papers

bims-barned

Biomed News

on BBB and Neurodegeneration-ALS

Issue of 2026–04–12
thirty-one papers selected by
Luca Bolliger, lxBio

Mortality From Amyotrophic Lateral Sclerosis in Finland 1987-2022.
Synergistic Neuroprotection of MFSD2A Overexpression and DHA Supplementation in Amyotrophic Lateral Sclerosis.
Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.
Blood-Brain Barrier: Structure, Function, Diseases, and Drug Delivery Systems.
Amyotrophic Lateral Sclerosis: A Cross-sectional Survey on Sialorrhoea.
Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.
The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.
The Repercussions of Amyotrophic Lateral Sclerosis on the Orofacial Sphere: A One-Year Prospective Longitudinal Study.
Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis.
Connectivity in ALS II (CoALS II): a study of structural and functional connectivity in ALS.
Integration of Single-cell RNA Sequencing and Mendelian Randomization Analysis for Identifying Potential Immune Therapeutic Targets in Amyotrophic Lateral Sclerosis.
Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival.
Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.
Accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.
Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.
Astrocytic K+ regulation during neurodegenerative diseases.
Characterisation of a patient-derived iPSC-based model for studying the blood-brain barrier in Alzheimer's disease.
The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives.
Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases.
Blood-spinal cord barrier disruption after spinal cord injury: a time-dependent mechanistic review.
Focused Ultrasound-activated Extracellular Vesicles-nanoparticle Hybrids for Targeted Brain Drug Delivery: Engineering Strategies and Translational Outlook.
Immune dysregulation in pediatric tic disorders: mechanisms, biomarkers, and therapeutic frontiers.
Voice Biomarkers: Cognitive Impairment, including Alzheimer's Disease, Dementia, or Mild Cognitive Impairment: Introduction to Peripheral Neuropathy.
Enhancing Early Diagnosis: Multimodal AI Approaches for Neurodegenerative Diseases.
Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.
Detection of inflammation-related blood-brain barrier dysfunction using PET and MR imaging: a pilot study.
SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential.
P2X7 receptor and neuroinflammation in neurodegenerative disorders: an autoradiography study with [18F]JNJ-64413739.
Human blood-brain barrier tissue model to characterize lipid nanoparticle delivery and transport mechanisms.
The evolutionary origins of multiple sclerosis.
Disappearing corticospinal tract on routine MRI: dynamic signal evolution in primary lateral sclerosis.

Eur J Neurol. 2026 Apr;33(4): e70586

Mortality From Amyotrophic Lateral Sclerosis in Finland 1987-2022.

Milla Laine, Jani Raitanen, Anssi Auvinen.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.
METHODS: Numbers of deaths caused by ALS (ICD-10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age-standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.
RESULTS: Mortality from ALS increased in Finland from 1987 to 2022. The age-standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age-standardized mortality increased on average by 1.7% (95% CI 1.5%-2.0%) annually. In men, the age-standardized mortality increased on average by 1.2% (95% CI 0.9%-1.6%) annually and in women by 2.0% (95% CI 1.6%-2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%-2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%-8.0%) in 1987-1997 and 1.0% (95% CI 0.5%-1.4%) during 1997-2022.
CONCLUSION: Similar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35 years. Further research on possible reasons is needed.

Keywords:  Finland; amyotrophic lateral sclerosis; epidemiology; mortality; motor neuron disease

DOI:  https://doi.org/10.1111/ene.70586
Mol Neurobiol. 2026 Apr 09. pii: 555. [Epub ahead of print]63(1):

Synergistic Neuroprotection of MFSD2A Overexpression and DHA Supplementation in Amyotrophic Lateral Sclerosis.

Song Luo, Qiang Zheng, Miaomiao Wang, Xiaorui Wang, Bo Ma, Dongliang Liu, Li Li, Yi Lu, Daoqian Sang, Lijuan Yang.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss, with limited effective therapies. Docosahexaenoic acid (DHA) exhibits neuroprotective effects, but its limited transport across the blood-brain barrier (BBB) restricts clinical utility. Major facilitator superfamily domain-containing protein 2A (MFSD2A) is the primary transporter of DHA into the central nervous system, yet its role in ALS remains unclear. This study investigated the therapeutic potential and mechanisms of MFSD2A overexpression combined with DHA supplementation in male SOD1^G93A ALS mice. We found that MFSD2A expression was markedly reduced in ALS mice and correlated with impaired motor function and neuronal damage. DHA supplementation or MFSD2A overexpression partially improved behavioral deficits, while their combination produced synergistic benefits. Histological analyses revealed attenuated neuronal degeneration and reduced muscle fibrosis following combined treatment. Furthermore, MFSD2A physically interacted with the E3 ubiquitin ligase TRIM21, regulating glycolytic metabolism by modulating key enzymes (GLUT1, HK2, LDHA, PDK1) and products (lactate/pyruvate and NADH/NADPH ratio). TRIM21 knockdown reversed MFSD2A-mediated neuroprotection and impaired glycolytic metabolism, indicating its critical role in this pathway. The combined intervention also suppressed systemic inflammation and oxidative stress by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restoring antioxidant enzyme activities (GSH-Px), while reducing lipid peroxidation (MDA). These findings suggest that MFSD2A facilitates DHA's neuroprotective effects by enhancing glycolytic metabolism and mitigating neuroinflammation. This study highlights MFSD2A and DHA as promising therapeutic targets in ALS and provides novel insights into overcoming BBB transport limitations for neurodegenerative disease treatment.

Keywords:  Amyotrophic lateral sclerosis (ALS); Blood–brain barrier (BBB); Docosahexaenoic acid (DHA); Major facilitator superfamily domain-containing protein 2A (MFSD2A); Neuroprotection

DOI:  https://doi.org/10.1007/s12035-026-05843-7
PLoS One. 2026 ;21(4): e0346613

Characterization of a C9orf72 Knockout Danio rerio model for ALS and cross-species validation of potential therapeutics screened in Caenorhabditis elegans.

Alexandre Emond, Carl Laflamme, Martine Therrien, Meijiang Liao, Claudia Maios, Audrey Labarre, Pierre Drapeau, J Alex Parker.

Intronic hexanucleotide repeat expansions in the C9orf72 gene represent the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases C9orf72 expression in affected patients, indicating that loss of C9orf72 function (LOF) acts as a pathogenic mechanism. Several models using Danio rerio (zebrafish) for C9orf72 depletion have been developed to explore disease mechanisms and the consequences of C9orf72 LOF. However, inconsistencies exist in reported phenotypes, and many have yet to be validated in stable germline ablation models. To address this, we created a zebrafish C9orf72 knockout model using CRISPR/Cas9. The C9orf72 LOF model demonstrates, in a generally dose-dependent manner, increased larval mortality, persistent growth reduction, and motor deficits. Additionally, homozygous C9orf72 LOF larvae exhibited mild overbranching of spinal motoneurons. To identify potential therapeutic compounds, we performed a screen on an established Caenorhabditis elegans (C. elegans) C9orf72 homologue (alfa-1) LOF model, identifying 12 compounds that enhanced motility, reduced neurodegeneration, and alleviated paralysis phenotypes. Motivated by the shared motor phenotype, 2 of those compounds were tested in our zebrafish C9orf72 LOF model. Pizotifen malate was found to significantly improve motor deficits in C9orf72 LOF zebrafish larvae. We introduce a novel zebrafish C9orf72 knockout model that exhibits phenotypic differences from depletion models, providing a valuable tool for in vivo C9orf72 research and ALS therapeutic validation. Furthermore, we identify pizotifen malate as a promising compound for further preclinical evaluation.

DOI: https://doi.org/10.1371/journal.pone.0346613
MedComm (2020). 2026 Apr;7(4): e70712

Blood-Brain Barrier: Structure, Function, Diseases, and Drug Delivery Systems.

Yanan He, Mengyao Qu, Lu Yu, Lipeng He, Yixun Lu, Jin Hong, Miao Sun, Huikai Yang, Weidong Mi, Hang Guo, Yulong Ma.

  The blood-brain barrier (BBB) is a highly selective and dynamic neurovascular interface essential for maintaining central nervous system homeostasis. This specialized barrier comprises brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes and astrocytic end-feet within the neurovascular unit. While protecting the brain from circulating pathogens and toxins, the BBB presents formidable obstacles to drug delivery, restricting approximately 98% of small-molecule therapeutics and nearly all large biomolecules from reaching the brain parenchyma. BBB dysfunction is critically implicated in the pathogenesis and progression of numerous neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain tumors. This comprehensive review systematically examines the structural organization and functional characteristics of the BBB, elucidates its pathophysiological roles across major neurological diseases, and critically evaluates innovative drug delivery strategies designed to overcome this biological barrier. We analyze passive targeting approaches, active targeting mechanisms via receptor-mediated transcytosis, and stimuli-responsive systems including focused ultrasound and magnetic guidance. Additionally, we discuss multifunctional nanoplatforms, biomimetic cell membrane-coated delivery systems, current preclinical evidence, and clinical translation challenges. Finally, we propose future research directions and identify specific experimental pathways to accelerate the development of next-generation BBB-targeted therapeutics from preclinical promise to clinical application.

Keywords:  blood–brain barrier; drug delivery systems; ischemic stroke; nanoparticles; neurological diseases; neurovascular unit; targeted therapy

DOI:  https://doi.org/10.1002/mco2.70712
Indian J Palliat Care. 2026 Jan-Mar;32(1):32(1): 85-90

Amyotrophic Lateral Sclerosis: A Cross-sectional Survey on Sialorrhoea.

Priya Baby, Jobimol John, P B Binesha, Muddasu Suhasini Keerthipriya, Sheena Ramazanu, Saraswati Nashi, Deepak Menon, Seena Vengalil, Priya Treesa Thomas, Atchayaram Nalini.

   Objectives: One of the major distressing symptoms related to Amyotrophic Lateral Sclerosis (ALS) is excessive drooling of saliva, also termed sialorrhoea. Evaluating its prevalence and severity among Indian patients with ALS is essential for understanding the magnitude and impact of the problem. A cross-sectional survey was conducted to estimate the prevalence and severity of sialorrhoea among individuals diagnosed with ALS. We also intended to assess the current pharmacological management practice for sialorrhoea in ALS patients.
Materials and Methods: Patients with ALS enrolled in the Neuropalliative Registry of a quaternary care centre for neurological disorders were included in the study. As part of routine follow-up, telephonic interviews were conducted with either the patients or their next of kin. The extent of sialorrhoea was assessed using the sialorrhoea scoring scale.
Results: Seventy patients were included in the study. The mean age at presentation was 51.8 (standard deviation [SD]-12.8) years. The majority were males (74.3%). The mean duration of illness was 21.6 (SD 15.7) months. The majority (80%) had limb onset ALS. Forty per cent of the patients in the study had some degree of sialorrhoea. Mild drooling was present in 15 patients (21.4%), moderate in 9 (12.9%), severe in 2 (2.9%) and profuse drooling in another 2.9% of patients. A total of 9 patients (12.9%) were receiving anticholinergic medication. Patients diagnosed with bulbar onset ALS had a significantly greater degree of sialorrhoea than those with limb onset presentation (P = 0.008). In addition, a longer duration of illness showed a positive correlation with the severity of sialorrhoea (r = 0.30, P = 0.012).
Conclusion: Sialorrhoea is a prevalent and clinically significant symptom in individuals with ALS. The severity of sialorrhoea is greater in patients with bulbar onset ALS and tends to increase with longer illness duration. A substantial proportion of patients may benefit from recommended treatment for excessive salivation and saliva-related issues. This study underscores the need for screening of distressing symptoms as sialorrhoea, in ALS patients. The treating teams need to have a heightened awareness regarding the same so that treatment options can be offered to the patients.

Keywords:  Amyotrophic lateral sclerosis; Distress; Prevalence; Sialorrhoea

DOI:  https://doi.org/10.25259/IJPC_369_2024
Ageing Res Rev. 2026 Apr 08. pii: S1568-1637(26)00125-X. [Epub ahead of print] 103133

Mechanistic Research and Therapeutic Prospects of Alternative Splicing in Neurodegenerative Diseases.

Xiaolan Ran, Mei Wang, Juan Huang, Nanyu Kuang, Peng Tian, Jingjing Wu, Fei Feng, Yong Luo, Nanqu Huang.

  One essential post-transcriptional regulatory mechanism that increases protein diversity in eukaryotes is alternative splicing. This process is crucial for maintaining nervous system function and is highly active in neurons. Dysregulation of alternative splicing is a common pathogenic factor in many neurodegenerative diseases. For example, splicing variants of tau protein and amyloid precursor protein are implicated in Alzheimer's disease; aberrant splicing of α-synuclein (SNCA) and upregulation of specific transcript variants of the Parkin (PARK2) gene occurs in Parkinson's disease; and aberrant splicing of Stathmin-2 (STMN2) pre-mRNA leads to the loss of axonal maintenance proteins in amyotrophic lateral sclerosis and frontotemporal dementia. This process is precisely regulated by trans-acting factors, a class of RBPs that specifically recognize and bind to cis-acting elements on precursor mRNA (pre-mRNA). These factors are primarily categorized into two major groups: serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). Although hnRNPs and SR proteins have been shown to regulate neuronal alternative splicing, their complex regulatory networks and associated disease mechanisms remain incompletely understood, hindering the development of targeted therapies. This review summarizes the molecular mechanisms of alternative splicing and its regulatory features in neurodegenerative diseases. It also summarizes recent advances in splicing-based therapies and biomarkers, providing insights into disease mechanisms and therapeutic development.

Keywords:  Alternative splicing; Alzheimer's disease; Neurodegenerative diseases; Parkinson's disease; Splicing factors; Therapeutics

DOI:  https://doi.org/10.1016/j.arr.2026.103133
Muscle Nerve. 2026 Apr 11.

The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.

Alana K O Hodgson, Christopher J McDermott, Pamela J Shaw, James J P Alix.

   INTRODUCTION/AIMS: Recent work suggests that nerve excitability testing has diagnostic potential in amyotrophic lateral sclerosis (ALS). The diagnostic performance of nerve excitability across hand muscles is currently unknown. This study aimed to assess if muscles of the so-called split hand (abductor pollicis brevis [APB], first dorsal interosseous [FDI], and abductor digiti minimi [ADM]) manifest differences in diagnostic performance.
METHODS: We prospectively recruited 60 consecutive patients investigated for ALS. Nerve excitability, motor unit number and size (MScanFit), needle electromyography (EMG), and standard clinical data were collected. ALS and non-ALS groups were compared using t tests, area under receiver operating characteristic curves (AUROC), and multivariate modeling.
RESULTS: Forty-eight patients completed testing of all three muscles, 25 were diagnosed with ALS. The most prominent nerve excitability changes were in superexcitability (APB p = 0.001, FDI p = 0.0001, ADM p = 0.002). Diagnostic performance with superexcitability was similar across the three muscles (p > 0.05). Reductions in motor unit number were observed in ALS patients. Changes in excitability were evident without loss of motor units, most frequently in APB (40% of recordings). Improvements to the AUROC were obtained using combined excitability/motor unit parameters from APB/FDI (AUROC 0.97, p = 0.01 vs. FDI superexcitability alone). Combined excitability and motor unit modeling outperformed detection of EMG abnormalities.
DISCUSSION: Disturbances to nerve excitability are similar across the split hand muscles at the time of ALS diagnosis. These occurred prior to motor unit loss and traditional EMG changes. Combining excitability and motor unit parameters in the lateral hand can identify early pathology and potentially lead to earlier diagnosis.

Keywords:  amyotrophic lateral sclerosis; diagnosis; motor unit number; nerve excitability

DOI:  https://doi.org/10.1002/mus.70239
Spec Care Dentist. 2026 Mar-Apr;46(2):46(2): e70170

The Repercussions of Amyotrophic Lateral Sclerosis on the Orofacial Sphere: A One-Year Prospective Longitudinal Study.

Vincent Vaudroz, Annemarie Hübers, Stavros Kiliaridis, Gregory S Antonarakis.

AIM: The aim of this longitudinal study was to evaluate the repercussions of amyotrophic lateral sclerosis (ALS) on orofacial function, dental health, and the development of malocclusions, in order to assess whether disease progression influences oral and craniofacial outcomes.
SUBJECTS AND METHODS: Thirteen patients diagnosed with ALS according to the Gold Coast criteria were enrolled to be examined at two time points (T1 and T2), with a one-year interval. The ALS Functional Rating Scale-Revised (ALS-FRS-R), the Nordic Orofacial Test Screening (NOT-S), the Decayed Missing and Filled Teeth (DMFT) index, Plaque Index, and standard orthodontic assessments were used to quantify changes in disease progression, orofacial function, dental health, and occlusal parameters, respectively. Statistical evaluation: Paired sample t-tests were performed to evaluate differences between T1 and T2 for continuous variables. Chi-square and Fisher's exact tests were used for categorical data. Multiple linear regression analyses were carried out to assess potential associations between general disease progression, ALS type, and orofacial functional or dental health decline. A significance level of p < 0.05 was adopted for all analyses.
RESULTS: Thirteen patients were examined at T1, 10 of whom completed both evaluations. A significant deterioration in the general disease condition was observed (ALS-FRS-R: mean difference -6.0 ± 6.98; p = 0.024). Orofacial function worsened significantly as reflected by an increase in NOT-S total score (+2.3; p = 0.001). Dental health also declined, with a significant increase in DMFT (+1.8; p = 0.014) and Plaque Index (+0.4; p = 0.004). However, occlusal parameters remained stable over the 12-month period, with no significant changes in overjet (p = 0.860) or overbite (p = 0.347). The bulbar type of ALS seems to show worse deterioration of orofacial function over time, and individuals with more significant general disease progression also showed worse orofacial functional decline.
CONCLUSIONS: ALS has a significant impact on orofacial function and dental health, characterized by neuromuscular deterioration, increased plaque accumulation, and a higher number of affected teeth. Despite this decline, dental occlusion appears to remain stable in the short term. These findings highlight the need for interdisciplinary and preventive oral care strategies in the management of patients with ALS, aiming to preserve oral function and quality of life in a progressively disabling disease.

DOI: https://doi.org/10.1111/scd.70170
Brain Res Bull. 2026 Apr 04. pii: S0361-9230(26)00136-X. [Epub ahead of print]239 111850

Abnormal cortical hierarchy revealed by gradient dysfunction in patients with definite amyotrophic lateral sclerosis.

Zi-Wei Cai, Shao-Peng Zhuang, Zhe-Yi Huang, Jia-Yan Shi, Nao-Xin Huang, Sheng Chen, Zhang-Yu Zou, Hua-Jun Chen.

   PURPOSE: Cortical multisystem dysfunction in amyotrophic lateral sclerosis (ALS) has been investigated, but disruptions in unimodal-to-transmodal cortical hierarchy remained unexplored. We identified cortical hierarchy abnormalities using functional connectivity gradient (FCG) analysis and evaluated their clinical relevance in ALS.
METHODS: Resting-state functional MRI images were acquired from 17 definite ALS patients and 29 healthy controls. Unimodal-to-transmodal cortical gradient values were derived from functional connectivity matrices using diffusion map embedding, a nonlinear dimensionality reduction method. Intergroup differences were examined with two-sample t tests at the voxel and network levels.
RESULTS: Gradients primarily in transmodal areas (including the bilateral frontal and parietal cortex and anterior cingulate gyrus) decreased, and gradients primarily in unimodal areas (including the bilateral precentral and postcentral gyrus and occipital cortex) increased in ALS patients (false discovery rate (FDR)-corrected P < 0.05). Network-level gradients in ALS were elevated in the sensorimotor (SMN) and visual networks (VN) but reduced in the frontoparietal (FPN) and limbic networks (FDR-corrected P < 0.05). Among ALS patients, the gradient values in SMN (r = 0.506; P = 0.038), VN (r = 0.534; P = 0.027) and FPN (r = -0.792; P < 0.001) correlated with disease duration, and the gradient value in FPN correlated with disease severity (r = 0.532; P = 0.028). Gradient measures demonstrated moderate accuracy for diagnosing ALS (AUC = 0.712-0.866).
CONCLUSION: Aberrant cortical hierarchy may elucidate pathophysiological mechanisms of multisystem dysfunction in ALS. FCG analysis may provide biomarkers related to hierarchical functional systems for assessing ALS progression and diagnosis.

Keywords:  amyotrophic lateral sclerosis; cortical hierarchy; functional connectivity gradient; motor dysfunction; resting-state functional magnetic resonance imaging

DOI:  https://doi.org/10.1016/j.brainresbull.2026.111850
Front Neurol. 2026 ;17 1743723

Connectivity in ALS II (CoALS II): a study of structural and functional connectivity in ALS.

Vijay Renga, Charlotte A Jeffreys, Gina E Kersey, Elijah W Stommel.

   Background: Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a network-level neurodegenerative disease involving distributed disruptions across structural and functional systems. While previous studies have often examined white matter integrity or functional connectivity in isolation, the nature of structure-function coupling and its reorganization in ALS remains poorly understood.
Methods: We conducted a multimodal connectomic analysis in ALS patients and matched controls, integrating cortical thickness-based structural covariance networks, diffusion MRI tractography, and resting-state and task-based functional MRI. Graph-theoretical metrics were derived, and cross-modal structure-function correspondence was quantified using ROI-wise correlation analyses. A comprehensive 104-node parcellation scheme based on the Desikan-Killiany atlas was employed.
Results: ALS participants showed preserved global network topology (p > 0.05 for efficiency and small-worldness) but evidence of selective reorganization, particularly within motor and interhemispheric pathways. Cortical covariance networks exhibited minimal association with functional dynamics, whereas diffusion-derived white matter connectivity remained closely aligned with functional organization. This structure-function coupling was maintained or even enhanced during task performance (p = 0.005), suggesting adaptive reconfiguration rather than uniform disconnection.
Conclusions: Structure-function coupling in ALS is not globally diminished but reorganized, with robust white matter-functional relationships coexisting alongside weak cortical covariance-functional associations. These findings refine the traditional disconnection model and highlight the utility of multimodal metrics for understanding disease mechanisms and developing biomarkers for progression and therapeutic response.

Keywords:  ALS; DTI; brain network; connectivity; fMRI

DOI:  https://doi.org/10.3389/fneur.2026.1743723
Biomed Environ Sci. 2026 Mar 20. 39(3): 327-341

Integration of Single-cell RNA Sequencing and Mendelian Randomization Analysis for Identifying Potential Immune Therapeutic Targets in Amyotrophic Lateral Sclerosis.

Xin Yuan Pang, Hong Fen Wang, Jiong Ming Bai, Xu Sheng Huang.

   Objective: Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+ cytotoxic T cell-related genes and ALS risk.
Methods: Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from patients with ALS and healthy controls (HC) was used to identify differentially expressed genes (DEGs) in CD4+ cytotoxic T cells. Comprehensive analyses of CD4+ cytotoxic T cells, including pseudotemporal trajectory, intercellular communication, and metabolic pathway analysis, were performed. Mendelian randomization (MR) analysis evaluated the causal effects of DEGs on ALS risk, with validation using independent genome-wide association study (GWAS) data. Expression patterns of the causal genes were further verified using scRNA-seq, bulk-seq, and clinical samples.
Results: CD4+ cytotoxic T cells were significantly expanded in patients with ALS. The upregulated genes S100A6, SERPINB6, SMAD7, and TPST2 were positively correlated with ALS susceptibility, whereas DIP2A showed a protective association.
Conclusion: S100A6, SERPINB6, SMAD7, TPST2, and DIP2A were identified as causal genes and potential therapeutic targets in ALS, implicating CD4+ cytotoxic T cells in the disease mechanisms. Further studies targeting these genes and neuroinflammatory pathways are warranted.

Keywords:  Amyotrophic lateral sclerosis; CD4+ cytotoxic T cells; Drug target; Mendelian randomization; Single-cell RNA sequencing

DOI:  https://doi.org/10.3967/bes2026.011
Ann Clin Transl Neurol. 2026 Apr 06.

Longitudinal Assessment of Biomarkers in ALS: Discriminative Biomarkers for Disease Progression and Survival.

David R Beers, Yueh-Yun Lin, Jason R Thonhoff, Aaron D Thome, Alireza Faridar, Weihua Zhao, Shixiang Wen, Stanley H Appel.

   OBJECTIVE: To assess the association and discriminative performance of serum biomarkers with clinical disease progression and survival in patients with amyotrophic lateral sclerosis (ALS).
METHODS: This retrospective study, conducted at Houston Methodist Hospital, Houston, TX, used longitudinal serum samples collected between January 2018 and December 2022. A cohort of 100 patients with sporadic or familial ALS was randomly selected and assayed by ELISAs for biomarkers 4-hydroxy-2-nonenal (4-HNE), lipopolysaccharide binding protein (LBP), and neurofilament light chain (NfL) levels.
RESULTS: Each biomarker was increased in patients. 4-HNE and LBP were increased at diagnosis and continued to increase as the disease progressed; both correlated with progression rates and survival. NfL was increased at diagnosis, then plateaued relatively. LBP correlated with ALSFRS-R at diagnosis; NfL did not correlate. 4-HNE and LBP were increased in bulbar onset patients who survived a shorter period of time; NfL levels for bulbar/limb onsets were not different. Receiver operating characteristic analyses with apparent and optimism-adjusted area-under-the-curve (AUC) demonstrated that 4-HNE and LBP discriminated rapid progression and survival, whereas NfL showed modest discrimination for rapid progression. The combination of biomarkers yielded improved AUCs as depicted in Venn diagrams across individual and combined biomarkers.
INTERPRETATION: 4-HNE, LBP, and NfL are biomarkers of lipid peroxidation, systemic inflammation, and axonal integrity. 4-HNE and LBP correlated with disease burden, disease progression, and survival. In the bulbar onset, survival was shortened and associated with increased 4-HNE and LBP. This exploratory longitudinal study suggests the utility of combining biomarkers to discriminate disease progression and survival and monitor clinical trial outcomes.

Keywords:  amyotrophic lateral sclerosis; biomarker; discriminative

DOI:  https://doi.org/10.1002/acn3.70381
Brain Commun. 2026 ;8(2): fcag104

Amygdala TDP-43 pathology is associated with behavioural dysfunction and ferritin accumulation in amyotrophic lateral sclerosis.

Olivia M Rifai, Fergal M Waldron, Judi O'Shaughnessy, Fiona L Read, Martina Gilodi, Annalisa Pastore, Neil A Shneider, Gian Gaetano Tartaglia, Elsa Zacco, Holly Spence, Jenna M Gregory.

  Cognitive and behavioural symptoms associated with amyotrophic lateral sclerosis and frontotemporal spectrum disorders (ALS-FTSD) are thought to be driven, at least in part, by the pathological accumulation of TDP-43. Here we examine post-mortem tissue from six brain regions associated with cognitive and behavioural symptoms in a cohort of 30 people with sporadic ALS (sALS), a proportion (12/30) of which underwent standardized neuropsychological behavioural assessment as part of the Edinburgh Cognitive ALS Screen (ECAS). Overall, the behavioural screen performed as part of the ECAS predicted accumulation of pathological phosphorylated TDP-43 (pTDP-43) with 100% specificity and 86% sensitivity in behaviour-associated brain regions. Notably, of these regions, pathology in the amygdala was the most predictive correlate of behavioural dysfunction in sALS. In the amygdala of sALS patients, we show variation in morphology, cell-type predominance and severity of pTDP-43 pathology. Further, we demonstrate that the presence and severity of intra-neuronal pTDP-43 pathology, but not astroglial pathology, or phosphorylated Tau pathology, is associated with behavioural dysfunction. Cases were also evaluated using a TDP-43 aptamer (TDP-43APT), which revealed that pathology was not only associated with behavioural symptoms, but also with ferritin levels, a measure of brain iron. Intra-neuronal pTDP-43 and cytoplasmic TDP-43APT pathology in the amygdala is associated with behavioural symptoms in sALS. TDP-43APT staining intensity is also associated with increased ferritin, regardless of behavioural phenotype, suggesting that ferritin increases may occur upstream of clinical manifestation, in line with early TDP-43APT pathology, representing a potential region-specific imaging biomarker (e.g. volumetric or susceptibility-weighted MR imaging) of early disease in ALS.

Keywords:  ALS; ECAS; TDP-43; behaviour; cognition

DOI:  https://doi.org/10.1093/braincomms/fcag104
J Neurol. 2026 Apr 06. pii: 250. [Epub ahead of print]273(4):

Accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Zhuojuan Tang, Yanping Lei, Ju Huang, Ruyang He, Yujun Wu, Min Li, Zhi Ye, Xiaoyan He, Hao Heng, Yunhong Zha, Jun Wei.

   PURPOSE: This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of muscle ultrasonography in detecting fasciculations for the diagnosis of amyotrophic lateral sclerosis (ALS).
METHODS: Following PRISMA-DTA guidelines, we systematically searched PubMed, Embase, Cochrane Library, Ovid Medline, Sinomed, Web of Science, CNKI and VIP for studies published up to July 8, 2025 that evaluated muscle ultrasonography to detect fasciculations for ALS diagnosis. The study protocol was registered in PROSPERO (CRD420251057866). Studies were screened using predefined inclusion and exclusion criteria and data were extracted. Risk of bias was assessed with QUADAS-2. Statistical analyses (Stata 16.0 and R 4.5.1 with the "midas," "metandi," and "mada" packages) were used to calculate pooled sensitivity (Sen), specificity (Spe), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR). We constructed forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, summary ROC (SROC) curves and calculated the area under the SROC curve (AUC). Univariate meta-regression and subgroup analyses explored sources of heterogeneity. Publication bias was assessed using Deeks' funnel plot asymmetry test. Fagan nomograms were also used to illustrate the changes from pre-test to post-test probability and to enhance clinical interpretability.
RESULTS: Thirteen studies involving 1176 participants met the inclusion criteria. Muscle ultrasonography for fasciculation detection in ALS yielded a pooled sensitivity of 0.87 (95% CI 0.83-0.91) and specificity of 0.91 (95% CI 0.86-0.94). The pooled LR+ was 9.81 (95% CI 6.25-15.40) and LR- was 0.14 (95% CI 0.10-0.19), with a DOR of 70.03 (95% CI 41.72-117.56). The area under the SROC curve was 0.94 (95% CI 0.91-0.95). Meta-regression identified scan duration as a primary factor influencing diagnostic accuracy, with scan durations ≥ 30 s associated with higher sensitivity but relatively lower specificity. Deeks' funnel plot showed no significant asymmetry (p = 0.61), indicating no notable publication bias. Fagan nomograms showed that, at a pre-test probability of 30%, the post-test probability increased to 81% after a positive MUS result and decreased to 6% after a negative result.
CONCLUSION: Muscle ultrasonography demonstrates good pooled diagnostic accuracy for detecting fasciculations in ALS and may serve as a useful adjunct to electrodiagnostic evaluation. Scan duration appears to significantly affect the diagnostic performance, with longer scanning improving sensitivity at the cost of reduced specificity. We speculate that prolonged scanning may be more useful in clinical scenarios where fasciculations are subtle or atypical, whereas shorter scanning may be sufficient when fasciculations are already readily apparent. Nevertheless, further large-scale prospective studies are needed to validate standardized scanning protocols and to better define the clinical role of MUS in ALS diagnostic pathways.

Keywords:  Amyotrophic lateral sclerosis; Fasciculations; Meta-analysis; Muscle ultrasonography; Systematic review

DOI:  https://doi.org/10.1007/s00415-026-13775-4
Front Neurol. 2026 ;17 1792829

Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.

Alkusha Naim, Azhar Mahmood Farooqui, Badruddeen, Mohammad Irfan Khan, Juber Akhtar, Asad Ahmad, Sumel Ashique, Anas Islam.

  Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.

Keywords:  blood–brain barrier; brain targeting; nano-phytomedicine; nanocarriers; neurodegeneration; phytochemicals

DOI:  https://doi.org/10.3389/fneur.2026.1792829
Front Aging Neurosci. 2026 ;18 1782460

Astrocytic K+ regulation during neurodegenerative diseases.

Evgeniia Samokhina, Yossi Buskila.

  Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na+, Ca2+, K+) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.

Keywords:  ALS; Alzheimer's disease; astrocytes; homeostasis; neurodegeneration; potassium

DOI:  https://doi.org/10.3389/fnagi.2026.1782460
Brain Res Bull. 2026 Apr 04. pii: S0361-9230(26)00158-9. [Epub ahead of print]239 111872

Characterisation of a patient-derived iPSC-based model for studying the blood-brain barrier in Alzheimer's disease.

Sylvia Wagner, Karin Danz, Jooseppi Hyvärinen, Anna-Lena Fischer, Katja M Kanninen, Mikko Gynther, Elena Puris.

  The blood-brain barrier (BBB) comprised of the brain capillary endothelial cells (BCECs), with its tight junctions (TJ), transporters and receptors, regulates the passage of solutes, such as nutrients, metabolites, and xenobiotics, including drugs. In Alzheimer's disease (AD), characterised by the accumulation of amyloid-β peptide (Aβ) and the formation of hyperphosphorylated tau aggregates, a compromised BBB integrity was reported. There is a lack of knowledge about the effects of tau pathology on BBB function in AD. Advances in developing BBB models using human induced pluripotent stem cell (hiPSC)-derived BCECs have opened a new avenue for investigating AD-related changes in BBB functional integrity. Here, we characterised the BBB model derived from hiPSCs generated from an AD patient with a tau-related mutation (STBCi 062-A) versus the one based on a healthy person's cells (UKKi 011-A) in terms of mimicking AD-related changes in paracellular permeability, TJs, transporters, receptors and other proteins playing a role in BBB integrity. The STBCi 062-A-derived BCECs showed lower TEER values and increased permeability associated with downregulation of proteins regulating TJ organization and BBB integrity, as compared to UKKi 011-A-derived BCECs. We revealed AD-relevant increase in protein expression of efflux transporter BCRP and amino acid transporter ASCT1, as well as transferrin receptor protein 1 in the STBCi 062-A-derived BCECs compared to UKKi 011-A-derived BCECs. The developed AD-patient-hiPSC-derived BCEC model possesses several important characteristics that recapitulate changes in BBB integrity in AD and can serve as a robust tool for developing AD treatments.

Keywords:  Alzheimer’s disease (AD); Blood-brain barrier (BBB); Efflux transporters; Human induced pluripotent stem cells (hiPSCs); Solute carrier (SLC) transporters; Tau

DOI:  https://doi.org/10.1016/j.brainresbull.2026.111872
Pharmacol Res. 2026 Apr 03. pii: S1043-6618(26)00100-3. [Epub ahead of print] 108185

The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives.

Gabriela Mantovani Baldasso, Rodrigo Sebben Paes, Artur Graeff Moreira, Sofia Gallo Salvadori, Christian Limberger, Fiorentina Roviezzo, Rafaelle Capasso, Rafael Cypriano Dutra.

  Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs - including Alzheimer's, Parkinson's, Huntington's diseases and multiple sclerosis - the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions. The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes. Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation. In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision. By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.

Keywords:  Cannabinoid receptors; Endocannabinoid system; Neurodegeneration; Neuroimmune signaling; Neuroinflammation; Translational therapeutics

DOI:  https://doi.org/10.1016/j.phrs.2026.108185
Med Sci Monit. 2026 Apr 11. 32 e950453

Comprehensive Review of Anesthetic Strategies for Patients With Neurodegenerative Diseases.

Łukasz Grabarczyk.

Patients with neurodegenerative diseases (NDDs) represent a unique and challenging population from an anesthesiological perspective due to their neurological vulnerability. This issue is becoming increasingly relevant as the incidence of certain NDDs rises with population aging. Effective perioperative management in patients with NDDs requires detailed preoperative evaluation, with emphasis on neurological status, cardiopulmonary function, and a thorough review of current medications. Intraoperatively, careful selection of anesthetic agents and monitoring strategies is essential because of altered drug sensitivity, increased susceptibility to malignant hyperthermia, and potential drug interactions. Particular attention must be given to neuromuscular blockade. The use of nondepolarizing neuromuscular blocking agents is generally risky due to their potentially prolonged and unpredictable effects; their use may be considered under strictly controlled conditions. In contrast, propofol and inhalational agents have demonstrated safety and efficacy in this patient population. This article aims to review the perioperative anesthetic management of patients with NDDs, including Huntington disease, (spino)cerebellar ataxia, Friedreich ataxia, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.

DOI: https://doi.org/10.12659/MSM.950453
Front Cell Neurosci. 2026 ;20 1805529

Blood-spinal cord barrier disruption after spinal cord injury: a time-dependent mechanistic review.

Zhirui Jiang, Ce Zhang, Zejing Zhao, Bin Ning.

  The blood-spinal cord barrier (BSCB) is a specialized vascular interface that preserves spinal cord homeostasis by regulating molecular and cellular trafficking between blood and neural tissue. Disruption of BSCB integrity is a critical pathological event follow-ing spinal cord injury (SCI), leading to increased permeability, inflammatory cell infil-tration, and secondary neurodegeneration. Increasing evidence indicates that BSCB breakdown is not a single event but a dynamic, time-dependent process. In this review, we summarize the molecular and cellular mechanisms responsible for BSCB disruption after SCI in a chronological manner. Key pathological events occurring during the acute, subacute, and chronic phases are discussed, including pathological hemody-namic changes, endothelial stress responses, epigenetic regulation, inflammatory me-diators, immune cell-endothelial interactions, and extracellular matrix remodeling. We further highlight endogenous protective and reparative mechanisms that emerge at later stages. A comprehensive understanding of the temporal characteristics of BSCB disruption may facilitate the development of phase-specific therapeutic strate-gies aimed at preserving barrier integrity, limiting secondary injury, and improving neurological recovery after SCI. This temporal perspective underscores the need for stage-specific interventions to preserve BSCB integrity and improve outcomes after SCI.

Keywords:  blood-spinal cord barrier; neuroinflammation; spinal cord injury; therapeutic targets; timeline

DOI:  https://doi.org/10.3389/fncel.2026.1805529
CNS Neurol Disord Drug Targets. 2026 Apr 02.

Focused Ultrasound-activated Extracellular Vesicles-nanoparticle Hybrids for Targeted Brain Drug Delivery: Engineering Strategies and Translational Outlook.

Yash Kalra, Shikha Baghel Chauhan, Indu Singh, Chirag Jain.

  A revolutionary method for targeted neurotherapeutics is focused ultrasound (FUS)-mediated blood-brain barrier (BBB) regulation. In order to enable controlled and targeted intracerebral drug delivery, recent developments in hybrid extracellular vessssicle-nanoparticle (EV-NP) platforms combine the biological compatibility of natural vesicles with the adjustable characteristics of synthetic nanocarriers. The engineering approaches, translational difficulties, and molecular underpinnings of FUS-activated EV-NP hybrids are all thoroughly examined in this paper. Mechanistically, FUS uses acoustic cavitation to provide a temporary and reversible opening of the blood-brain barrier, which allows therapeutic medicines to pass through selectively while reducing side effects. Thermosensitive lipid and perfluorocarbon inclusion, ligand-mediated targeting, and stimuli-responsive surface design are examples of engineering advancements that improve biodistribution and release accuracy. When compared to traditional systems, preclinical models show higher therapeutic indices, prolonged drug retention, and brain penetration efficiencies of up to 90%. Large-scale production, standardization, and regulatory validation still face difficulties, nevertheless, especially with regard to long-term safety and reproducibility. New developments have a strong emphasis on combining synthetic biology, microfluidics, and artificial intelligence to improve design parameters and guarantee clinical scalability. All things considered, FUS-activated EV-NP hybrids offer a potential new avenue for precision neuropharmacology, bridging the gap between next-generation tailored therapies and non-invasive delivery methods.

Keywords:  Focused ultrasound (FUS); blood-brain barrier (BBB); engineering strategies.; extracellular vesicle (EV); hybrid drug delivery; nanoparticles (NPs); neurotherapeutics

DOI:  https://doi.org/10.2174/0118715273460963260314133640
Front Immunol. 2026 ;17 1708940

Immune dysregulation in pediatric tic disorders: mechanisms, biomarkers, and therapeutic frontiers.

Xu Sun, Xiaohong Bai.

  Tic Disorders (TDs) are common neurodevelopmental disorders characterized by complex pathophysiological mechanisms. A growing body of evidence in recent years suggests that immune system dysregulation plays a critical role in the pathogenesis and clinical course of TDs in a subset of pediatric patients. This review aims to systematically summarize the current understanding of the core mechanisms of immune dysregulation in pediatric TDs, potential biomarkers, and related therapeutic frontiers. We detail three core pathophysiological pathways, Post infectious autoimmunity, represented by the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) models. Its core mechanism involves the production of autoantibodies induced by molecular mimicry, which target basal ganglia neurons, such as cholinergic interneurons and dopamine receptors. Neuroinflammation is another critical pathway. This process involves T helper 17 (Th17) cell-mediated disruption of the blood-brain barrier and microglial activation. It is further characterized by elevated pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-12 (IL-12). Microbiota-gut-brain axis dysregulation, wherein gut dysbiosis and compromised intestinal barrier function influence central nervous system (CNS) function through the neuro immune endocrine network. Building upon this framework, we evaluate potential biomarkers across various dimensions, including the findings and limitations in serology (cytokines), cerebrospinal fluid analysis (oligoclonal bands, MCP-1), neuroimaging (volumetric changes in the basal ganglia and PET imaging of neuroinflammation), and genetics (variations in the IL-1RN gene). Finally, we discuss the evolution from conventional treatments to emerging immune-targeted therapies. This encompasses core immunomodulatory therapies (Intravenous Immunoglobulin (IVIG) and plasmapheresis) and promising future strategies, such as fecal microbiota transplantation (FMT), targeted B-cell therapies, and small-molecule anti-inflammatory drugs. In conclusion, a deeper understanding of the immunological basis of TDs is paving the way for the development of more precise diagnostic tools and novel, individualized immunomodulatory interventions.

Keywords:  PANDAS/PANS; Tourette syndrome; immune dysregulation; neuroinflammation; tic disorders

DOI:  https://doi.org/10.3389/fimmu.2026.1708940
Curr Alzheimer Res. 2026 Apr 06.

Voice Biomarkers: Cognitive Impairment, including Alzheimer's Disease, Dementia, or Mild Cognitive Impairment: Introduction to Peripheral Neuropathy.

Fatma Özcan.

   INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) can cause certain nervous disorders, which in turn can lead to voice disorders and abnormal values for certain acoustic parameters. Mild cognitive impairment (MCI) is probably the early stage of the disease. Dementia is one of the causes of Alzheimer's disease. Whether or not there is a link between these three cognitive impairments, lesions affecting the vocal cords or articulators can be caused by neurological structures that influence phonation. The potential of biomarkers in the detection of cognitive impairment is remarkable. In our study, we will examine vocal biomarkers obtained from the extraction of acoustic features. The aim of this study is to combine vocal biomarkers with cognitive diseases.
METHODS: The standardised dataset used has recently been made publicly available. Cognitive impairment, including Alzheimer's disease, dementia, or MCI, is diagnosed from /a/ and diadochokinesis-pataka vocalisations using Mel-Frequency Cepstral Coefficients (MFCCs) transformed into 2D scalogram images. For processing, we will use the pre-trained OpenL3 network, and our less resource-intensive network called Op1Net to classify diseased and healthy groups.
RESULTS: A significant difference was observed compared to the control group. For the /a/ vocalisation, classification accuracy across all ages and genders was 82.1%, and the AUC value was 88.3%, while for diadochokinesis-pataka, accuracy was 69.8% and the AUC value was 75.4%. In the group of women over 55 years of age, the accuracy was 80.93%, and the AUC value was 87.12%.
DISCUSSION: Performance results clearly show that there is a correlation between the voice and the neurodegenerative disease AD, dementia, or MCI. We can see that the results of the data classification, including all ages and genders, for the sound /a/ are higher than those for the 'pataka' vocalisations. The prolonged vowel provides more information about the disease.
CONCLUSION: This preliminary multidisciplinary study clearly demonstrates the existence of a link between neurological disease and the voice, and raises several questions concerning the nervous system, particularly the vagus nerve and associated neuropathy.

Keywords:  Alzheimer's Disease; deep learning; neuropathy.; scalogram; vocal biomarkers

DOI:  https://doi.org/10.2174/0115672050454281260307134058
J Biotechnol Biomed. 2026 ;9(1): 67-76

Enhancing Early Diagnosis: Multimodal AI Approaches for Neurodegenerative Diseases.

Aneesh Swamy, Devendra K Agrawal.

  Neurodegenerative diseases such as Alzheimer's and Parkinson's impose a staggering global burden, yet timely identification remains hindered by a fundamental mismatch between the slow unfolding of pathology and the static nature of traditional diagnostic frameworks. While conventional clinical markers often fail to identify decline until irreversible neuronal loss has occurred, artificial intelligence (AI)-driven biomarkers derived from neuroimaging, electrophysiology, and digital phenotyping offer a transformative proactive paradigm. This review evaluates how machine-learning models extract high- dimensional, subvisual patterns from MRI, PET, and EEG datasets to detect preclinical deviations that outpace traditional markers in predictive timelines. We argue that the primary value of these technologies lies in a categorical shift toward continuous, temporally informed disease modeling designed to fill the "detection gap" between early protein accumulation and overt clinical impairment. By synthesizing evidence across various modalities, we highlight the superior performance of multimodal fusion architectures in capturing the biological complexity of neurodegeneration. However, clinical translation faces significant hurdles, including data heterogeneity, the "black-box" nature of deep learning, and the necessity for global equity in dataset representation. Ultimately, by integrating explainable AI with longitudinal data streams, these biomarkers can redefine neurodegenerative care-transforming diagnosis from a reactive confirmation of damage into a precise tool for risk stratification, trial enrichment, and early therapeutic intervention.

Keywords:  AI-Driven Biomarkers; Artificial intelligence (AI); Digital Phenotyping; Early detection; Electrophysiology (EEG); Explainable AI (XAI); Longitudinal Monitoring; Multimodal Fusion; Neurodegenerative Diseases; Neuroimaging (MRI/PET); Predictive Modeling

DOI:  https://doi.org/10.26502/jbb.2642-91280211
bioRxiv. 2026 Apr 04. pii: 2026.04.02.716122. [Epub ahead of print]

Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.

Aaron Burberry, Penelope Benchek, Mark Lowe, Wanyong Shin, Blake McCourt, Quintasha Beamon, Shinjon Chakrabarti, Sara Ramaiah, Elizabeth Woidke, Maria Khrestian, Holden Maecker, Lynn M Bekris, Stephen Rao, Daniel Ontaneda, James B Leverenz, William Bush, Jagan A Pillai.

Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.

DOI: https://doi.org/10.64898/2026.04.02.716122
Sci Rep. 2026 Apr 10. pii: 12014. [Epub ahead of print]16(1):

Detection of inflammation-related blood-brain barrier dysfunction using PET and MR imaging: a pilot study.

Colmar F Hilbrig, Bernd Baumann, Wolfgang Sievert, Rebecca Halbgebauer, Markus Huber-Lang, Ambros J Beer, Volker Rasche, Jessica Löffler.

  The purpose of this study is to non-invasively image subtle blood-brain barrier (BBB) permeability changes in a state of chronic neuroinflammation using radiolabelled human serum albumin (HSA). Although biomarker-based methods for detecting BBB dysfunctions have been established, sensitive spatial and quantitative imaging of low-grade, chronic BBB permeability changes remains limited. This study seeks to establish radiolabelled albumin as a sensitive radiotracer for visualizing and quantifying BBB dysfunction during chronic neuroinflammation. This study evaluated the utility of radiolabeled serum albumin ([89Zr]Zr-DFO-HSA) for assessing BBB permeability using co-registered PET and MR imaging in a transgenic mouse model of neuroinflammation mediated by IKK/NF-κB activation. PET and MRI revealed significantly increased radiotracer accumulation in the cerebellum of neuroinflammatory mice, corroborated by ex vivo analyses. Quantitative PET data revealed elevated intracerebral radiotracer concentrations over 24 h, even in the absence of morphological changes in histological evaluations. These findings emphasize the sensitivity of [89Zr]Zr-DFO-HSA in detecting early-stage BBB permeability changes prior to the onset of overt morphological damage or clinical symptoms. As a surrogate marker for macromolecular leakage, this non invasive imaging approach shows promise for advancing preclinical research into neuroinflammatory disorders and barrier dysfunctions.

Keywords:  Albumin; BBB-dysfunction; Neuroinflammation; PET/MR imaging

DOI:  https://doi.org/10.1038/s41598-026-47352-6
Neuromolecular Med. 2026 Apr 04. pii: 20. [Epub ahead of print]28(1):

SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential.

Ayman Ali Mohammed Alameen, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Marios Papadakis, Safaa A Faheem, Gaber El-Saber Batiha.

  The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.

Keywords:  Brain aging; Geroprotectors; Neuroinflammation; Oxidative stress; SIRT1

DOI:  https://doi.org/10.1007/s12017-026-08923-y
Nucl Med Commun. 2026 Apr 03.

P2X7 receptor and neuroinflammation in neurodegenerative disorders: an autoradiography study with [18F]JNJ-64413739.

Abhishekh Hulegar Ashok, Sophie Field, Nisha Kuzhuppilly Ramakrishnan, Stephen Thompson, John T O'Brien, Franklin I Aigbirhio.

   BACKGROUND: Neuroinflammation plays a crucial role in neurodegenerative disorders such as Alzheimer's disease. The P2X7 receptor (P2X7R), expressed on microglia, is involved in neuroinflammatory responses. Despite evidence of P2X7R upregulation in Alzheimer's disease models, its role in human Alzheimer's disease remains unclear. The PET radioligand [18F]JNJ-64413739 enables the assessment of P2X7R distribution in post-mortem Alzheimer's disease brain tissue.
METHODS: Post-mortem brain tissue from Alzheimer's disease and control subjects was obtained. [18F]JNJ-64413739 was synthesised and applied to tissue sections from the temporal and parietal cortex. Autoradiography was conducted with and without the P2X7R antagonist JNJ54173717.
RESULTS: [18F]JNJ-64413739 binding was observed across all brain regions, with effective blocking confirming specificity. No significant differences were found between Alzheimer's disease and controls in the temporal (P = 0.84) or parietal cortex (P = 0.90) in the first experiment. The second experiment, using a modified protocol also did not reveal a significant difference between controls and Alzheimer's disease in either temporal (P = 0.66) or parietal cortex (P = 0.38). White matter exhibited significantly higher binding than grey matter (P < 0.01), but no disease-specific differences were noted.
CONCLUSION: This study demonstrates P2X7 receptor-specific binding of [18F]JNJ-64413739 but finds no significant differences between post-mortem tissue of Alzheimer's disease cases and controls. These findings suggest that while the tracer shows promising in vitro characteristics, the role of P2X7R in Alzheimer's disease pathology and its utility as a biomarker require further validation through in vivo imaging studies across disease stages.

Keywords:  ; Alzheimer’s disease; neuroinflammation; positron emission tomography

DOI:  https://doi.org/10.1097/MNM.0000000000002153
Biomaterials. 2026 Apr 04. pii: S0142-9612(26)00226-7. [Epub ahead of print]333 124202

Human blood-brain barrier tissue model to characterize lipid nanoparticle delivery and transport mechanisms.

Xiaohan Zhang, Zhongfeng Ye, Shangyuan Cui, Taisia Shmushkovich, Hiroaki Tani, Ying Chen, Marly Coe, Artem Arkhangelskiy, Mariah L Arral, Maria G Savvidou, Liam Power, Lihan Liu, Yuchen Zhao, Julia Howell, Xingyan Liu, Evan C Marcet, Seok-Man Ho, Zhefu Que, Glenn Leung, Adam S Mullis, Qiaobing Xu, David L Kaplan.

  Crossing the blood-brain barrier (BBB) to deliver lipid nanoparticles (LNPs) for central nervous system (CNS) therapies remains a major challenge. Here, we present a compartmentalized, human-derived 3D BBB tissue model incorporating five cell types, integrating a BBB with a protein composite scaffold system, to support parenchymal elements within a single integrated brain tissue system. This tissue model recapitulates key structural and functional features of the native human BBB, including enhanced tight junction formation, neuronal maturation, polarized endothelial morphology, low permeability, and a more homeostatic microenvironment. The silk-collagen composite provided physiologically relevant extracellular matrix stiffness that supported long-term culture stability and parenchymal development. Translational utility for evaluating CNS-penetrating LNPs was demonstrated by showing that LNP transport efficiency and parenchyma penetration capability in vitro correlated with in vivo brain delivery following systemic administration in mice. Furthermore, this in vitro tissue model enables mechanistic investigation of LNP transport via receptor modulation using siRNA knockdown and pharmacological inhibition, revealing scavenger receptor class B type I (SR-B1) and insulin receptor (INSR) as key mediators of receptor-dependent transcytosis. By enabling the integrated assessment of permeability, transport mechanisms, and toxicity within a single human-relevant in vitro tissue platform, this model serves as a tool to bridge the translational gap between LNP design, in vitro screening, and in vivo validation, to support the optimization of CNS drug delivery. Among the tested formulations, LNP1 exhibited superior BBB penetration, neuronal transfection, and low toxicity, highlighting its potential as a promising lead candidate for CNS mRNA therapeutics for neurological diseases.

Keywords:  3D human tissue model; Blood–brain barrier; CNS drug delivery; Lipid nanoparticles; Translational model

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124202
Rev Neurol (Paris). 2026 Apr 01. pii: S0035-3787(26)00496-0. [Epub ahead of print]

The evolutionary origins of multiple sclerosis.

W Barrie.

  There are two main evolutionary theories for why modern humans develop multiple sclerosis (MS). The first, antagonistic pleiotropy, argues that genetic variants that predispose people to MS are protective against infections; this explains why these genetic variants persist at high frequency. The second, the Old Friends hypothesis, argues that reduced exposure to ancient, co-evolved micro-organisms like helminths results in immune dysregulation and overreactions to harmless infections and substances; this explains why MS prevalence increases with sanitation. Here, I assess these theories in the light of recent ancient DNA (aDNA) studies. These suggest that populations from the Pontic-Caspian Steppe which migrated across Eurasia in the Bronze Age evolved a strong pro-inflammatory immune response due to increased zoonotic infections resulting from their pastoralist lifestyle. It is possible that this may have occurred in a context of high levels of anti-inflammatory helminth infections, which resulted in a balanced pro- and anti- inflammatory response. In the modern sanitary world, with a lower helminth burden, the immune system 'overshoots' the level of inflammation required. This explains why genetic risk for MS is higher in northern Europe where people have higher genetic ancestry from the ancient Steppe population, and why disease penetrance is increasing.

Keywords:  Ancient DNA; Antagonistic pleiotropy; Evolution; Multiple sclerosis; Old friends

DOI:  https://doi.org/10.1016/j.neurol.2026.03.004
BMJ Case Rep. 2026 Apr 08. pii: e270652. [Epub ahead of print]19(4):

Disappearing corticospinal tract on routine MRI: dynamic signal evolution in primary lateral sclerosis.

Christian Marques Couto, Silma Amanda Marques Caetano Gomes, Ricardo Silva Carvalho, Osvaldo Jm Nascimento.

  Primary lateral sclerosis (PLS) may show corticospinal tract (CST) hyperintensity on fluid-attenuated inversion recovery and motor cortex hypointensity on susceptibility-weighted imaging (SWI); however, its longitudinal evolution remains poorly understood. Here, we describe two cases with definite PLS, who were followed up for 15 and 6 years and assessed using qualitative visual magnetic resonance imaging (MRI) scores. Both patients initially exhibited CST hyperintensity. Despite progressive clinical deterioration due to wheelchair/walker dependence, serial MRI demonstrated complete CST normalisation (score 0/16). Concurrently, SWI revealed progressive motor cortex hypointensity, consistent with iron deposition. These cases illustrate a possible dissociation between conventional and susceptibility-based MRI markers, suggesting dynamic pathophysiological processes and potentially early inflammation followed by gliotic remodelling, although technical factors cannot be excluded. A normal-appearing CST should not exclude advanced PLS, and progressive motor cortex hypointensity may provide a more stable marker. Prospective studies with standardised protocols are required to validate these observations.

Keywords:  Amyotrophic Lateral Sclerosis; Magnetic Resonance Imaging; Motor neurone disease; Radiology

DOI:  https://doi.org/10.1136/bcr-2025-270652