Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.
Limited therapies exist to preserve tissue function in ischemia-reperfusion injury, particularly for ischemic stroke, where intravenous thrombolysis remains a primary but risky treatment option. During stroke reperfusion, mechanical forces including hemodynamic shear stress and tissue stiffness change rapidly. However, how the neurovascular endothelium senses and responds to these physical cues to drive pathological injury remains unclear. Using a transient middle cerebral artery occlusion and reperfusion mouse model, we mapped acute shear stress and stiffness remodeling via near-infrared II imaging and atomic force microscopy. In vivo fiber photometry, single-cell transcriptomics, electron microscopy, biochemical assays and cell-type-specific conditional knockout mice were utilized to decode the Piezo1-dependent mechanochemical signaling. Reperfusion-induced disturbed blood flow and aberrant tissue stiffening robustly over-activated the mechanosensitive channel Piezo1 specifically in vascular endothelial cells. Although Piezo1 was broadly detected in glial cells, genetic ablation of Piezo1 exclusively in endothelial cells, but not in astrocytes or microglia, significantly reduced infarct volume and improved neurological deficits. Mechanistically, endothelial Piezo1 hyperactivation induced adenylyl cyclase 1, driving a surge in intracellular cyclic AMP (cAMP). This triggered the assembly and release of cAMP-enriched extracellular microvesicles, which preferentially accumulated within adjacent perivascular astrocytes. The vesicular cAMP payload subsequently activated the downstream effector Epac1, dictating a spatially restricted wave of astrocyte apoptosis. Concordantly, astrocyte-specific genetic ablation of Epac1 replicated the neuroprotective phenotype, significantly alleviating ischemic brain injury. These findings delineate a pathogenic mechanochemical cascade at the neurovascular interface, establishing that endothelial Piezo1 translates post-ischemic mechanical stress into an apoptotic chemical signal via microvesicular cAMP-Epac1 communication. Targeting the upstream endothelial Piezo1 mechanosensor or the downstream astrocytic Epac1 effector offers a promising therapeutic strategy to preserve neurovascular unit integrity following stroke reperfusion.
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
The precise neuromodulatory mechanisms underlying consciousness and its disorders, despite growing evidence in both animals and humans, remain poorly understood at the subcortical level. The basal ganglia, a key component of the cortico-basal ganglia-thalamo-cortical loop, are known to play a crucial role in mediating consciousness and behavioural responsiveness to the environment. Here, we aimed to present a comprehensive mapping of the distinct contributions of basal ganglia nuclei and their associated neurotransmitter systems in pharmacologically induced and pathological loss of responsiveness. We used functional MRI to provide a systematic investigation of 9 major nuclei (putamen, caudate, nucleus accumbens, globus pallidus external, globus pallidus internal, substantia nigra pars compacta, substantia nigra pars reticulata, ventral pallidus, and subthalamic nucleus) and their functional relationship with 19 major neurotransmitter systems in loss of responsiveness, in both healthy volunteers under propofol anaesthesia (n = 16) and patients with disorders of consciousness (DOC) (i.e. minimally conscious, unresponsive wakefulness syndrome) (n = 22). We found that in pharmacologically-induced loss of responsiveness, the functional connectivity changes of the putamen (Pu) correlated with the norepinephrine transporter (NET), and the globus pallidus external (GPe) with the serotonin transporter (5-HTT) and vesicular acetylcholine transporter (VAChT); additionally, altered connectivity in the ventral pallidum (VeP) was associated with the norepinephrine transporter (NET). In contrast, with pathological-induced loss of responsiveness, we found that connectivity changes of the caudate were associated with the serotonin transporter (5-HTT), dopamine transporter (DAT), and GABAA receptor, and connectivity changes of the substantia nigra pars compacta (SNc) were associated with the cannabinoid (CB1) receptor. Finally, we report that among all basal ganglia nuclei, a key dopamine-rich area of the basal ganglia-the substantia nigra-was found to have the largest DOC subgroup difference in functional connectivity, following stratification based on mental-imagery task responsiveness. Critically, we provide evidence that pharmacological and pathological loss of responsiveness involve distinct neurotransmitter system contributions across individual basal ganglia nuclei, offering a novel framework for targeted therapeutic interventions in patients with disorders of consciousness.
This scientific commentary refers to ‘Data-driven modelling of tau pathology reveals distinct progressive supranuclear palsy subtypes’, by Cullinane et al. (https://doi.org/10.1093/brain/awag131).
Corticobasal degeneration (CBD) is a late onset progressive neurodegenerative condition of the 4-repeat-tauopathy-type, classically presenting with asymmetrical rigidity, dystonia and myoclonus. In the most recent diagnostic criteria, Armstrong and colleagues (2013) described four clinical phenotypes associated with this pathology, including corticobasal syndrome (CBS), through a large retrospective analysis of published cases and confirmed brain bank cases of CBD. However, predicting CBD pathology remains challenging. With the advent of disease-modifying therapies, it has become particularly important to distinguish Alzheimer's disease pathology from other underlying pathologies. We therefore combined two prospectively recruited cohorts of patients with CBS and analysed their key demographic, clinical and biomarker features. We included a separate cohort from UK brain banks who were diagnosed with CBS in life. We divided patients into three groups: CBS-Alzheimer's (CBS-AD), CBS-non-Alzheimer's (CBS-non-AD) and CBS-indeterminate (CBS-IDT) based on biomarkers and pathology, comparing clinical features, regional volumetric MRI measures and Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) blood protein levels between groups. We performed additional analyses of pathologically verified cases. We included 397 participants, of which 57.7% were female. The mean age at symptom onset was 65.9 years. AD biomarkers and pathology permitted classifying 47 (11.8%) of the cases as CBS-AD, 134 (33.8%) as CBS-non-AD and 216 (54.4%) as CBS-IDT. Patients with CBS-AD had a younger age at onset (61.8 years vs 66.1 years, P < 0.01 and less severe motor deficits (non-significantly lower scores on MDS-UPDRS and PSPRS) and more severe cognitive impairment (non-significantly lower scores on MoCA). Patients with CBS-AD had higher rates of cortical sensory impairment (P = 0.087) and lower rates of limb dystonia (P < 0.01) and falls (P < 0.01) compared to the CBS-non-AD group. Volumetric MRI analysis revealed smaller parietal lobe volumes in CBS-AD (P = 0.01). The most common pathological diagnoses were PSP, CBD and AD. Limb dystonia was more common in people with CBD and PSP pathology (P = 0.077). Falls, impaired verbal fluency and impaired vertical saccades were confirmed as more common in PSP (P = 0.046, P = 0.040, P = 0.012, respectively). In summary, younger onset, less parkinsonism and more cognitive and cortical sensory impairment, along with reduced MRI parietal volumes point to CBS-AD, while limb dystonia, falls and worse verbal fluency relate to CBS-non-AD. Clinical, imaging and blood-biomarkers in can augment the Armstrong criteria in predicting the underlying pathology of corticobasal syndromes.
Palmer et al. review the discovery of cholinergic dysfunction in Alzheimer’s disease, tracing how David Bowen’s landmark September 1976 Brain paper laid the foundations for the cholinergic hypothesis and symptomatic treatments, and highlighting its continuing relevance in a complex, multi-system disorder.
Abstract Background Borderline personality disorder (BPD) is characterized by severe emotional vulnerability, including heightened sensitivity, exaggerated reactivity, and delayed recovery from emotional arousal. Altered interoceptive-affective processing may contribute to these features. Transcutaneous auricular vagus nerve stimulation (taVNS) provides a non-invasive method for modulating vagal-afferent pathways involved in interoception and emotion regulation. This study examined whether active taVNS, relative to sham stimulation, was associated with lower self-reported negative affect during a video-based mood-induction paradigm in women with BPD. Methods Thirty-four female psychiatric outpatients with DSM-5 BPD were randomized to receive active taVNS or sham stimulation during a single-session experimental paradigm. Self-reported negative affect was assessed repeatedly using the Positive and Negative Affect Schedule (PANAS) Negative Affect scale. The primary analysis modeled PANAS Negative Affect across four collapsed task phases: Pre-Induction, Post-Neutral, Post-Negative, and Recovery-Negative, adjusting for baseline negative affect and stimulation intensity. Exploratory physiological analyses examined heart rate, lnRMSSD, phasic electrodermal activity (EDA) response frequency, and tonic skin conductance level. Results Active taVNS was associated with lower PANAS Negative Affect across the mood-induction paradigm compared with sham stimulation, Treatment Group: F(1, 36.44) = 5.74, p = 0.022. Negative affect varied significantly across task phases, F(3, 94.12) = 22.60, p < 0.001, confirming successful mood induction. The Treatment Group × Phase interaction was not significant, F(3, 94.12) = 0.75, p = 0.525. Exploratory physiological analyses showed no treatment-related effects on heart rate, lnRMSSD, or phasic EDA response frequency. Tonic skin conductance level showed no main effect of Treatment Group, but an exploratory Treatment Group × Epoch interaction. Conclusions In this preliminary single-session randomized sham-controlled study, active taVNS was associated with lower self-reported negative affect during a mood-induction paradigm in women with BPD. This subjective effect was not accompanied by treatment-related effects on heart rate, lnRMSSD, or phasic EDA response frequency, while the tonic skin conductance interaction should be interpreted cautiously as exploratory. These findings support further investigation of taVNS as a mechanistic probe of acute affective responding in BPD. Trial registration ClinicalTrials.gov NCT05892900. Retrospectively registered 7 June 2023.
Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.
Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.
Epilepsy care is often guided by incomplete snapshots: patient-reported seizures, intermittent drug levels and medication histories that may not reflect current exposure. Between these snapshots, clinicians have little objective information about how the brain is responding to antiseizure medication. In this study, we tested whether intracranial EEG synchrony, a measure of coordinated neural activity across intracranial electrodes, tracks antiseizure medication load in patients with drug-resistant epilepsy. We retrospectively studied 80 consecutive patients with drug-resistant epilepsy who underwent presurgical intracranial EEG monitoring at the Hospital of the University of Pennsylvania. Antiseizure medication load was estimated continuously from medication administration records using a validated pharmacokinetic model. Synchrony was computed from intracranial EEG using the Kuramoto order parameter. We first compared synchrony within the same patient during high and low medication exposure. We then tested the continuous association between synchrony and medication load across the epilepsy monitoring unit admission, adjusting for time since admission, seizure timing, wakefulness, time of day and interictal spike rate. Analyses accounted for repeated measurements within patients and tested robustness to temporal structure in the recordings. We also assessed whether synchrony dynamics were preserved when fewer electrodes were sampled. Forty-five patients had sufficient high- and low-exposure data after peri-ictal exclusion. Synchrony was higher during low medication exposure in 32 of 45 patients, corresponding to a median 7.4% increase and a median paired difference of 0.0082 on the 0-1 synchrony scale (sign test P = 0.007; Wilcoxon P < 0.001). In the continuous analysis of 67 patients and 23,402 repeated 10-minute observations, higher synchrony was associated with lower medication load (β = -0.153, 95% confidence interval -0.293 to -0.012, P = 0.033); interictal spike rate was not independently associated with medication load. The inverse association remained evident in circular-shift, temporally binned and likelihood-based sensitivity analyses. Relative synchrony dynamics were preserved under electrode subsampling, with a median correlation of 0.85 with full-array synchrony at 40% sampling. These findings support synchrony as a candidate continuous physiological readout of antiseizure medication load in patients with drug-resistant epilepsy. By linking medication exposure to a measurable brain-network state, synchrony may help move epilepsy monitoring beyond seizure counting alone and toward continuous assessment of how the brain is responding to treatment.
Abstract Introduced in 2014 and revised in 2018, the entropic brain hypothesis has accrued a wealth of supportive evidence. The hypothesis states that—along a dimension of the size of phenomenal consciousness—expansive states reliably exhibit increased brain entropy whereas the inverse applies for states of no or reduced consciousness. Examples of expansive states include expert meditation, flicker light stimulation, near-death-like experiences, atypical breathing, rapid-eye-movement sleep, the pre-ictal aura, unmedicated early psychosis and psychedelic drug states. Examples of states of no or reduced consciousness with low brain entropy, include disorders of consciousness, deep sleep, the anesthetized state, seizure, post-stroke, ageing, cognitive impairment, and neurodegenerative illness. It is shown that the entropic brain has convergent, correlative, predictive, discriminative and external validity. Regarding its predictive validity, increased brain entropy under psilocybin (in a supportive context) predicts subsequent improvements in mental health (improved wellbeing 1-month post-dose). Regarding its discriminative validity, changes in brain entropy selectively index the breadth of subjective experience versus alternative dimensions, such as arousal. Regarding portability/external validity, an entropy-related function is applied in generative artificial intelligence. In conclusion, the entropic brain is a useful model of conscious states.
