Fibromyalgia syndrome (FM) is characterized by widespread pain and fatigue. People living with FM also experience tactile allodynia, cold-evoked pain, paraesthesia and dysaesthesia. There is evidence of small fibre neuropathy and hyperexcitability of nociceptors in FM; however, the presence of other sensory abnormalities suggests involvement of large diameter sensory fibres. The passive transfer of FM IgG to mice causes cold and mechanical hyperalgesia associated with changes in A- and C-nociceptor function. However, whether FM IgG also confers sensitivity to light touch and whether large diameter sensory fibres contribute to symptoms evoked by cold is unknown.Here we demonstrate that the presence of sensory abnormalities such as tingling, correlate with the impact of FM, and that people with FM describe the sensation of cutaneous cooling with neuropathic descriptors such as tingling/pins and needles. We find a causal link between circulating FM IgG and the sensitization of large diameter, Aβ low threshold mechanoreceptors (Aβ-LTMRs) to mechanical and cold stimuli in mice ex vivo and in vivo. In keeping with our experimental observations, a larger proportion of Aβ-LTMRs respond to cold stimulation in people with FM, but in contrast to our results ex vivo, the same fibres display reduced responses to mechanical stimuli.These results expand the pathophysiological role of IgG in FM and will inform future studies of sensory symptoms and pain in people with FM.

The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression.In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns.Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions.Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Cortical cerebral microinfarcts are associated with brain atrophy in cross-sectional studies, with further investigation using longitudinal datasets being warranted. Moreover, little is known about their combined impact on cognition. This study aimed to establish the association between cortical cerebral microinfarcts and brain volume loss over time and explore whether they synergistically contribute to cognitive decline.A total of 475 patients, aged 72.7 ± 7.9 years, were enrolled from a memory clinic cohort, who underwent neuroimaging and neuropsychological assessments at least twice over 5 years. Cortical cerebral microinfarcts and other cerebrovascular disease were assessed using 3-T MRI. Brain volumes were calculated semi-automatically using FreeSurfer. Cognitive function was assessed using a neuropsychological test battery including six domains. Linear mixed-effect models were utilized to examine the association between cortical cerebral microinfarcts and brain volume loss and their interaction on cognitive decline. Estimated marginal means were derived to plot global cognitive trajectories.Cortical cerebral microinfarcts were associated with a greater decrease over 2 years in total brain volume [β = −1.94 (−3.07, −0.82) at Year 2, P-interaction with time < 0.001], grey matter volume [β = −1.00 (−1.69, −0.30) at Year 2, P-interaction = 0.002] and white matter volume [β = −0.95 (−1.54, −0.35) at Year 2, P-interaction < 0.001]. Brain volume loss was more pronounced in patients with multiple microinfarcts. Patients with high brain volume loss and cortical cerebral microinfarcts, particularly multiple microinfarcts, exhibited significantly lower global cognitive scores [single microinfarct: β = −1.83 (−2.68, −0.97) at Year 5, P-interaction with time < 0.001; multiple microinfarcts: β = −3.13 (−4.21, −2.05) at Year 5, P-interaction < 0.001]. The synergistic effects were more significant in the domains of executive function, memory, language and visuospatial function. Global cognitive trajectories revealed greater cognitive decline in patients with high brain volume loss and single or multiple microinfarcts, with the latter showing the steepest slope.This study established a longitudinal association between cortical cerebral microinfarcts and brain atrophy progression, with higher microinfarct burden associated with more pronounced brain volume loss. Furthermore, cortical cerebral microinfarcts and brain atrophy showed synergistic effects on cognitive decline. These findings highlight the importance of investigating the role of mixed pathologies in the development of cognitive impairment and dementia in future research.

This review examines the principles, applications and methodological foundations of normative modelling, emphasizing its potential to assist in mitigating longstanding challenges in traumatic brain injury (TBI) research and management. TBI remains a major global health concern, with an incidence exceeding 50–60 million cases worldwide. Progress in research and clinical practice has been hindered by the complex and heterogeneous nature of TBI, arising from diverse aetiologies, injury mechanisms and pathophysiological processes that lead to variable clinical presentations.A significant obstacle, particularly present within neuroimaging, is the continued reliance on classification scales and analytical models that do not account for nuanced differences among patients. For example, the Glasgow Coma Scale and many prevalent models categorize injury severity levels by assuming homogeneity within groups, which inevitably results in heterogeneity and obscures individual variability. Similarly, traditional case-control research designs separate injury and control groups to conduct group difference testing, diluting valuable individual data by focusing on mean comparisons.We advocate for a paradigm shift towards normative modelling—a flexible framework that assesses individual differences by comparing patients to a reference cohort. This approach moves beyond traditional methods that emphasize group differences, addressing the limitations of conventional classification by avoiding the aggregation of TBI patients into heterogeneous categories based on simplistic measures. By capturing the full spectrum of variability, normative modelling has the potential to improve patient selection in clinical trials and foster more personalized treatment strategies. Adopting this innovative approach aims to enhance outcomes for TBI patients by emphasizing individual variability rather than relying on broad group classifications. Normative modelling promises to transform the translation of TBI research into clinical practice, ultimately driving progress towards more effective, tailored interventions.

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges. In this study, we developed a synthetic biology strategy to reprogram the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a CMV promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on sEV surface. Theoretically, upon liver uptake, this construct reprograms liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons. Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss, and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice. Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.

This scientific commentary refers to ‘Neuropathologic correlates of distinct plasma biomarker profiles in community-living older adults’ by Yu et al. (https://doi.org/10.1093/brain/awaf211).

Recent anatomical studies have shown that, compared to other primates, the human frontal pole (FP) contains a unique lateral subdivision (FPl). This area provides an important target for understanding the uniqueness of human intelligence. Paradoxically, patients with FP lesions often perform normally on standard neuropsychological tests, while experiencing problems in real-life or simulated situations.This paper aims to review the complex functions of the FPl that may account for the dysfunctions observed in these patients. First, we consider studies of FP lesion patients that reveal deficits in analogical reasoning and prospective memory. Second, we review, mainly based on neuroimaging and neurostimulation studies, the FPl’s involvement in exploratory decision making, information integration and the representation of abstract rules. We argue that these functions primarily stem from the FPl’s capacity to manage multiple sources of information and to reduce that information into simpler features for guiding behaviour. Finally, we propose a model of the FPl that emphasizes its role in decomposing high-dimensional information to enhance decision making processes in conjunction with connected regions, including the posterior cingulate cortex, anterior cingulate cortex, and dorsolateral prefrontal cortex.

Neurological disorders result from the complex and poorly understood contributions of many cell types. It is therefore essential to uncover mechanisms behind these disorders and identify specific therapeutic targets. Single-nucleus technologies have advanced brain disease research, but remain limited by their low nuclear transcriptional coverage, high cost and technical complexity.To address this, we applied a transformer-based deep learning model that restores cell type-specific investigation transcriptional programs from bulk RNA sequencing, significantly outperforming previous methods. This enables large-scale and cost-effective investigation of cell type-specific transcriptomes in complex and heterogeneous phenotypes such as cognitive resilience or brain resistance to Alzheimer's disease.Our analysis identified astrocytes as the major cell mediator of Alzheimer's disease resilience across cerebral cortex regions, while excitatory neurons and oligodendrocyte progenitor cells emerged as the major cell mediators of resistance, maintaining synaptic function and preserving neuron health.Finally, we show that our approach could restore the whole tissue transcriptome, offering an unbiased framework for exploring cell-specific functions beyond single-nucleus data.

The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%–15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum.Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.