Parkinson's disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously ide...Parkinson's disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy. In the current case-control study, we expanded the PD cohort to further corroborate the structure-symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7T fMRI to assess LC responsivity to arousing auditory and visual stimuli in two fMRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order. In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in caudal LC relative to the control group (P = 0.010). This structural disintegration correlated with orthostatic hypotension (P = 0.009) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.105). In an exploratory analysis of a smaller sub-sample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.007). Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures impaired functional responsivity of caudal LC. The presence of arousal-induced hypoactivation of caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.
Sen A, Tai XY, Galanopoulou A
… +12 more, Thom M, Aronica E, Vivash L, Hardmeier M, Amos A, Ruegg S, Koepp M, Winter Y, Helmstaedter C, Noebels JL, Lashuel HA, O'Brien TJ
The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between e...The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental animal epilepsy models to human epileptic syndromes. Seizure prevalence is evaluated across established primary and secondary tauopathies to understand the associated hyperexcitability phenotype. We discuss the use of neurophysiology, metabolic imaging and novel fluid biomarkers as non-invasive measures of potential underlying neurodegeneration in epilepsy. It may, for example, be that these can be combined with remote measures of cognition and other physiological parameters to provide accurate longitudinal monitoring of cognition and underlying pathology. We also explore clinical trials that have targeted pathological tau accumulation in neurodegenerative conditions and consider an ongoing clinical study with sodium selenate, an enhancer of protein phosphatase enzyme PP2A, in people with epilepsy. These efforts signify a novel disease-modifying era with treatments that reduce seizures and modify cognitive outcomes in people with epilepsy. Our analysis of the literature underscores the need for more in-depth characterization of tau pathology, at biochemical and structural levels, in brain tissue and peripheral samples from people with epilepsy as an important step to deciphering the role of tau in the pathogenesis of epilepsy and related disorders. Examining the relationships between tau pathology and cognitive impairment in those with epilepsy provides critical perspectives on a potential causal tau pathomechanism that may have important roles in epileptogenesis and dementia.
Yamamuro K, Ikehara M, Noriyama Y
… +16 more, Okuda M, Okumura K, Matsuoka K, Kashida N, Ishida R, Takeda T, Toritsuka M, Ochi T, Miyasaka T, Tai Y, Tatsumi K, Hattori T, Tanaka T, Saito Y, Iwata N, Makinodan M
Oxytocin has been implicated in regulating social behaviour and emotional responses; however, the underlying neural circuits remain incompletely understood. Neurons expressing oxytocin receptors (OTRs) in the paraventric...Oxytocin has been implicated in regulating social behaviour and emotional responses; however, the underlying neural circuits remain incompletely understood. Neurons expressing oxytocin receptors (OTRs) in the paraventricular thalamus (PVT) are emerging as a potential modulator of these processes. In this study, we investigated the specific role of OTR-expressing PVT neurons in sociability and fear-related behaviours. Using chemogenetic approaches, we found that bidirectional manipulation of these neurons significantly modulated social behaviour and fear extinction in mice. Inhibition of OTR-expressing PVT neurons impaired sociability and fear extinction, whereas activation selectively enhanced early extinction learning without affecting sociability. Electrophysiological analyses revealed that oxytocin increases tonic firing in PVT neurons, suggesting a mechanism for heightened excitability. In contrast, manipulation of OTR-expressing neurons in the medial prefrontal cortex had no effect on sociability. In a complementary human dataset, salivary oxytocin levels were modestly associated with thalamic microstructure and autism spectrum disorder trait severity. Although the experimental paradigms differed across species, these findings collectively suggest that OTR-expressing PVT neurons may contribute to social and emotional behaviours through circuit-specific mechanisms. These findings may have implications for psychiatric conditions such as autism spectrum disorder and anxiety. Future translational studies should explore the therapeutic potential of targeting oxytocin-related PVT function to treat social and fear-related deficits. Overall, these findings advance our understanding of the role of oxytocin in brain function and its relevance to mental health.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is no cure. While the precise etiology of ALS remains elusive, growing evidence suggests a pathogenic role for human endogeno...Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is no cure. While the precise etiology of ALS remains elusive, growing evidence suggests a pathogenic role for human endogenous retrovirus-K (HERV-K) in ALS. Expression of HERV-K subtype HML-2 envelope protein in neurons causes neurotoxicity in vitro and induces ALS-like symptoms in mice. We investigated the use of the Adeno-Associated Virus-9 (AAV9)-mediated artificial microRNA (amiRNA) targeting the HML-2 env gene in an ALS mouse model. From an in vitro screen of amiRNAs targeting the HML-2 env gene three were chosen and inserted in tandem into an AAV9 vector and validated in vitro. This approach provided robust silencing of the transgene, with tandem amiRNA achieving robust reduction in gene and protein expression levels. Its therapeutic effectiveness was tested in an HML-2 Env transgenic mouse model in which the env gene is expressed under the neuron-specific thy1 promoter and develops an ALS-like phenotype. A single intracerebroventricular injection of AAV9 vector encoding the amiRNAs into the mice at postnatal day 1 effectively reduced HML-2 Env expression in the brain and spinal cord at 84 days post-injection which was the longest time point studied. Knockdown of HML-2 env decreased the loss of cortical and spinal motor neurons and alleviated muscle fiber degeneration and fiber type grouping. This led to improved motor function. Our results provide compelling evidence supporting the use of multiple amiRNAs delivered in an AAV9 vector for treating forms of ALS linked to HML-2.
Efforts to predict schizophrenia risk using biological data have been hampered by the heterogeneity of current "clinical-high-risk" (CHR-P) criteria, which pool phenomenologically and biologically distinct syndromes unde...Efforts to predict schizophrenia risk using biological data have been hampered by the heterogeneity of current "clinical-high-risk" (CHR-P) criteria, which pool phenomenologically and biologically distinct syndromes under a single label. In particular, the field has focused almost exclusively on ultra-high-risk (UHR) symptoms, while cognitive basic symptoms (COGDIS)-despite their close alignment with schizophrenia's core features such as formal thought disorder-have remained underutilised. To date, no study has directly compared brain signatures of different CHR-P definitions with respect to their similarity to schizophrenia and their diagnostic, biopsychosocial, and prognostic profiles. We applied machine learning to structural MRI data from 1,425 patients (CHR-P subgroups, recent-onset psychosis, depression) and 907 healthy controls to derive and compare diagnostic brain signatures for Cognitive Disturbances (COGDIS), Ultra-High-Risk (UHR), their overlap (MIXED), and schizophrenia. The MIXED and UHR signatures lacked diagnostic separability and similarity with schizophrenia. Contrarily, the COGDIS signature distinguished patients from controls (BAC=69%, P < .001) and aligned with the schizophrenia signature (r = 0.60), involving shared fronto-parieto-perisylvian volume reductions. UHR was characterised by volume enlargements, whereas MIXED exhibited a mixed pattern of reductions and enlargements relative to healthy controls. COGDIS and schizophrenia signature expressions were predictable with 12%-21% variance explained based on polygenic, cognitive, and exposomal factors both in a transdiagnostic patient cohort and in healthy controls. Their expressions increased from health to schizophrenia. MIXED signature expression was also predictable from biopsychosocial data, but with higher explained variance in patient samples (21%) than in healthy controls (3%). UHR signature expression showed no significant biopsychosocial predictability in either group. Cell-enriched polygenic risk profiles differed across signatures, with COGDIS and schizophrenia showing enrichment patterns implicated in neurodevelopmental processes, while MIXED being associated with immune- and blood-brain-barrier-related enrichments. Longitudinally, COGDIS and schizophrenia brain scores stratified patients with functional disability, while UHR scores predicted better outcomes. Together, these findings indicate that psychosis-risk syndromes differ markedly in the diagnostic specificity, biopsychosocial informativeness and prognostic value of their underlying brain signatures. UHR symptoms are linked to a weak and diagnostically unspecific brain pattern, while the MIXED phenotype is characterised by a dimensional, transdiagnostic signature enriched across early psychotic and affective disease states. In contrast, COGDIS aligns with a neurodevelopmentally grounded vulnerability pattern that converges with schizophrenia's cognitive-disorganisation dimension. These distinctions support a biologically informed reconceptualization of psychosis risk, with cognitive basic symptoms capturing a core liability dimension of schizophrenia, while other risk states reflecting more transient processes underlying psychotic symptom expression.
Functional neurological disorder (FND) presents disabling symptoms that fluctuate, migrate across systems, and yet routinely show preserved structural integrity-features that can frustrate diagnosis and patient education...Functional neurological disorder (FND) presents disabling symptoms that fluctuate, migrate across systems, and yet routinely show preserved structural integrity-features that can frustrate diagnosis and patient education. Crucially, these symptoms are genuine and reflect altered brain regulation across multiple systems rather than tissue damage or conscious control. This paper offers a clinically usable account of these puzzles by reframing FND as a disorder of precision control within predictive coding. The brain's confidence (precision) in its own predictions is modelled as a dynamic quantity that can surge with arousal, settle back toward baseline, and slowly recalibrate over longer periods. Placing this mechanism in a four-level hierarchy (affective, interoceptive, proprioceptive, spinal) shows how arousal can temporarily make an unhelpful expectation dominate, suppress corrective feedback, and produce motor, sensory, cognitive, or visceral symptoms-often in combination. The same dynamics explain rule-in positive signs such as distractibility, entrainment, and give-way weakness, and clarify the lived experience of reduced agency without implying wilfulness or malingering. For clinicians, the framework provides an intuitive way to explain symptoms to patients ('a temporary gain miscalibration that overweights predictions and underweights sensory feedback'), and to justify why physiotherapy (amplifying proprioceptive feedback), psychotherapy (reducing arousal), and mindfulness or biofeedback (raising the effective threshold for arousal-driven 'gain spikes') can all help by recalibrating that weighting. The framework also yields concrete, falsifiable tests, linking bedside observation to measurable biomarkers and offering ways to refine it further. By centring dynamic precision, the account unifies diagnosis, communication, and treatment planning, and provides a mechanistic foundation for precision-guided care in FND.
Damage to the amygdala has been linked to impairments in empathy, typically documented as deficits in accurately identifying others' emotional experiences, especially fear. This has led some to theorize that amygdala dys...Damage to the amygdala has been linked to impairments in empathy, typically documented as deficits in accurately identifying others' emotional experiences, especially fear. This has led some to theorize that amygdala dysfunction is a core feature of psychopathy. There is growing evidence, however, that motivation to empathize is distinct from empathic accuracy. Moreover, anecdotal observations in patients with amygdala lesions have noted their tendencies to approach, rather than avoid, empathic encounters with strangers, even when the patients have impairments in empathic accuracy. We conducted a novel investigation specifically examining empathy motivation in patients with amygdala damage. We used a free-choice paradigm to assess motivation to empathize. We found that damage to the amygdala was not associated with avoidance of affective or cognitive forms of empathy motivation. Patients with amygdala lesions (n = 21) exhibited similar levels of empathy motivation compared with patients with damage outside the amygdala (n = 22) and healthy individuals with no brain damage (n = 24). These findings suggest that amygdala damage does not necessarily disrupt the motivation to empathize. A potential implication of the findings is that amygdala damage or dysfunction may not be associated with traits such as callousness, apathy or lack of caring that are often linked to psychopathy.
The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signaling, yet its influence on CNS myelinogenesis, a pivotal process for neural circuit maturation,...The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signaling, yet its influence on CNS myelinogenesis, a pivotal process for neural circuit maturation, remains poorly understood. Here, using antibiotic-induced maternal dysbiosis models, we identify propionate (PA), a short-chain fatty acid (SCFA) derived from the maternal microbiome, as a key epigenetic modulator of oligodendrocyte precursor cell (OPC) differentiation. Maternal antibiotic-induced gut dysbiosis led to significant hypomyelination in offspring, an effect that could be rescued by postnatal PA supplementation. PA not only enhanced developmental myelination but also promoted remyelination following lysolecithin-induced demyelination by inducing OPC differentiation. Mechanistically, PA induced histone H4K12 lactylation (H4K12la), thereby activating transcription of cGMP-PKG signaling components (e.g., Gna12) and upregulating Sox family transcription factors essential for oligodendrocyte differentiation. Taken together, our findings delineate a PA-H4K12la-cGMP-PKG pathway that links maternal microbial metabolism to offspring myelination, offering a promising SCFA-mediated epigenetic strategy for the treatment of CNS demyelinating disorders.
Voltage-gated sodium channels (VGSCs) in primary sensory neurons are essential mediators of nociceptive signal transmission and represent promising therapeutic targets for pain management. Here, we demonstrate that Nav1....Voltage-gated sodium channels (VGSCs) in primary sensory neurons are essential mediators of nociceptive signal transmission and represent promising therapeutic targets for pain management. Here, we demonstrate that Nav1.5, which is traditionally known to be a cardiac sodium channel, as a major determinant of mechanical sensitivity in the somatosensory system. Immunostaining and single-cell RNA sequencing analyses revealed that Nav1.5 is predominantly expressed in myelinated TrkB-positive A-fibre neurons within the dorsal root ganglion (DRG). Through conditional knockout studies, we found that Nav1.5 deletion in TrkB neurons or DRG tissue specifically impairs mechanical sensitivity while preserving other sensory and motor functions. Notably, Nav1.5 ablation significantly attenuated mechanical hypersensitivity in both neuropathic and visceral pain models. Mechanistically, Nav1.5 contributes to action potential generation and firing patterns in TrkB-positive neurons. In summary, these findings establish Nav1.5 as a critical regulator of mechanical hypersensitivity.
A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protei...A hexanucleotide (GGGGCC) repeat expansion in C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders including ALS/FTD, yet the pathogenic mechanisms remain unresolved. Here, we demonstrate in vivo C9orf72 loss of function leads to cerebellar atrophy, loss of GABAergic interneurons, and depletion of Purkinje and Granule cells. Additionally, we demonstrate that these cerebellar anomalies precede motor defects. Single-cell transcriptomics of the C9orf72-zebrafish brain revealed the downregulation of a purine biosynthetic gene paics in Purkinje cells. Furthermore, we demonstrate the reduced expression of PAICS in the human post-mortem cerebellar sections and iPSC-derived motor neurons from C9orf72 and sporadic ALS patients. Knockout of paics in zebrafish recapitulates cerebellar neuronal loss, neuromuscular junction disruption, motor impairment and widespread DNA damage and repair (DDR) defects including suppression of key DNA repair pathways. Restoring paics expression in C9orf72 zebrafish resolves DNA damage and preserves Purkinje cells and Granule cells, revealing PAICS as a critical mediator of cerebellar degeneration and a promising therapeutic avenue for C9orf72-associated ALS and FTD.
Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia...Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.
Prina ML, Goyette AR, Abdulkareem AF
… +12 more, Tariq K, Burgess N, Su J, Wang W, Li M, Drucker LL, Seo HH, Desmet NM, Overstreet-Wadiche L, Shafit-Zagardo B, Weston MC, Luikart BW
Phosphatase and tensin homolog on chromosome 10 (PTEN) is a key negative regulator of the AKT/mTOR signaling pathway. Mutations in PTEN are highly implicated in Autism Spectrum Disorder (ASD), epilepsy, congenital hydroc...Phosphatase and tensin homolog on chromosome 10 (PTEN) is a key negative regulator of the AKT/mTOR signaling pathway. Mutations in PTEN are highly implicated in Autism Spectrum Disorder (ASD), epilepsy, congenital hydrocephaly, and macrocephaly. While the conditional genetic knockout of Pten in murine neurons results in hypertrophy, increased migration, excitatory synaptogenesis, hyperexcitability, and epileptiform activity, the specific downstream signalling mediators of these pathologies remain to be fully elucidated. Using retroviral-mediated genetic manipulation of individual neurons within the Cre-lox system, we have analyzed pathway outputs in response to the manipulation of various genes using immunohistochemistry, confocal microscopy, and extensive morphological analyses, alongside whole-cell patch-clamp electrophysiology and 120-hour video-EEG monitoring for seizure assessment. Here, we demonstrate that signaling through AKT is necessary for the development of neuronal overgrowth, increased excitatory synapse formation, excessive migration, and hyperexcitability fueled by the loss of PTEN function. Notably, the concurrent deletion of Akt1 and Akt3 isoforms was sufficient to effectively rescue hypertrophic neuronal morphology and physiology. These findings establish AKT as the essential mediator through which PTEN deficiency manifests, providing a transformative therapeutic target to correct the morphological and functional defects central to PTEN-related neurodevelopmental disorders.
The skull bone marrow contributes to brain immune homeostasis via recently discovered skull-meningeal channels, enabling the bidirectional trafficking of immune cells between skull bone and underlying dura mater. In mult...The skull bone marrow contributes to brain immune homeostasis via recently discovered skull-meningeal channels, enabling the bidirectional trafficking of immune cells between skull bone and underlying dura mater. In multiple sclerosis, autoreactive T cells migrate to the bone marrow and shift its haematopoietic output towards myeloid differentiation, contributing to disease progression. However, the role of the skull bone marrow in multiple sclerosis pathophysiology, and its relationship to brain damage and clinical disability remain largely unexplored. We utilized simultaneous MR-PET with the second-generation radioligand ¹¹C-PBR28 to characterize within the skull bone of multiple sclerosis patients the in vivo expression of the translocator protein (TSPO), an 18-kDa mitochondrial membrane protein largely expressed by microglia, astrocytes, and peripheral myeloid cells. Sixty-five multiple sclerosis subjects (46 relapsing-remitting, 19 secondary progressive) and 26 healthy controls underwent ¹¹C-PBR28 MR-PET to acquire 60-90-min post-injection standardized uptake value maps and anatomical scans for brain volumetrics. Voxel-wise analyses of skull TSPO signal were conducted to assess group differences and associations with demographic, clinical and brain volumetrics. Voxel-wise analyses revealed a divergent association between age and skull TSPO signal, with a negative correlation in healthy controls in bilateral frontal and right parietal regions (r = -0.67, P < 0.001), and a positive correlation in multiple sclerosis patients in bilateral parietal and occipital skull bone regions (r = 0.44, P < 0.001). Compared to both healthy controls and relapsing-remitting multiple sclerosis, patients with secondary progressive multiple sclerosis showed widespread elevation in skull TSPO signal in frontal, parietal, temporal, occipital and skull base regions. No significant differences were detected between relapsing-remitting multiple sclerosis and healthy controls. Elevated skull TSPO signal was also observed in patients with more severe neurological disability, irrespective of clinical phenotype. Widespread skull TSPO expression was observed to be positively correlated with Expanded Disability Status Scale (EDSS) scores (ρ = 0.49, P < 0.001) while a negative association was observed with white matter volume (r = -0.45, P < 0.001) and Symbol Digit Modalities Test (SDMT) z-scores (r = -0.48, P < 0.001). In multivariable regression analysis, skull TSPO signal [β = 6.63, standard error (SE) = 1.92, P = 0.001] and T2-hyperintense white matter lesion volume (β = 0.34, SE = 0.14, P = 0.020) were independently associated with disability, while white matter, cortical and subcortical grey matter volumes did not retain statistical significance (all P > 0.550). We provide in vivo evidence of skull TSPO overexpression in multiple sclerosis, observed in progressive disease and associated with clinical disability and structural brain damage. Overall, these findings suggest a role for the skull bone marrow in disease-related processes and highlight its potential as a novel radiological marker and therapeutic target.
Behavioural rigidity, the tendency to persist with inflexible patterns of thoughts or actions, is increasingly recognised as a transdiagnostic symptom across psychiatric, neurodevelopmental, and neurodegenerative disorde...Behavioural rigidity, the tendency to persist with inflexible patterns of thoughts or actions, is increasingly recognised as a transdiagnostic symptom across psychiatric, neurodevelopmental, and neurodegenerative disorders. Empirical studies exploring the prevalence and underlying neural mechanisms of behavioural rigidity in dementia, however, are lacking. This cross-sectional study sought to delineate the structural and functional neural correlates of behavioural rigidity using a transdiagnostic approach looking across the frontotemporal lobar degeneration (FTLD) spectrum and Alzheimer's disease. A total of 204 participants were recruited, including 110 frontotemporal dementia (FTD), 53 Alzheimer's disease (AD), and 41 healthy older control participants. Within the FTD group, 66 cases were diagnosed with clinically probable behavioural variant FTD (bvFTD), 26 presented with semantic dementia (SD), and 18 cases had progressive non-fluent aphasia (PNFA). Behavioural rigidity was assessed using the Stereotypical and Motor Behaviour subscale of the Cambridge Behavioural Inventory-Revised. Voxel-based morphometry (VBM) was performed to identify grey matter regions associated with behavioural rigidity transdiagnostically, the results of which informed subsequent seed-based voxel-wise functional connectivity analyses. All imaging analyses were adjusted for relevant demographic and technical covariates. Statistical thresholds were set at voxel-level p < 0.001 (uncorrected) and cluster-level p < 0.05 (FDR-corrected). Our main finding was that behavioural rigidity is pervasive across dementia subtypes, ranging from most pronounced in bvFTD to milder/relatively absent in PNFA, relative to Controls. Whole-brain VBM across the entire patient sample revealed a significant negative association between behavioural rigidity and grey matter intensity exclusively in the bilateral nucleus accumbens. Using the bilateral nucleus accumbens as seeds, resting-state functional connectivity analysis showed that higher levels of behavioural rigidity were associated with stronger connectivity between the left nucleus accumbens and the left supplementary motor area, paracentral lobule, and precuneus. This is the first study, to our knowledge, to examine the neural substrates of behavioural rigidity across FTLD syndromes transdiagnostically using structural and functional neuroimaging approaches. Our findings reveal a gradation of rigid and repetitive behaviours, most apparent in bvFTD, which in turn reflects pathological disruption of the nucleus accumbens. Taken together, our findings highlight the need to consider repetitive and rigid behaviours as a transdiagnostic feature in neurodegenerative disorders, and one which indexes underlying nucleus accumbens pathology. More broadly, this study underscores the importance of screening for rigid and repetitive behaviours in the clinic and identifies the nucleus accumbens as a promising neural target to ameliorate these symptoms.