Xin JW, Wang ZY, Guo Y
… +16 more, Chen KL, Lu JY, Wang J, Huang YY, Wang MY, Peng BH, Chen YL, Chen SF, Cheng W, Yen TC, Wischik CM, Cui M, Zuo CT, Zhao QH, Chen XC, Yu JT
The diagnostic efficacy of tau positron emission tomography (PET) relative to amyloid PET in memory clinic settings remains underexplored. In this study, 1008 consecutive Han Chinese individuals with cognitive impairment...The diagnostic efficacy of tau positron emission tomography (PET) relative to amyloid PET in memory clinic settings remains underexplored. In this study, 1008 consecutive Han Chinese individuals with cognitive impairments were recruited between March 2020 and July 2025. They underwent comprehensive clinical assessment, amyloid PET, and tau PET. Diagnostic reclassification, accuracy, and changes in diagnostic confidence were evaluated across cognitive stages and etiologic categories. For Alzheimer's disease (AD) diagnosis, tau PET demonstrated high sensitivity (97.8%) and specificity (95.4%), showing substantial agreement with amyloid PET. Moreover, tau PET provided additional information beyond that offered by amyloid PET alone. In patients clinically diagnosed with non-AD disorders, tau PET led to a significantly higher rate of diagnostic change compared with amyloid PET (p = 0.018). After a diagnosis based on amyloid PET results, the subsequent addition of tau PET information still resulted in a diagnostic change in 10.0% of patients, highlighting its incremental value. Furthermore, tau PET significantly improved diagnostic confidence (from 68.6% to 84.2%), and the confidence gained from tau PET was significantly greater than that from amyloid PET alone within non-AD diseases. Our findings suggest tau PET offers diagnostic performance for AD comparable to that of amyloid PET, while providing additional value in detecting non-AD tauopathies and clarifying complex cases. These observations support the potential for tau PET to complement existing diagnostic workflows in memory clinic settings.
Investigators collecting human brain data are under growing pressure to share data widely to accelerate scientific discovery and improve outcomes in neurological and psychiatric disorders, while at the same time facing i...Investigators collecting human brain data are under growing pressure to share data widely to accelerate scientific discovery and improve outcomes in neurological and psychiatric disorders, while at the same time facing increasing concerns about potential misuse of brain data and threats to mental privacy. Several commentators have therefore called for clearer ethical guidance on brain data sharing. This article reviews the bioethics and neuroscience literature on the risks of sharing individual-level human brain data and adds to it using insights from a National Institutes of Health (NIH) workshop and normative analysis. The substantial burden of brain disorders creates a strong ethical imperative to share data. We argue that the risks of sharing brain data are not uniform and depend on both the likelihood of re-identification and the range of inferences that can realistically be drawn from the data given scientific capabilities. Certain types of brain data are more likely to be re-identifiable and to enable sensitive inferences-such as those related to current and future health, behaviour, or identity-relevant traits-and thus could be misused to harm individuals or communities. In these cases, brain data may pose greater risks than many, though not all, other forms of biomedical data. At the same time, strategies to mitigate these risks-such as restricting access or reducing data granularity-may limit the scientific value of shared data. We argue that responsible brain data sharing requires calibrating protections to the specific risks associated with sharing a dataset, enabling data sharing that maximizes scientific and clinical value while protecting participants and maintaining trust. To support this, we propose categories of lower-, medium-, and higher-risk data based on inferential sensitivity and the likelihood of re-identification or linkage to harm-relevant groups. We suggest safeguards to consider across these risk levels, including data collection and sharing practices that limit access to data, informed consent approaches, and data-use governance.
Lambert N, El Moussaoui M, Le Guilloux A
… +54 more, Joly M, Del Carmen Garcia Martearena M, Mainardi I, Bernard-Valnet R, Pinnetti C, Antinori A, Mondi A, Greve KF, Brousse X, Westendorp WF, Wijburg MT, Grote-Levi L, Möhn N, Pourcher V, Gressens SB, Cruz CV, van Pesch V, Vidal M, Redor A, Makinson A, Konitsioti AM, Hoellinger B, Nitsch L, Ney DE, Faure E, Alstadhaug KB, Martinot M, Genderini FG, Legras J, Garzaro M, Blanchi S, Gazaignes S, Borrelli S, Patrat-Delon S, Vydrář D, Nicolas-Vullierme P, Moutel M, Cartau T, London F, Cabié A, Bouiller K, Montcuquet A, Loubet P, Sayre N, Le Marechal M, Clifford DB, Skripuletz T, Brouwer MC, Bodilsen J, Du Pasquier R, Cortese I, Cinque P, Sommet A, Martin-Blondel G
Despite improved survival in recent years, long-term outcomes in patients surviving progressive multifocal leukoencephalopathy beyond the first year remain poorly defined. This international multicenter retrospective stu...Despite improved survival in recent years, long-term outcomes in patients surviving progressive multifocal leukoencephalopathy beyond the first year remain poorly defined. This international multicenter retrospective study aimed to characterize the three-year prognosis of patients with progressive multifocal leukoencephalopathy who had survived at least one year, identify factors associated with favorable outcomes and late mortality, and determine recurrence rate. Data were collected through standardized questionnaires across forty-one centers in twelve countries. Patients were eligible if they met the 2013 diagnostic criteria for definite progressive multifocal leukoencephalopathy of the American Academy of Neurology, survived at least one year after diagnosis, and had documented follow-up three years after diagnosis. Demographic, clinical, virological, and radiological data were retrieved at diagnosis, one year, and three years. Functional status was assessed using the modified Rankin Scale, with scores of 0-2 defining a favorable outcome. Generalized linear mixed models identified independent predictors of three-year functional status and late mortality. Among 1877 screened cases, 245 patients met inclusion criteria. The most common underlying causes of immunosuppression were HIV infection (48%), autoimmune/inflammatory diseases (26%), and hematological malignancies (18%). At three years, 220 patients (89.8% of the cohort) were alive and 188 (85.5% of survivors) had neurological sequelae, most frequently motor or cognitive impairment. Overall, 112/245 (45.7%) achieved a favorable functional outcome. HIV-associated progressive multifocal leukoencephalopathy (OR 2.36, 95% CI 1.05-5.28) was associated with a favourable outcome, whereas higher modified Rankin Scale score at diagnosis (OR 0.48, 95% CI 0.35-0.66) and higher number of affected brain regions on baseline MRI (OR 0.78, 95% CI 0.64-0.95) were independently associated with poorer functional outcome. Among variables collected one year after diagnosis, good functional status at that time was significantly associated with long-term favorable outcome (OR 0.01, 95% CI <0.01-0.03). Twenty-five patients (10.2%) died after the first year, with mortality associated with higher lesion burden at diagnosis and primary immunodeficiency as underlying disease. Even beyond the first year, progressive multifocal leukoencephalopathy remained the leading cause of death (11/25). Recurrence occurred in seven patients (2.9%) and was almost always fatal (6/7). This study provides a comprehensive evaluation of long-term outcomes among survivors of progressive multifocal leukoencephalopathy. These findings present a nuanced picture: while most remain neurologically impaired, nearly half achieve functional independence at three years. The results emphasize the prognostic relevance of the initial clinical and radiological burden and early functional trajectory and highlight the need for research into mechanisms driving disease recurrence.
Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct...Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques. We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability. Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.
Tur C, Susin-Calle S, Otero-Romero S
… +29 more, Carvajal R, Carbonell-Mirabent P, Cobo-Calvo Á, Roos I, Arévalo MJ, Ariño H, Arrambide G, Auger C, Castilló J, Comabella M, Elosua I, Galán I, Masot-Llima A, Midaglia L, Mongay-Ochoa N, Nos C, Pappolla A, Pareto D, Río J, Rodríguez-Acevedo B, Saez de Gordoa E, Vidal-Jordana Á, Vilaseca A, Zabalza A, Rovira À, Sastre-Garriga J, Kalincik T, Montalban X, Tintoré M
Multiple sclerosis (MS) is a potentially disabling disease that shows marked variability in its severity and underlying mechanisms. Early prediction of patients at risk of specific unfavourable outcomes may be key to tre...Multiple sclerosis (MS) is a potentially disabling disease that shows marked variability in its severity and underlying mechanisms. Early prediction of patients at risk of specific unfavourable outcomes may be key to treatment stratification and management. Here, we propose a prognostic framework, called the Spider-MS model, to predict a wide range of relevant outcomes at the individual level, at symptom onset. We included patients from the Barcelona first-attack cohort, i.e. with a first demyelinating attack suggestive of multiple sclerosis, younger than 50 years old at symptom onset and seen in the clinic within 3 months of the first attack, to build the Spider-MS model (original cohort). Patients with a first demyelinating attack from the Royal Melbourne Hospital were used to validate the model externally (validation cohort). All patients were prospectively assessed clinically, with the Expanded Disability Status Scale (EDSS) and relapse tracking, and through brain and, in some cases, spinal cord MRI. Spider-MS was built as a set of eight accelerated failure models with Weibull distribution, one for each outcome, including McDonald 2017 diagnosis, second attack, yearly rate of new T2 lesions > 2, relapse-associated worsening (RAW) at the first attack and at subsequent attacks, confirmed and sustained disability worsening, progression independent of relapse activity (PIRA) and EDSS 3.0. Model predictors included age, sex, first attack topography, brain and spinal cord lesions, CSF oligoclonal bands and percentage of time on high-/moderate-efficacy treatment before the outcome. We included 1180 patients from Barcelona (mean age 32.37 years, 810 females) and 108 from Melbourne (32.41 years, 78 females). Median follow-up times were 10.80 and 11.10 years, respectively. In the original cohort, 797/1180 (67.5%) fulfilled the McDonald criteria, 121/1180 (10.3%) developed RAW at subsequent relapses and 290/1180 (24.6%) developed PIRA over the follow-up period. The prediction models reached moderate-high accuracy levels (Harrell's C values: 0.653-0.823) and showed that older age, cord involvement at first attack, greater number of brain and cord lesions, presence of CSF oligoclonal bands and lower percentage of time on treatment predicted a greater risk of unfavourable outcomes, with varying effects depending on the outcome. When the Spider-MS model was applied to the external cohort, for all outcomes except for RAW at first or subsequent attacks, the prediction models reached moderate-high accuracy values (Harrell's C = 0.623-0.766). In general, patients with the highest predicted risks experienced acute inflammatory activity or disability earlier than lower-risk patients. In conclusion, our Spider-MS model can be considered a promising individual predictive tool with the potential to inform clinical practice.
Beucke JC, May L, Diez I
… +13 more, Franke J, Kaufmann C, Pol-Fuster J, de la Cruz LF, de Schipper E, Brander G, Remnélius KL, Neufeld J, Fransson P, Sepulcre J, Van den Heuvel OA, Bölte S, Mataix-Cols D
Traditional case-control studies show that obsessive-compulsive disorder (OCD) is associated with disturbances in cortico-striatal-thalamo-cortical (CSTC) brain circuits. Whether these findings represent underlying famil...Traditional case-control studies show that obsessive-compulsive disorder (OCD) is associated with disturbances in cortico-striatal-thalamo-cortical (CSTC) brain circuits. Whether these findings represent underlying familial vulnerabilities (i.e., shared genetic and environmental factors) or are the result of acquired non-shared environmental influences, such as chronic stress or lifestyle factors, is unknown. Using a unique sample of monozygotic twin pairs discordant for lifetime OCD diagnoses (14 pairs, 28 twins) and resting-state functional magnetic resonance imaging, we examined the contribution of non-shared environmental influences to CSTC functional connectivity while strictly controlling for shared genetic and environmental factors. Further, we examined familial vulnerability effects by comparing the unaffected co-twins of OCD-affected twins to a sample of control twins (14 pairs, 28 twins). Non-shared environmental influences were statistically significantly associated with thalamostriatal hypoconnectivity, whereas familial vulnerability was significantly associated with heightened connectivity between the striatum and the medial orbitofrontal cortex. These findings suggest that non-shared environmental and familial factors may differentially relate to distinct CSTC circuit disturbances in OCD.
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 rel...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.
Accumulating preclinical evidence has highlighted the importance of cerebrospinal fluid (CSF) compartmentalization and transport. However, detailed structural characterization in humans remains challenging. This study ut...Accumulating preclinical evidence has highlighted the importance of cerebrospinal fluid (CSF) compartmentalization and transport. However, detailed structural characterization in humans remains challenging. This study utilized contrast-enhanced T2-fluid-attenuated inversion recovery imaging on 3-Tesla magnetic resonance imaging (MRI) in a cohort of 477 patients, primarily with reversible cerebral vasoconstriction syndrome (RCVS), to provide a noninvasive in vivo diseased model to delineate distinct subarachnoid compartmentalization and potential leptomeningeal arteriovenous perivascular shunting. We characterized a homogeneous CSF milieu within the ensheathed periarterial glymphatic space. This environment, structurally defined by the perivascular membrane, exhibited uniform tracer intensities across both proximal and distal arterial segments (p = 0.118) on both static and dynamic models, opposed to the heterogeneous CSF appearance observed outside the perivascular membrane. We also observed nodal tracer enrichment in specific locations of the leptomeningeal perivenous space (PVeS) across initial and follow-up MRI. Furthermore, the periarterial tracer enrichment intensities matched those in these nodal portions of the PVeS but significantly exceeded those in the non-nodal portions (p < 0.0001). A dynamic MRI subgroup analysis further revealed that the periarterial tracer kinetics were nearly identical to those of these PVeS nodes. Notably, the nodal-non-nodal gradient of the tracer intensity was significantly amplified in participants exhibiting overt periarterial tracer leakage (p = 0.0006). Although we could not directly visualize the arteriovenous perivascular shunting demonstrated in animal models, our findings may be supportive of potential human periarterial and meningeal border pathways. By establishing a diseased model-based imaging framework to characterize these glymphatic microstructures noninvasively, our results offer a preliminary basis for understanding the perivascular CSF environment and a hypothesized periarterial and meningeal border pathways in living humans.
Agrawal M, Kirkise N, Rygel K
… +10 more, Sahoo PK, Vincent CJ, Joyner D, Aguilar-Alvarez R, Philipp TR, Dhillon PS, Patel J, Twiss J, Jasnow AM, Welshhans K
Down syndrome results from the triplication of human chromosome 21 and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on human chromosome 21 and is overproduced i...Down syndrome results from the triplication of human chromosome 21 and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on human chromosome 21 and is overproduced in Down syndrome. DSCAM is a homophilic cell adhesion molecule, a receptor for netrin-1, and plays a critical role in neural wiring during brain development. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in Down syndrome. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. DSCAM overexpression also reduces interhemispheric connectivity in vivo. Furthermore, we find that DSCAM overexpression leads to impaired hippocampal-dependent learning and reduced anxiety in adult mice. Down syndrome human induced pluripotent stem cell-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in Down syndrome human induced pluripotent stem cell-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. This study presents the first comprehensive cellular, molecular, and behavioural evidence that DSCAM is a significant contributor to multiple Down syndrome phenotypes, providing insight into a pathway for treatment. In summary, these results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in Down syndrome.
Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to pro...Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. Emerging evidence links several autism susceptibility genes...Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. Emerging evidence links several autism susceptibility genes to the nonsense-mediated decay (NMD) pathway, which maintains the homeostasis of gene transcription and protein translation in the nervous system. However, the role of Suppressor with morphogenetic effect on genitalia 7 (Smg7), an essential NMD factor, in brain function and ASD remains largely unknown. Here, we generated an Emx1-Cre-mediated conditional Smg7 knockout (Smg7cko) mouse model to investigate its neurological consequences. We found that both male and female Smg7cko mice exhibited autism-like behaviors, including impaired social interaction and communication, repetitive behaviors, anxiety-like traits, and learning and memory deficits. These phenotypes were accompanied by neuronal hyperexcitability and increased dendritic spine density in layer II/III pyramidal neurons of the hippocampus and the medial prefrontal cortex (mPFC). Notably, Smg7 deletion led to pronounced upregulation of Protein Kinase D1 (PKD1) transcripts, an NMD target, in these brain regions. Strikingly, adeno-associated virus (AAV)-mediated PKD1 knockdown (AAVsh-PKD1) in the hippocampus and mPFC significantly rescued social deficits in Smg7-deficient mice. Together, these findings identify Smg7 as a key regulator of neuronal function and behavior, and reveal PKD1 upregulation as a pathogenic mechanism underlying ASD-like phenotypes, providing new insight into NMD deficiency in ASD pathophysiology and a potential therapeutic target.
Dirkx N, Kaji M, De Vriendt E
… +15 more, Carleo G, Miceli F, Asselbergh B, Verstraelen P, Zonnekein N, Carotenuto L, Dang LT, Sommers V, Vlaemynck E, Lagae L, Ceulemans B, De Jonghe P, De Vos WH, Taglialatela M, Weckhuysen S
Loss-of-function (LOF) variants in KCNQ2, encoding the potassium channel subunit Kv7.2, cause a spectrum of neonatal epilepsies ranging from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and e...Loss-of-function (LOF) variants in KCNQ2, encoding the potassium channel subunit Kv7.2, cause a spectrum of neonatal epilepsies ranging from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of Kv7.2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2-DEE and KCNQ2-SeLFNE. KCNQ2-LOF variants induced a biphasic dysfunction at both single-cell and network levels, characterized by early Kv7-driven hyperexcitability accompanied by a clear reduction M-current density, which was rescued by acute Retigabine treatment. At later stages, intrinsic excitability and M-current normalized, yet network activity diverged further from control trajectories, indicating compensatory and ultimately maladaptive network remodeling. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF variants disrupt human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.
White matter hyperintensities (WMHs) are the imaging hallmark of cerebral small vessel disease (SVD), yet their microstructural composition, spatial heterogeneity, and relationship to diffuse normal-appearing white matte...White matter hyperintensities (WMHs) are the imaging hallmark of cerebral small vessel disease (SVD), yet their microstructural composition, spatial heterogeneity, and relationship to diffuse normal-appearing white matter (NAWM) damage and cardiovascular risk remain incompletely defined. In 363 community-dwelling adults from the BrainLaus cohort (mean age 55.5 years; range 19.8-89.4; 48.8% male), we combined quantitative relaxometry (MTsat, R1, R2*) and diffusion-derived metrics (FA, MD, NODDI, g-ratio). WMHs were automatically segmented on FLAIR and microstructure was quantified across lobes, white matter compartments, and geodesic layers extending from the WMH core into surrounding NAWM. Multivariate organisation was assessed using principal component analysis, and associations with cardiovascular risk factors were tested using partial least squares. Our analysis revealed demyelination, axonal loss, and extracellular fluid accumulation, particularly in periventricular regions. Layer-specific profiles showed a centrifugal gradient, with myelin loss and oedema at the core and axonal alteration in surrounding tissue. These signatures were associated with age-related cardiovascular risk factors, including higher blood pressure, bioimpedance, and lower haemoglobin levels. WMHs index the endpoint of a broader, spatially structured white matter injury process that extends into NAWM, is regionally concentrated in periventricular tissue, and covaries with systemic vascular/metabolic factors. These findings support sustained vascular risk management to mitigate CSVD-related white matter degeneration.
Kim H, Seo Y, Kho H
… +16 more, Singh SS, Lee J, Lee H, Hwang JW, Riew TR, Koh S, Choi JY, Roh HW, Son SJ, Kim GT, Cho SK, Jin HS, Jeong SY, Lee KI, Lee JY, Kim BG
Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) serving as a key imaging biomarker. Despite their clinical significance, the pathophysiolo...Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) serving as a key imaging biomarker. Despite their clinical significance, the pathophysiological mechanisms underlying cerebral small vessel disease remain poorly understood owing to a lack of appropriate animal models. We performed targeted deletion of Col4a1 in brain microvessels of adult mice using brain endothelium-specific adeno-associated virus (AAV)-BR1 vectors with clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Eight-week-old Cas9 transgenic mice received retro-orbital injections of AAV-BR1 containing single guide RNA (sgRNA) targeting Col4a1 or control Rosa26 sequences. Animals underwent longitudinal behavioural testing, including novel object recognition, Y-maze and rotarod tests, over 6 months. Brain pathology was assessed using T2*-weighted MRI, histological analysis and electron microscopy. For human studies, we analysed MRI and genomic data from 836 participants from the BICWALZS biobank, examining associations between genetic variants and CMB burden using linear regression and χ2 analyses. T2*-weighted MRI revealed numerous CMBs with distributions remarkably similar to human CMBs, appearing within 3 months post-injection. CMB burden increased progressively over 6 months in a dose-dependent manner. Behaviourally, mice exhibited progressive cognitive decline and motor incoordination. Histological examinations revealed haemosiderin deposits corresponding to MRI-detected CMBs, without macroscopic intracerebral haemorrhage or white matter changes. Ultrastructural analysis demonstrated significant basement membrane thinning in Col4a1-depleted microvessels. CMB accumulation was associated with widespread astrocytic reactivity extending beyond microbleed sites, whereas microglial activation remained localized. In human subjects, we identified significant associations between four genetic variants of TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2 and CMB burden, with odds ratios of 1.50-1.96 for increased microbleed susceptibility. This work provides the first animal model demonstrating that selective disruption of collagen IV in adult brain microvessels is sufficient to generate CMBs with high penetrance and dose-dependent tunability. Our findings establish that basement membrane integrity is critical for preventing microbleed formation and suggest that dysregulated collagen IV homeostasis underlies sporadic human CMB development.