Cortical neurodegeneration and glial activation are major drivers of disability progression in multiple sclerosis, but the molecular mechanisms underlying these processes remain poorly defined. Members of the NR4A nuclear receptor family are stress-responsive transcription factors that regulate neuronal survival, inflammatory signalling and cellular adaptation to metabolic and oxidative stress. In particular, neuron-derived orphan receptor 1 (NR4A3) has been implicated in neuroprotective and stress-adaptive responses in other neurological conditions, but its role in multiple sclerosis has not been investigated. Given its dual involvement in neuronal stress regulation and inflammatory modulation, neuron-derived orphan receptor 1 represents a plausible molecular link between chronic neuroinflammation, biological ageing and cortical neurodegeneration in multiple sclerosis. Here, we examined neuron-derived orphan receptor 1 expression in the motor cortex of post-mortem multiple sclerosis (n = 50) and control (n = 10) cases across lesional and non-lesional cortical layers of the motor cortex. Neuron-derived orphan receptor 1 was expressed by various cell types but predominantly localized to the neuronal cytoplasm and was reduced in multiple sclerosis non-lesional grey matter compared with controls, in particular in the functionally relevant layer V. In layer V, neuron-derived orphan receptor 1 loss was linked to exacerbated astrocytic (GFAP+) and microglial/macrophage (CD68+) expression, and higher levels of senescence markers (p19^INK4d, p21^CIP1), suggesting that loss of neuron-derived orphan receptor 1 relates to neuroinflammation and biological ageing processes. In contrast, in layer III, neuron-derived orphan receptor 1 expression was positively associated with neuronal density (NeuN) and Nurr1 expression, a transcription factor from the same NR4A family with established neuroprotective functions. Together, our findings identify neuron-derived orphan receptor 1 as a previously unrecognized, layer-specific regulator of cortical pathology in multiple sclerosis. Loss of neuron-derived orphan receptor 1 in deep-layer projection neurons aligns with inflammatory amplification and ageing-associated stress responses, whereas its preservation in upper layers may support neuronal integrity and neuroprotective signalling. These data position neuron-derived orphan receptor 1 as a candidate molecular node linking neuroinflammation, senescence and cortical neurodegeneration in progressive multiple sclerosis, and support that strategies aimed at preserving or restoring neuron-derived orphan receptor 1 activity may support neuron resilience and mitigate cortical disease progression in this incurable disease.

BACKGROUND:Reliable biomarkers for predicting disease progression in multiple sclerosis (MS) are crucial for advancing precision medicine and optimising treatment strategies. This study evaluates the predictive potential of serum nuclear magnetic resonance (NMR)-based metabolomics, individually and in combination with well-established biomarkers of neuroinflammation (serum glial fibrillary acidic protein, sGFAP) and axonal damage (neurofilament light chain, sNfL), in an extreme-phenotype subset of the Swiss Multiple Sclerosis Cohort (SMSC). METHODS:Serum samples were analysed using NMR-based metabolomics, along with quantification of sNfL and sGFAP. Supervised multivariate analysis was performed to differentiate MS phenotypes and identify future progressors. Multivariable receiver operating characteristic (ROC) analysis evaluated predictive performance, with key metabolite findings validated in an independent Oxford MS cohort. RESULTS:NMR-based metabolomics reliably distinguishes relapsing-remitting MS (RRMS) from secondary-progressive MS (SPMS) and predicts individual transitions. The identified predictive metabolites (lipoproteins, glutamine, alanine, valine, glucose) are also associated with progression independent of relapse activity (PIRA), a clinically relevant marker of sustained disability worsening. This demonstrates that the approach can both stage disease and forecast progression irrespective of stage. ROC analysis shows strong predictive performance (AUC = 0.81, p = 0.001), with external validation confirming robustness. Integration of NMR-metabolomics with sGFAP and sNfL further improves accuracy, yielding AUCs of 0.91 (p < 0.0001) and 0.87 (p = 0.0002), respectively, supported by independent validation. CONCLUSIONS:The integration of metabolic and protein biomarkers enables both accurate staging of RRMS versus SPMS and, critically, early prediction of progression irrespective of stage. This dual capability provides a clinically actionable, serum-based tool that can refine monitoring, improve therapeutic decision-making, and support a shift towards stage-agnostic, progression-focused care in MS.

There is increasing concern that head injuries in Association Football (or soccer) may lead to adverse health outcomes. The aim of this study was to determine whether head impacts or injuries are associated with an increased risk of neurodegenerative disease. We performed a systematic search using PubMed, Embase, and Ovid (up to April 2025). Studies included investigated neurodegenerative diseases in football in comparison to control athletic and general populations. Data were extracted according to PRISMA guidelines. Studies with an odds ratio (OR) were included in the meta-analysis. A total of ten studies were included in this review, of which nine were suitable for meta-analysis from eight cohorts. The risk for developing any neurodegeneration was 1.69 OR (95%CI 1.11 to 2.59; p = 0.01); for Dementia, it was 2.16 OR (95%CI 1.60 to 2.93; p < 0.01; for Motor Neurone Disease (MND), it was 1.39 OR (95%CI 0.67 to 2.53; p = 0.21); for Parkinson’s Disease (PD), it was 1.14 OR (95%CI 0.55 to 2.89; p = 0.79). Heterogeneity was reduced following the removal of two studies and the revised risk scores for any neurodegenerative disease; Dementia increased, with that for MND reaching significance, 1.81 OR (95%CI 1.22 to 2.30; p = 0.01), but there remained no association with PD. Evidence suggests that professional football significantly increases the odds of neurodegenerative disease.

Outcomes following paediatric mild traumatic brain injury (mTBI) are extremely heterogenous. While emerging biomarkers promise enhanced prognostic accuracy, a critical question remains unanswered—which outcome measures provide the most accurate assessment of injury impact? In this article, we highlight barriers to selecting appropriate outcome measures, including variability in how outcomes are defined and the wide range of assessment tools used. With reference to the most recent literature, we summarise current evidence of adverse outcomes following paediatric mTBI and highlight emerging candidate biomarkers of these outcomes. We emphasise the unique challenges associated with interpreting outcome measures in younger patients, from the impact of developmental stage and assessment timing to the influence of injury-independent factors. We assert the need to consider these obstacles when designing and interpreting mTBI biomarker studies. To realise the potential of prognostic biomarkers, future research should prioritise establishing consensus definitions, compiling a set of accessible and comprehensive outcome measures, and capturing injury-independent factors through longitudinal study designs.

ABSTRACT Background Cachexia is a clinically challenging multifactorial and multi‐organ syndrome, associated with poor outcome in cancer patients, and characterised by inflammation, wasting and loss of appetite. The syndrome leads to central nervous system (CNS) function dysregulation and to neuroinflammation; nevertheless, the mechanisms involved in human cachexia remain unclear. Methods We used in vivo structural and functional magnetic resonance imaging (Cohort 1), as well as postmortem neuropathological analyses (Cohort 2) in cachectic cancer (CC) patients compared to weight stable cancer (WSC) patients. Cohort 1 included treatment‐naïve adults diagnosed with colorectal cancer, further divided into WSC (n = 12; 6/6 [male/female], 61.3 ± 3.89 years) and CC (n = 10; 6/4, 63.0 ± 2.74 years). Cohort 2 was composed by human postmortem cases where gastrointestinal carcinoma was the underlying cause of death (WSC n = 6; 3/3, 82.7 ± 3.33 years and CC n = 10; 5/5, 84.2 ± 2.28 years). Results Here we demonstrate that the CNS of CC patients presents regional structural differences within the grey matter (GM). Cachectic patients presented an augmented area within the region of the orbitofrontal cortex, olfactory tract and the gyrus rectus (coordinates X, Y, Z = 6, 20,−24; 311 voxels; pFWE = 0.023); increased caudate and putamen volume (−10, 20, −8; 110 voxel; pFWE = 0.005); and reduced GM in superior temporal gyrus and rolandic operculum (56,0,2; 156 voxels; pFWE = 0.010). Disrupted functional connectivity was found in several regions such as the salience network, subcortical and temporal cortical areas of cachectic patients (20 decreased and 5 increased regions connectivity pattern, pFDR < 0.05). Postmortem neuropathological analyses identified abnormal neuronal morphology and density, increased microglia/macrophage burden, astrocyte profile disruption and mTOR pathway related neuroinflammation (p < 0.05). Conclusions Our results indicate that cachexia compromises CNS morphology mostly causing changes in the GM of cachectic patients, leading to alterations in regional volume patterns, functional connectivity, neuronal morphology, neuroglia profile and inducing neuroinflammation, all of which may contribute to the loss of homeostasis control and to deficient information processing, as well as to the metabolic and behavioural derangements commonly observed in human cachexia. This first human mapping of CNS cachexia responses will now pave the way to mechanistically interrogate these pathways in terms of their therapeutic potential.

BACKGROUND AND OBJECTIVES:Differentiating multiple sclerosis (MS) from antibody (Ab)-defined diseases, such as neuromyelitis optica spectrum disorders (NMOSDs), remains challenging, particularly as Ab levels decline. N-glycans play a key role in immunity, with changes in branching and fucosylation linked to T/B-cell function and MS onset while increased N-acetylglucosamine residues correlate with disease progression. Despite growing recognition of glycosylation in neuroinflammation, direct comparisons of the N-glycome between MS and Ab-defined diseases are lacking. This study aims to assess whether plasma N-glycome profiling can effectively differentiate these conditions and their subtypes. METHODS:This cohort study included 120 participants: 30 with relapsing-remitting MS (RRMS), 30 with secondary progressive MS (SPMS), 30 with myelin oligodendrocyte glycoprotein Ab-associated disease (MOGAD), and 30 with aquaporin-4 (AQP4)-Ab NMOSD, recruited from the John Radcliffe Hospital, Oxford University Hospitals National Health System (NHS) Trust. Plasma N-glycans were analyzed using ultra-high-performance (UHPLC) hydrophilic interaction liquid chromatography (HILIC) coupled with high-resolution mass spectrometry. Orthogonal partial least-squares discriminant analysis was applied to identify disease-specific glycomic patterns. RESULTS:Distinct N-glycome profiles were identified across diseases and phenotypes. Plasma N-glycans differentiated MS from Ab-defined diseases with 80.5% accuracy (±1.5%), MOGAD from AQP4-Ab NMOSD with 77.8% accuracy (±3.1%), and RRMS from SPMS with 75.2% accuracy (±3.6%). Key discriminatory features included increased monosialylation (S1; odds ratio [OR] = 2.57, p < 0.0001), trigalactosylation (G3; OR = 2.70, p < 0.0001), highly branched N-glycans (OR = 2.32, p = 0.0002), and antennary fucosylation (OR = 2.89, p < 0.0001), effectively distinguishing Ab-defined diseases from MS, independent of Ab serostatus at the time of sampling. DISCUSSION:These findings underscore the potential of plasma N-glycomics as a diagnostic tool for neuroinflammatory diseases. While further research is needed to clarify the mechanistic links between glycomic alterations and disease pathology, our results suggest that plasma N-glycan profiling could improve disease classification. Given its noninvasive and cost-effective nature, this approach holds promise as a complementary diagnostic tool for CNS demyelinating diseases in clinical practice.

Multiple sclerosis (MS) and Alzheimer's disease are neurodegenerative diseases with age-related disability accumulation. In MS, inflammation spans decades, whereas AD is characterized by Aβ plaques and neurofibrillary tangles (NFT). Few studies explore accumulation of amyloids in MS. We examined Aβ deposition and NFT density in temporal and frontal cortices from postmortem MS (n = 75) and control (n = 66) cases. Compared with controls, MS cases showed reduced Aβ, especially in those aged <65 years, and reduced NFT, notably in cases aged >65 years. Aβ deposition predicted greater NFT density both in MS cases and controls. MS-related factors may affect Aβ/NFT deposition and/or clearance, offering new therapeutic insights for both diseases. ANN NEUROL 2025;97:1067-1073.

Traumatic brain injury (TBI) is a modifiable risk factor for Alzheimer’s disease (AD). TBI and AD share several histopathological hallmarks: namely, beta-amyloid aggregation, tau hyperphosphorylation, and plasma protein infiltration. The relative contributions of these proteinopathies and their interplay in the pathogenesis of both conditions remains unclear although important differences are emerging. This review synthesises emerging evidence for the critical role of the neurovascular unit in mediating protein accumulation and neurotoxicity in both TBI and AD. We propose a shared pathogenic cascade centred on a neurovascular unit, in which increased blood-brain barrier permeability induces a series of noxious mechanisms leading to neuronal loss, synaptic dysfunction and ultimately cognitive dysfunction in both conditions. We explore the application of this hypothesis to outstanding research questions and potential treatments for TBI and AD, as well as other neurodegenerative and neuroinflammatory conditions. Limitations of this hypothesis, including the challenges of establishing a causal relationship between neurovascular damage and proteinopathies, are also discussed.

ABSTRACT Background Understanding the mechanisms underlying disease progression in Multiple Sclerosis (MS) is fundamental to pave the way to treatment advances. Smoldering demyelinating inflammation characterized by iron deposition is observed at the edges of chronic active lesions and represents a relevant substrate of disease progression in MS. However, the influence of genetic factors on these mechanisms is not known. Leveraging the importance of iron deposition in smoldering inflammation, we assessed whether variants in genes belonging to iron-related pathways affect disease progression in MS. Methods We investigated the association between Single Nucleotide Polymorphisms (SNPs) mapping to 334 genes in iron-related pathways and the risk of disease progression, studying 2,817 MS patients from Italy (n=755) and Sweden (n=2,062), and comparing relapsing-remitting (RR-MS) with secondary progressive (SP-MS) disease course. To better understand the link of the identified variant with smoldering inflammation, we applied a multilayered approach using independent cohorts from Italy, Sweden and the United Kingdom and encompassing gene expression, PRL analysis, neurofilament levels, post-mortem spinal cord pathology and pharmacogenomics. Results We found an association between a locus in the Hypoxia-Inducible Factor 1-alpha ( HIF1A ) gene and the odds of SP-MS transition in the Italian cohort (rs11621525; SP-MS OR 0.57, 95% CI 0.44-0.72; P=3.30×10 - 6 ), which was replicated in the Swedish dataset (rs1951795; OR 0.79, 95% CI 0.67-0.95; P=0.0079). Additional analyses showed that patients carrying the protective allele exhibited reduced HIF1A expression in the immune cells, lower PRL volume, lower plasma/cerebrospinal fluid neurofilament levels, and lower inflammation and acute axonal injury in the post-mortem spinal cord. Moreover, the variant influenced the response to dimethyl fumarate, an approved MS drug with effect on mechanisms shared with HIF1A pathway. Conclusion A novel locus in the HIF1A gene, a crucial hub for iron-binding capacity, inflammation, and hypoxia response, is associated with the risk of disease progression in MS. Converging lines of evidence support the role of this locus in smoldering inflammation, prompting future studies to explore the potential of HIF1A as a therapeutic target in progressive MS.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA-DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA-DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA-DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA-DRB*15-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA-DRB1*15-positive and 23 HLA-DRB1*15-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (-36.5%, p = 0.036 and - 24.7%, p = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA-DRB1*15-positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated demyelinating disease that is challenging to differentiate from multiple sclerosis (MS), as the clinical phenotypes overlap, and people with MOGAD can fulfil the current MRI-based diagnostic criteria for MS. In addition, the MOG antibody assays that are an essential component of MOGAD diagnosis are not standardized. Accurate diagnosis of MOGAD is crucial because the treatments and long-term prognosis differ from those for MS. This Expert Recommendation summarizes the outcomes from a Magnetic Resonance Imaging in MS workshop held in Oxford, UK in May 2022, in which MS and MOGAD experts reflected on the pathology and clinical features of these disorders, the contributions of MRI to their diagnosis and the clinical use of the MOG antibody assay. We also critically reviewed the literature to assess the validity of distinctive imaging features in the current MS and MOGAD criteria. We conclude that dedicated orbital and spinal cord imaging (with axial slices) can inform MOGAD diagnosis and also illuminate differential diagnoses. We provide practical guidance to neurologists and neuroradiologists on how to navigate the current MOGAD and MS criteria. We suggest a strategy that includes useful imaging discriminators on standard clinical MRI and discuss imaging features detected by non-conventional MRI sequences that demonstrate promise in differentiating these two disorders.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

PURPOSE:This study aimed to evaluate 1) whether having a vascular comorbidity (i.e., hypertension, hyperlipidemia, heart disease, and diabetes) was associated with self-reported issues with functional activities among persons with multiple sclerosis (MS) and 2) if certain contributing factors (i.e., disability, depression, and fatigue) might explain the observed relationships. MATERIALS AND METHODS:Participants (n = 263) completed the Functional Status Index (FSI), which assessed five domains: gross mobility, hand activities, personal care, home chores, and social/role activities. After bivariate analyses, individual linear regressions were conducted for each FSI domain, controlling for demographics. Follow-up mediation analyses were done for each of the three mediators. RESULTS:Participants with vascular comorbidities endorsed more issues on all five domains, with the demographic-adjusted associations with gross mobility (b = 0.34, p = 0.002), hand activities (b = 0.15, p = 0.006), home chores (b = 0.44, p = 0.003), and social/role activities (b = 0.32, p = 0.024) remaining significant. Disability fully mediated the effects of vascular comorbidities on these domains, with partial and full mediations observed with depression and fatigue. Diabetes emerged as a significant individual comorbidity in several models. CONCLUSIONS:Vascular comorbidities, diabetes in particular, are associated with persons with MS endorsing worse ratings on functional outcomes, with disability, depression, and fatigue explaining these associations.

In the aftermath of World War II (WWII), a young neurologist was sat at a desk in a corridor, which he called his office, organising index cards, which his colleagues affectionately referred to as his "folly" [1] (Fig. 1).This man was Ritchie Russell, who, if he is known at all today, is probably remembered for establishing the link between post-traumatic amnesia (PTA) and severity of traumatic brain injury (TBI).Russell would go on to become the first professor of clinical neurology at the University of Oxford, where his legacy can still be felt today.But the story of how he became a pioneer in neurology holds valuable lessons for everyone dedicated to enhancing the lives of people with neurological conditions.William Ritchie Russell was born in 1903, the same year which saw the formation of the suffragette movement.Ten years earlier, his mother Beatrice Ritchie (whose maiden name would become his preferred name), gained a medical degree from the University of Brussels, having been one of the first women to study medicine in Scotland [2].Although fully qualified, she was denied a license to practice medicine.When war broke out in 1914, women were still not allowed to join the Royal Army Medical Corps.Instead, Beatrice joined the Scottish Women's Hospitals movement, through which more than a thousand women volunteered to run a network of fourteen hospitals across Europe.In Edinburgh, Beatrice led the personnel committee, orchestrating the people and resources that sustained this network, working 'quietly and unostentatiously from beginning to end' [2].Her spirit and character are vividly reflected in the remarkable contributions her son made when conflict returned to Europe during WWII.

This narrative review provides an overview of the posterior circulation and the clinical features of common posterior circulation stroke (PCS) syndromes in the posterior arterial territories and how to distinguish them from mimics. We outline the hyperacute management of patients with suspected PCS with emphasis on how to identify those who are likely to benefit from intervention based on imaging findings. Finally, we review advances in treatment options, including developments in endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT), and the principles of medical management and indications for neurosurgery. Observational and randomised clinical trial data have been equivocal regarding EVT in PCS, but more recent studies strongly support its efficacy. There have been concomitant advances in imaging of posterior stroke to guide optimal patient selection for thrombectomy. Recent evidence suggests that clinicians should have a heightened suspicion of posterior circulation events with the resultant implementation of timely, evidence-based management.

The majority of individuals with Alzheimer’s disease (AD) exhibit vascular damage in the brain including reduced cerebral blood flow (CBF) and blood-brain-barrier (BBB) breakdown. Growing evidence suggests pericytes, a vessel-residing cell able to modulate CBF and BBB integrity, are a major contributor to vascular dysfunction in AD. The close spatial relationship between microglia and capillaries led us to explore the hypothesis that microglia and pericytes functionally interact to influence vessel function in the healthy brain and that this interaction may become pathological in AD. We first characterized the spatial and functional relationship between microglia, capillaries and pericytes in the healthy central nervous system (CNS) in fixed tissue and using in vivo two-photon microscopy through cranial windows in adult NG2DsRed x CX3CR1 +/GFP mice. We then assessed the spatial relationship between microglia, capillaries and pericytes in the human superior frontal gyrus (SFG) of 12 control and 11 AD cases. We discovered a subset of microglia dynamically interacting with pericytes in the healthy CNS, which we termed pe ricyte-associated m icroglia (PEM). PEM are present throughout the capillary tree, often maintain their position for at least 28 days and frequently were found to associate with pericytes lacking astroglial endfeet coverage. The loss of PEM alters capillary width beneath pericytes, but deletion of the microglial fractalkine receptor (CX3CR1), which regulates the recruitment of microglia to sites of neuroinflammation, does not reduce the proportion of microglia that are PEM. In AD, we found the proportion of microglia associated with capillaries and pericytes declines in the superior frontal gyrus (SFG) and that this decline is exacerbated by the APOE ε3/ε4 genotype. This reduction occurs despite an overall increase in pericyte numbers in AD cases. We identify microglia specifically associating with pericytes in the healthy CNS and find these associations are reduced in AD. The changing relationship between microglia, capillaries and pericytes may be a novel mechanism contributing to vascular dysfunction in AD.