Vascular damage, central nervous system (CNS) injury, seizure or even psychological stress may trigger activation of microglia and infiltration of other immune cells, accompanied by high levels of expression and activity of extracellular proteases, such as matrix metalloproteinases (MMPs), and degradation/remodelling of the perivascular and perineuronal extracellular matrix (ECM). This acute response is followed by the recovery/chronic phase, during which the activation of astrocytes leads to the upregulated synthesis of ECM molecules, which, in combination with elevated expression of tissue inhibitor of metalloproteinases (TIMP) proteins, increases the aggregation of ECM molecules. This biphasic dysregulation of local balance between extracellular proteases and the ECM activates multiple temporally overlapping signalling cascades, involving receptor‐type protein tyrosine phosphatases, integrins, Toll‐like receptors, cell adhesion molecules, and ion channels, resulting in impaired synaptic plasticity and cognition. An additional level of complexity is related to the leakage of blood plasma proteins, such as fibrinogen, and the diffusion of perivascularly overproduced MMPs, TIMPs and ECM molecules into the CNS parenchyma, leading to diverse effects on neurons and incorporation of these molecules into the interstitial neural ECM. This review aims to outline these complex common mechanisms in stroke, CNS injury, depression, epilepsy, multiple sclerosis and cerebral small vessel disease and to discuss translational strategies to advance the development of new therapies for these neurological and psychiatric diseases.

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1^-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1^-/- mice. None of the Col18a1^-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot–Marie–Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood–nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

Background: Cerebral small vessel disease (CSVD) often coexists with neurodegenerative pathologies, yet their role remains underexplored. This study aims to determine their prevalence, risk factors, and cognitive effects in patients with deep perforator arteriopathy (DPA) or cerebral amyloid angiopathy (CAA) using the biomarker-based ATN classification. Methods: In this cross-sectional study 186 patients (median age 75 years, 41% females, 111 with probable CAA, 75 with DPA) underwent MRI for analysis of CSVD severity and etiology, and lumbar puncture for analysis of cerebrospinal fluid amyloid-β 42/40 ratio, phosphorylated-tau, total-tau and neurofilament light. ATN profiles were related to clinical characteristics, MRI markers and cognitive performance in multivariate regression models. Results: Among CSVD patients, 30% had normal biomarkers (A-T-N-), 33% were within the AD pathology continuum (A + T ± N ± : 47% in CAA vs. 13% in DPA, p < .001), and 37% showed non-AD pathological changes (A-T ± N + : 53% in DPA vs. 25% in CAA, p < .001). The AD pathology continuum was associated with a severe lobar hemorrhagic phenotype and cognitive impairment, while non-AD pathological change was related to CSVD severity, history of stroke and similarly cognitive impairment. Both pathological ATN profiles were further related to lower MMSE scores (A + T ± N ± : B = − 3.3, p = .006; A-T ± N + : B = − 2.7, p = .021). Conclusions: Using biomarkers, this study confirms in vivo that CSVD frequently co-occurs with neurodegenerative pathologies, exerting detrimental effects on cognitive health.

Background: Studies on risk factors for primary intracerebral haemorrhage (ICH) focus on short-term predictive values of distinct clinical parameters or computed tomography (CT) markers and disregard the others. We, therefore, studied independent predictive values of demographic, clinical, and CT markers regarding ICH expansion, late ICH recurrence, and late mortality. Methods: In a retrospective study of 288 patients with primary ICH, ICH localization (158 lobar, 81 deep, and 49 cerebellar), volume, blend sign, spot sign, finger-like projections, and subarachnoid haemorrhages were evaluated. ICH localization-specific differences for demographic (age, sex), clinical parameters (vascular risk factors, antiplatelet, and anticoagulation therapy), and CT markers were evaluated using logistic regression. We applied Cox proportional hazards modelling using these parameters to predict risk factors for ICH expansion, late ICH recurrence, and late mortality. Results: The blend sign in lobar ICH relates to increased risk of ICH expansion (HR2.3), late ICH recurrence (HR2.3), and mortality (HR1.6). Age, conditions requiring antiplatelet medication, deep ICH localization, volume, and blend sign represented the most important independent factors impacting overall mortality. Conclusions: Blend sign at baseline ICH is a manifestation of underlying detrimental vascular processes that signal increased ICH expansion risk, although is also indicative of long-term risks for late recurrent ICH and late mortality.