Anti-seizure effects of norepinephrine-induced free fatty acid release.

The brain's ability to rapidly transition between sleep, quiet wakefulness, and states of high vigilance is remarkable. Cerebral norepinephrine (NE) plays a key role in promoting wakefulness, but how does the brain avoid neuronal hyperexcitability upon arousal? Here, we show that NE exposure results in the generation of free fatty acids (FFAs) within the plasma membrane from both astrocytes and neurons. In turn, FFAs dampen excitability by differentially modulating the activity of astrocytic and neuronal Na+, K+, ATPase. Direct application of FFA to the occipital cortex in awake, behaving mice dampened visual-evoked potential (VEP). Conversely, blocking FFA production via local application of a lipase inhibitor heightened VEP and triggered seizure-like activity. These results suggest that FFA release is a crucial step in NE signaling that safeguards against hyperexcitability. Targeting lipid-signaling pathways may offer a novel therapeutic approach for seizure prevention.

Multifaceted role of thrombin in subarachnoid hemorrhage: Focusing on cerebrospinal fluid circulation disorder.

Subarachnoid hemorrhage (SAH) is a severe neurological condition characterized by high morbidity and mortality. The unfavorable prognosis of SAH is closely associated with early brain injury (EBI) and delayed cerebral ischemia (DCI), wherein thrombin plays a role as part of the secondary injury components following hemorrhage in these two pathological processes. Additionally, thrombin contributes to disruptions in the circulation of cerebrospinal fluid (CSF), thereby giving rise to a spectrum of sequelae following SAH, including cerebral edema, hydrocephalus, cognitive impairments, and depressive symptoms. This review aims to provide a comprehensive understanding of the pathological role of thrombin in EBI, DCI, and CSF circulation following SAH, with a specific focus on its impact on the glymphatic-meningeal lymphatic system-a crucial mechanism for waste clearance and neurohomeostatic regulation. Additionally, this review offers an overview of current pharmacological interventions and treatment modalities targeting pathogenic mechanisms, aiming to mitigate brain injury and promote neurological recovery post-SAH.

Association of glymphatic system dysfunction with cognitive impairment in temporal lobe epilepsy.

Objectives: To explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE). Methods: This study retrospectively included 38 patients with unilateral TLE and 26 age- and gender-matched healthy controls (HCs). The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), and cognitive assessment were obtained for each participant. Neuropsychological test batteries included Montreal Cognitive Assessment (MoCA), Minimum Mental State Examination, Arithmetic Test (AT), Digit Symbol Substitution Test (DSST), Digit Span Test (DST), Boston Naming Test, Block design, Phonological Fluency Test (PFT), and Semantic Verbal Fluency (SVF). Results: Compared to HCs, TLE patients had lower scores of MoCA, AT, DSST, DST, Block design, PFT and SVF (all p < 0.05) and lower values of mean DTI-ALPS index (1.491 ± 0.142 vs. 1.642 ± 0.123, p < 0.001). Significantly lower DTI-ALPS index values were observed in the ipsilateral hemisphere than in the contralateral hemisphere (1.466 ± 0.129 vs. 1.517 ± 0.175, p = 0.013) for patients with unilateral TLE. Correlation analyses found that SVF performance was significantly or borderline significantly associated with glymphatic function (FDR-corrected p < 0.05 for all DTI-ALPS index and FDR-corrected p = 0.057 for CPV) in TLE patients. Linear regression analyses showed that increased CPV and decreased DTI-ALPS index were independent risk factors for semantic fluency impairment (all p < 0.05). Furthermore, mediation analyses found the mediator role of the mean DTI-ALPS index in the relationship between choroid plexus enlargement and semantic fluency impairment (indirect effect: ß = -0.182, 95%CI = -0.486 to -0.037). Conclusion: These findings reveal the important role of the DTI-ALPS index and CPV in SVF performance in unilateral TLE. Decreased DTI-ALPS index and increased CPV are the independent risk factors for semantic fluency impairment. The DTI-ALPS index may fully mediate the relationship between CP enlargement and SVF performance. These insights provide a radiological foundation for further investigations into the mechanism of the glymphatic system in TLE pathophysiology.

May Glymphatic Drainage Improve Life Quality in Progressive Multiple Sclerosis Outpatients?

Background: The cerebral fluid-dynamic system plays a critical role in maintaining brain health and function. Recent studies identify the glymphatic system as primarily responsible for removing waste products and toxins from brain tissue. In recent years, we have achieved beneficial improvements in MS patients' symptoms and lifestyle using a specific Fluid Dynamic Intensive MAM (FD-MAM) protocol. Methods: We treated 40 outpatients with progressive MS, aged 45-55 years and with EDSS scores from 6 to 9. We applied FD-MAM in 10 daily sessions over two weeks. Before and after glymphatic drainage by FD-MAM, we assessed each patient's clinical status and quality of life using six validated questionnaires. Results: Data from the six validated questionnaires administered to the 40 MS patients show an improvement in 83% of the scores. At the same time, we observed a shift from pathological to physiological values in 50% of the pathological scores after 10 sessions of FD-MAM protocol. Conclusion: This study confirms the positive improvements on life quality in outpatients with progressive multiple sclerosis after one cycle of Fluid Dynamic Intensive MAM (FD-MAM) protocol. Initial follow-up on few patients treated with the FD-MAM protocol suggests that the results persist for six to ten months post-treatment. Future detailed studies, on MS outpatients' larger cohort, are essential to assess the duration of results and its effect on glymphatic system.

Continuous theta burst stimulation ameliorates cognitive deficits in microinfarcts mice via inhibiting glial activation and promoting paravascular CSF-ISF exchange.

Microinfarcts are widespread in the elderly, accompanied by varying degrees of cognitive decline. Continuous theta burst stimulation (cTBS) has been demonstrated to be neuroprotective on cognitive dysfunction, but the underlying cellular mechanism has been still not clear. In the present study, we evaluated the effects of cTBS on cognitive function and brain pathological changes in mice model of microinfarcts. The spatial learning and memory was assessed by Morris water maze (MWM), Glymphatic clearance efficiency was evaluated using in vivo two-photon imaging. The loss of neurons, activation of astrocytes and microglia, the expression and polarity distribution of the astrocytic aquaporin-4 (AQP4) were assessed by immunofluorescence staining. Our results showed that cTBS treatment significantly improved the spatial learning and memory, accelerated the efficiency of glymphatic clearance, up-regulated the AQP4 expression and improved the polarity distribution of AQP4 in microinfarcts mice. Besides, cTBS treatment increased the number of surviving neurons, whereas decreased the activated astrocytes and microglia. Our study suggested that cTBS accelerated glymphatic clearance and inhibited the excessive gliogenesis, which ultimately exerted neuroprotective effects on microinfarcts mice.

Glymphatic system dysfunction and risk of clinical milestones in patients with Parkinson disease.

BACKGROUND AND PURPOSE: Glymphatic dysfunction may play a significant role in the development of neurodegenerative diseases. We aimed to evaluate the association between glymphatic dysfunction and the risk of malignant event/clinical milestones in Parkinson disease (PD). METHODS: This study included 236 patients from August 2014 to December 2020. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index was calculated as an approximate measure of glymphatic function. The primary outcomes were four clinical milestones including recurrent falls, wheelchair dependence, dementia, and placement in residential or nursing home care. The associations of DTI-ALPS with the risk of clinical milestones were examined using multivariate Cox proportional hazards regression models. Then, logistic regression was repeated using clinical variables and DTI-ALPS index individually and in combination of the two to explore the ability to distinguish patients who reached clinical milestones within a 5-year period. RESULTS: A total of 175 PD patients with baseline DTI-ALPS index and follow-up clinical assessments were included. A lower DTI-ALPS was independently associated with increased risk of recurrent falls, wheelchair dependence, and dementia. Additionally, in 103 patients monitored over 5 years, a logistic regression model combining clinical variables and DTI-ALPS index showed better performance for predicting wheelchair dependence within 5 years than a model using clinical variables or DTI-ALPS index alone. CONCLUSIONS: Glymphatic dysfunction, as measured by the DTI-ALPS index, was associated with increased risk of clinical milestones in patients with PD. This finding implies that therapy targeting the glymphatic system may serve as a viable strategy for slowing down the progression of PD.

Alterations in the DTI-ALPS index and choroid plexus volume are associated with clinical symptoms in participants with narcolepsy type 1.

BACKGROUND: Narcolepsy type 1 (NT1) is a sleep disorder characterized by excessive daytime sleepiness accompanied by cataplexy. Sleep disorders have been shown to affect the glymphatic system. This study aimed to evaluate changes in the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus (CP) volume in NT1 participants, and to further explore their clinical significance. METHODS: We prospectively enrolled participants diagnosed with NT1 based on cerebrospinal fluid hypocretin-1 concentration and multiple sleep latency tests at our hospital. All participants underwent MRI to allow analysis of the DTI-ALPS index and CP volume. We subsequently performed correlation analyses between the DTI-ALPS index, CP volume, and important clinical parameters, including the Epworth Sleepiness Scale (ESS) score, Narcolepsy Severity Scale (NSS) score, stage rapid eye movement sleep (REM) ratio, stage 1 non-REM (N1) ratio, stage 2 non-REM (N2) ratio, and stage 3 non-REM (N3) ratio, among the NT1 participants. Inter-group and correlation analyses of DTI-ALPS index and CP volume were performed using age, sex, body mass index, and lateral ventricle volume as covariates. RESULTS: This study enrolled 41 NT1 participants and 42 healthy controls (HC). The DTI-ALPS index of NT1 participants was significantly lower than HC (1.444 ± 0.119 vs.1.661 ± 0.135, P < 0.001), while the CP volume of NT1 participants was significantly larger than those of HC (0.831 ± 0.146 vs. 0.645 ± 0.137, P < 0.001). The DTI-ALPS index was negatively correlated with both the ESS (PFDR-corrected<0.001) and NSS scores (PFDR-corrected = 0.010), but positively correlated with the Stage N3 ratio (PFDR-corrected = 0.033). The CP volume of NT1 participants was positively correlated with ESS (PFDR-corrected = 0.047) and NSS scores (PFDR-corrected = 0.047), but negatively correlated with the stage N3 ratio (PFDR-corrected = 0.047). CONCLUSION: Our study suggests that the DTI-ALPS index was lower and CP volume was larger in NT1 participants. The DTI-ALPS index and CP volume in the NT1 participants were related to disease severity and sleep structure. These findings may provide new insights into the mechanisms underlying NT1.

The Dysregulation of the Glymphatic System in Patients with Psychosis Spectrum Disorders Minimally Exposed to Antipsychotics: La dérégulation du système glymphatique en présence de troubles psychotiques chez des patients peu exposés à des antipsychotiques.

OBJECTIVE: The pathophysiological mechanisms influencing psychosis spectrum disorders are largely unknown. The glymphatic system, which is a brain waste clearance pathway, has recently been implicated in its pathophysiology and has also been shown to be disrupted in various neurodegenerative and vascular diseases. Initial studies examining the glymphatic system in psychosis spectrum disorders have reported disruptions, but the findings have been confounded by medication effects as they included antipsychotic-treated patients. In this study, we used diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) as a technique to measure the functionality of the glymphatic system in a sample of antipsychotic-minimally exposed patients with psychosis spectrum disorders and healthy controls. METHODS: The study included 13 antipsychotic-minimally exposed (2 weeks antipsychotic exposure in the past 3 months/lifetime) patients with psychosis spectrum disorders and 114 healthy controls. We quantified water diffusion metrics along the x-, y-, and z-axes in both projection and association fibres to derive the DTI-ALPS index, a proxy for glymphatic activity. Between-group differences were analyzed using two-way ANCOVA controlling for age and sex. Partial correlations were used to assess the association between the ALPS index and clinical variables. RESULTS: Analyses revealed that antipsychotic-minimally exposed psychosis spectrum disorder patients had a lower DTI-ALPS index value than healthy controls in both hemispheres and the whole brain (all P < 0.005). Significant differences were also observed between the x and y projections/associations between patients and healthy controls (P < 0.001). Furthermore, we did not find any significant correlations (all P > 0.05) between the DTI-ALPS index with age, body mass index, symptomatology, and metabolic parameters. CONCLUSION: This study shows that the glymphatic system is dysregulated in antipsychotic-minimally exposed patients with psychosis spectrum disorders. Understanding the mechanisms that influence the glymphatic system may help to understand the pathophysiology of psychosis spectrum disorders as proper waste clearance is needed for normal brain functioning.

Sleep Apnea and Amyotrophic Lateral Sclerosis: Cause, Correlation, Any Relation?

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with progressive neurodegeneration, affecting both the cortical and the spinal component of the motor neuron circuitry in patients. The cellular and molecular basis of selective neuronal vulnerability is beginning to emerge. Yet, there are no effective cures for ALS, which affects more than 200,000 people worldwide each year. Recent studies highlight the importance of the glymphatic system and its proper function for the clearance of the cerebral spinal fluid, which is achieved mostly during the sleep period. Therefore, a potential link between problems with sleep and neurodegenerative diseases has been postulated. This paper discusses the present understanding of this potential correlation.

Crucial role of Aquaporin-4 extended isoform in brain water Homeostasis and Amyloid-ß clearance: implications for Edema and neurodegenerative diseases.

The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-ß (Aß) removal was assessed using a fluorescent Aß intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aß clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aß removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aß. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's.

Choroid plexus enlargement in patients with end-stage renal disease: implications for glymphatic system dysfunction.

Objectives: The choroid plexus plays a role in eliminating detrimental metabolites from the brain as an integral component of the glymphatic system. This study aimed to investigate alterations in choroid plexus volume in patients with end-stage renal disease (ESRD) compared with healthy controls. Methods: We enrolled 40 patients with ESRD and 42 healthy controls. They underwent brain magnetic resonance imaging (MRI), specifically using three dimensional T1-weighted imaging. We analyzed choroid plexus volumes and compared them between patients with ESRD and healthy controls. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated. We compared the DTI-ALPS index between the ESRD patients and healthy controls. Additionally, we evaluated the association between choroid plexus volume and neuropsychological tests results in patients with ESRD. Results: There were significant differences in choroid plexus volumes between patients with ESRD and healthy controls. The choroid plexus volumes in patients with ESRD were higher than those in healthy controls (1.392 vs. 1.138%, p < 0.001). The DTI-ALPS index in patients with ESRD was lower than that in healthy controls (1.470 ± 0.239 vs. 1.641 ± 0.266, p = 0.005). There were no differences in choroid plexus volumes between patients with ESRD, regardless of the presence of cognitive impairment. However, among the neuropsychological tests, the scores for word-list recognition in verbal memory were negatively correlated with the choroid plexus volume (r = -0.428, p = 0.006). Conclusion: We demonstrated a significant enlargement of the choroid plexus volume in patients with ESRD compared to healthy controls. This finding suggests that patients with ESRD have glymphatic system dysfunction, which may be related to cognitive impairment.

A brain-wide solute transport model of the glymphatic system.

Brain waste is largely cleared via diffusion and advection in cerebrospinal fluid (CSF). CSF flows through a pathway referred to as the glymphatic system, which is also being targeted for delivering drugs to the brain. Despite the importance of solute transport, no brain-wide models for predicting clearance and delivery through perivascular pathways and adjacent parenchyma existed. We devised such a model by upgrading an existing model of CSF flow in the mouse brain to additionally solve advection-diffusion equations, thereby estimating solute transport. We simulated steady-state transport of 3 kDa dextran injected proximal to the perivascular space (PVS) of the middle cerebral artery, mimicking in vivo experiments. We performed a sensitivity analysis of 11 biological properties of PVSs and brain parenchyma by repeatedly simulating solute transport with varying parameter values. Parameter combinations that led to a large total pressure gradient, poor CSF perfusion or a steep solute gradient were deemed unrealistic. Solute concentrations in parenchyma were most sensitive to changes in pial PVS size, as this parameter linearly affects volume flow rates. We also found that realistic transport requires both highly permeable penetrating PVSs and high-resistance parenchyma. This study highlights the potential of brain-wide models to provide insights into solute transport processes.

Diffusion tensor imaging in cerebral small vessel disease applications: opportunities and challenges.

Cerebral small vessel disease (CSVD) is a syndrome of pathology, imaging, and clinical manifestations caused primarily by a variety of functional or structural lesions in the small blood vessels of the brain. CSVD contributes to approximately 45% of dementia and 25% of ischemic strokes worldwide and is one of the most important causes of disability. The disease progresses insidiously, and patients often have no typical symptoms in the early stages, but have an increased risk of stroke, death, and poor long-term prognosis. Therefore, early diagnosis of CSVD is particularly important. Neuroimaging is the most important diagnostic tool used for CSVD. Therefore, it is important to explore the imaging mechanisms of CSVD for its early diagnosis and precise treatment. In this article, we review the principles and analysis methods of DTI, analyze the latest DTI studies on CSVD, clarify the disease-lesion mapping relationships between cerebral white matter (WM) microstructural damage and CSVD, explore the pathogenic mechanisms and preclinical imaging features of CSVD, and summarize the latest research directions of CSVD and research methods to provide a comprehensive and objective imaging basis for the diagnosis and treatment of CSVD.

Effect of glymphatic system function on cognitive function in patients with chronic kidney disease.

Objectives: Studies have recently shown an alteration of the structural connectivity and a dysfunctional glymphatic system in patients with chronic kidney disease (CKD). In this study, we aimed to investigate the effects of the structural connectivity and glymphatic system on the cognitive function of patients with CKD. Methods: We prospectively enrolled patients with CKD and healthy controls. The CKD group was divided into two regarding their cognitive function. All patients received brain magnetic resonance imaging, including diffusion tensor imaging (DTI). We calculated the measures of structural connectivity and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, a neuroimaging marker of the glymphatic system function, and compared the indices between groups. Results: The mean clustering coefficient, local efficiency, and small-worldness index in patients with CKD were lower than those in healthy controls (0.125 ± 0.056 vs. 0.167 ± 0.082, p = 0.008; 1.191 ± 0.183 vs. 1.525 ± 0.651, p = 0.002; 0.090 ± 0.043 vs. 0.143 ± 0.102, p = 0.003; respectively). The DTI-ALPS index was lower in patients with CKD than in healthy controls (1.436 vs. 1.632, p < 0.001). Additionally, the DTI-ALPS index differed significantly between CKD patients with and without cognitive impairment. Notably, this index was lower in patients with CKD and cognitive impairment than in patients without cognitive impairment (1.338 vs. 1.494, p = 0.031). However, there were no differences of the structural connectivity between CKD patients with and without cognitive impairment. Conclusion: We found lower DTI-ALPS index in patients with CKD, which could be related with glymphatic system dysfunction. Moreover, those with cognitive impairment in the CKD group had a lower index than those without, indicating a link between the glymphatic system function and cognitive function.

Characterizing Protein Concentration in Cerebrospinal Fluid with T2 Component Analysis.

PURPOSE: T2 values are hypothesized to be reduced where protein accumulates in the cerebrospinal fluid (CSF). We aimed to verify the accuracy of Carr-Purcell-Meiboom-Gil (CPMG) pulses and non-negative least squares (NNLS) analysis in visualizing protein concentrations by mapping the T2 values. METHODS: We first dissolved 1.2g of bovine serum albumin powder in 4 mL of artificial CSF to purify an albumin solution with a concentration of 4.5 mM. Artificial CSF was added thereto, and eight types of albumin solutions, with concentrations of 0.002-4.5 mM, were purified. We acquired this albumin solution with CPMG pulses and NNLS, decomposed the T2 values per pixel, and derived 25 T2 component values of 60-2000 ms. We assessed the change of T2 values by the difference in albumin concentration of a single voxel. Finally, we used the method to assess T2 values from two patients, one with a subdural hematoma and one with a suprasellar cystic tumor. T2 component values were plotted graphically, presented individually, and created in color maps. RESULTS: T2 component values for albumin concentrations ranging from 0.056 to 4.55 mM showed different T2 peaks, whereas, for concentrations 0.002 to 0.019 mM, the peaks were similar heights and overlapped. Peak width was similar for all concentrations. The color maps successfully reflected the changes in T2 values across both RGB color patterns. T2 components for albumin samples with 2.5 mM and 6.1 mM concentrations within a single voxel were represented separately and reflected the ratio of the two samples in nine different regions of interest within one slice. In the clinical cases, the T2 component map imaged differences in albumin concentrations, similar to those observed in the albumin samples. CONCLUSION: The present method with CPMG sequences and NNLS provide adequate images to differentiate accumulating protein concentrations in the CSF, even at the level of a single pixel.

Influencing factors of glymphatic system during perioperative period.

The glymphatic system is a functional cerebrospinal fluid circulatory system that uses peri-arterial space for inflow of cerebrospinal fluid and peri-venous space for efflux of cerebrospinal fluid from brain parenchyma. This brain-wide fluid transport pathway facilitates the exchange between cerebrospinal fluid and interstitial fluid and clears metabolic waste from the metabolically active brain. Multiple lines of work show that the glymphatic system is crucial to normal brain functions, and the dysfunction of the glymphatic system is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury. Currently, it is common to explore the functional and molecular mechanisms of the glymphatic system based on animal models. The function of glymphatic system during perioperative period is affected by many factors such as physiological, pathological, anesthetic and operative methods. To provide a reference for the interpretation of the results of glymphatic system studies during perioperative period, this article comprehensively reviews the physiological and pathological factors that interfere with the function of the glymphatic system during perioperative period, investigates the effects of anesthetic drugs on glymphatic system function and the potential underlying mechanisms, describes operative methods that interfere with the function of the glymphatic system, and potential intervention strategies based on the glymphatic system. Future, these variables should be taken into account as critical covariates in the design of functional studies on the glymphatic system.

Lifetime history of head injury is associated with reduced perivascular space number in acute mild traumatic brain injury.

Traumatic brain injury impairs function of the glymphatic system, a perivascular network involved in waste clearance. Enlarged perivascular spaces visible on MRI are an emerging biomarker of glymphatic function. This study characterized enlarged perivascular spaces in acute head injury with 7 T MRI. Healthy controls (n = 8) and patients (n = 11) with mild traumatic brain injury underwent MRI within 7 days of injury and were evaluated for lifetime history of head injury, neurobehavioral symptoms and sleep disturbances. MRI-visible perivascular spaces were quantified and assessed according to published criteria. The number of enlarged perivascular spaces was significantly higher in traumatic brain injury patients than controls (P = 0.015). Among healthy controls, 6/8 scored 'none' or 'mild' on the perivascular space rating scale, while 10/11 patients scored 'moderate', 'frequent' or 'severe'. There was an inverse relationship between perivascular space number and number of lifetime head injuries. Patients with more prior head injuries exhibited fewer enlarged perivascular spaces (P = 0.014). These results indicate that mild head injury results in acute alterations in perivascular space number, and this effect is mediated by previous head injury history. Enlarged perivascular spaces may reflect a glymphatic response that is diminished after multiple head injuries, although this will require further study.

Development of capillary dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is currently considered the major cause of cognitive impairment in older adults. This explains the close attention to the issue of AD research. The pathomorphological basis of the disease is a neurodegenerative process, the early stages of which are formed in the hippocampus and the morphofunctionally deep parts of the temporal lobes of the brain closely related to it. Several hypotheses have been advanced concerning the causes of neurodegeneration: the amyloid hypothesis, the calcium homeostasis impairment hypothesis, the inflammatory hypothesis, and the prion hypothesis. However, these hypotheses cannot explain the early stages of the pathogenesis of neurodegenerative diseases, in particular Alzheimer's disease. This health problem requires further comprehensive study of available data, as well as additional investigations to determine the nature of such a process. In this review, the data on microcirculatory disorders in the capillaries of the hippocampus and mediobasal structures of the temporal lobes of the brain, which may be an initiating factor that triggers neurodegenerative events, are analyzed.

Perivascular phosphorylated TDP-43 inclusions are associated with Alzheimer's disease pathology and loss of CD146 and Aquaporin-4.

The majority of patients with Alzheimer's disease (AD) exhibit aggregates of Trans-active response DNA binding protein 43 (TDP-43) in their hippocampus, which is associated with a more aggressive disease progression. The TDP-43 inclusions are commonly found in neurons, but also in astrocytes. The impact of the inclusions in astrocytes is less known. In the current study, we investigate the presence of phosphorylated TDP-43 (pTDP-43) inclusions in astrocytic endfeet and their potential association with blood-brain barrier (BBB) damage, glymphatic system dysfunction, and AD pathology. By staining postmortem hippocampal sections from AD patients and non-demented controls against TDP-43 and pTDP-43 together with the astrocytic markers glial fibrillary acidic protein (GFAP), astrocytic endfeet marker Aquaporin-4 (AQP4), and markers for BBB alterations (CD146) and leakiness (Immunoglobulin A), we demonstrate a close association between perivascular pTDP-43 or TDP-43 inclusions and GFAP or AQP4. These perivascular inclusions were more prominent in AD and correlated with the disease severity and loss of CD146 and AQP4. The findings indicate a relationship between pTDP-43 accumulation in astrocytic endfeet and BBB and glymphatic system dysfunction, which may contribute to the downstream pathological events seen in AD patients and the aggressive disease progression.