[Assessment of the significance of dilated perivascular spaces and nocture arterial hypertension in the development of Alzheimer's disease]. / Otsenka znacheniya rasshirennykh perivaskulyarnykh prostranstv i nochnoi arterial'noi gipertenzii v razvitii bolezni Al'tsgeimera.

OBJECTIVE: To study the severity and localization of dilated perivascular spaces (DPVS), the levels of protein markers of amyloidosis and neurodegeneration in the cerebrospinal fluid (CSF) at different daily blood pressure (BP) profiles in patients with Alzheimer's disease (AD) and other types of cognitive impairment. MATERIAL AND METHODS: A total of 119 people, aged 53 to 92 years, including 55 patients with AD, 27 patients with vascular cognitive disorders (VCD), 19 patients with frontotemporal degeneration (FTD). All patients underwent BP monitoring for 24 hours using a standard oscillometric measurement method, lumbar puncture to assess Aß-42 and Aß-40 amyloid protein, total and phosphorylated tau protein in the CSF, magnetic resonance imaging tomography of the brain with subsequent assessment of the severity of expansion and localization of DPVS according to the G.M. Potter scale. RESULTS: In 58.3% of patients with AD, there is no adequate reduction in BP at night in comparison with patients with VCD (p<0.05). A significant degree of expansion of the DPVS turned out to be most typical for patients with AD: grade 3 was detected in 45.7% of patients, and the maximum, grade 4, was detected in 13.4%. At the same time, DPVSs were significantly more often detected in the group of subjects with insufficient reduction in diastolic BP (DBP) at night. A strong inverse correlation was established between the level of Aß-42 in the CSF and the variability of DBP at night (r= -0.92; p<0.05). The decrease in the level of Aß-42 in AD, especially at the prodromal stage, is directly related to the low variability of DBP at night, which is more characteristic of an insufficient decrease or increase in BP during night sleep. CONCLUSION: Patients with AD were characterized by an insufficient decrease in BP at night, which is associated with the severity and degree of maximum expansion of the DPVS. A decrease in the level of Aß-42 amyloid protein in the CSF strongly correlates with the variability of DBP at night.

Choroid plexus calcifications are not associated with putative markers of glymphatic dysfunction: A population study in middle-aged and older adults.

BACKGROUND AND PURPOSE: Recent studies have suggested an association between dysfunction of the choroid plexus and the glymphatic system. However, information is inconclusive. Following a population-based study design, we aimed to assess the association between choroid plexus calcifications (CPCs)-as a surrogate of choroid plexus dysfunction-and severity and progression of putative markers of glymphatic dysfunction, including white matter hyperintensities (WMH) of presumed vascular origin and abnormally enlarged basal ganglia perivascular spaces (BG-PVS). METHODS: This study recruited community-dwellers aged ≥40 years living in neighboring Ecuadorian villages. Participants who had baseline head CTs and brain MRIs were included in cross-sectional analyses and those who additional had follow-up MRIs (after a mean of 6.4 ± 1.5 years) were included in longitudinal analyses. Logistic and Poisson regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess associations between CPCs and WMH and enlarged BG-PVS severity and progression. RESULTS: A total of 590 individuals were included in the cross-sectional component of the study, and 215 in the longitudinal component. At baseline, 25% of participants had moderate-to-severe WMH and 27% had abnormally enlarged BG-PVS. At follow-up, 36% and 20% of participants had WMH and enlarged BG-PVS progression, respectively. Logistic regression models showed no significant differences between CPCs volumes stratified in quartiles and severity of WMH and enlarged BG-PVS. Poisson regression models showed no association between the exposure and WMH and enlarged BG-PVS progression. Baseline age remained significant in these models. CONCLUSIONS: Choroid plexus calcifications are not associated with putative markers of glymphatic system dysfunction.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Neonatal stress disrupts the glymphatic system development and increases the susceptibility to Parkinson's disease in later life.

INTRODUCTION: Neonatal stress disrupts brain development and increases the risk of neurological disorders later in life. However, the impact of neonatal stress on the development of the glymphatic system and susceptibility to Parkinson's disease (PD) remains largely unknown. METHODS: Neonatal maternal deprivation (NMD) was performed on mice for 14 consecutive days to model chronic neonatal stress. Adeno-associated virus expressing A53T-α-synuclein (α-syn) was injected into the substantia nigra to establish PD model mice. Glymphatic activity was determined using in vivo magnetic resonance imaging, ex vivo fluorescence imaging and microplate assay. The transcription and expression of aquaporin-4 (AQP4) and other molecules were evaluated by qPCR, western blotting, and immunofluorescence. Animal's responses to NMD and α-syn overexpression were observed using behavioral tests. RESULTS: Glymphatic activity was impaired in adult NMD mice. AQP4 polarization and platelet-derived growth factor B (PDGF-B) signaling were reduced in the frontal cortex and hippocampus of both young and adult NMD mice. Furthermore, exogenous α-syn accumulation was increased and PD-like symptoms were aggravated in adult NMD mice. CONCLUSION: The results demonstrated that NMD could disrupt the development of the glymphatic system through PDGF-B signaling and increase the risk of PD later in life, indicating that alleviating neonatal stress could be beneficial in protecting the glymphatic system and reducing susceptibility to neurodegeneration.

Diffusion-Weighted Imaging Reveals Impaired Glymphatic Clearance in Idiopathic Intracranial Hypertension.

BACKGROUND AND PURPOSE: The pathophysiology underlying idiopathic intracranial hypertension (IIH) remains incompletely understood. While one theory postulates impaired cerebral glymphatic clearance in IIH, there is a paucity of methods to quantify glymphatic activity in human brains. The purpose of this study was to use advanced diffusion-weighed imaging to evaluate the glymphatic clearance of IIH patients and how it may relate to clinical severity. MATERIALS AND METHODS: DWI was used to separately evaluate the diffusivity along the cerebral perivascular spaces and lateral association and projection fibers, with the degree of diffusivity used as a surrogate for glymphatic function (diffusion tensor image analysis along the perivascular space. Patients with IIH were compared with normal controls. Glymphatic clearance was correlated with several clinical metrics, including lumbar puncture opening pressure and Frisen papilledema grade (low grade: 0-2; high grade: 3-5). RESULTS: In total, 99 patients with IIH were identified and compared with 6 healthy controls. Overall, patients with IIH had significantly lower glymphatic clearance based on DWI-derived diffusivity compared with controls (P = .005). Additionally, in patients with IIH, there was a significant association between declining glymphatic clearance and increasing Frisen papilledema grade (P = .046) but no correlation between opening pressure and glymphatic clearance (P = .27). Furthermore, healthy controls had significantly higher glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .015) and high-grade papilledema (P = .002). Lastly, patients with IIH and high-grade papilledema had lower glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .005). CONCLUSIONS: Patients with IIH possess impaired glymphatic clearance, which is directly related to the extent of clinical severity. The DWI-derived parameters can be used for clinical diagnosis or to assess response to treatment.

The glymphatic system for neurosurgeons: a scoping review.

The discovery of the glymphatic system has revolutionized our understanding of cerebrospinal fluid (CSF) circulation and interstitial waste clearance in the brain. This scoping review aims to synthesize the current literature on the glymphatic system's role in neurosurgical conditions and its potential as a therapeutic target. We conducted a comprehensive search in PubMed and Scopus databases for studies published between January 1, 2012, and October 31, 2023. Studies were selected based on their relevance to neurosurgical conditions and glymphatic function, with both animal and human studies included. Data extraction focused on the methods for quantifying glymphatic function and the main results. A total of 67 articles were included, covering conditions such as idiopathic normal pressure hydrocephalus (iNPH), idiopathic intracranial hypertension (IIH), subarachnoid hemorrhage (SAH), stroke, intracranial tumors, and traumatic brain injury (TBI). Significant glymphatic dysregulation was noted in iNPH and IIH, with evidence of impaired CSF dynamics and delayed clearance. SAH studies indicated glymphatic dysfunction with the potential therapeutic effects of nimodipine and tissue plasminogen activator. In stroke, alterations in glymphatic activity correlated with the extent of edema and neurological recovery. TBI studies highlighted the role of the glymphatic system in post-injury cognitive outcomes. Results indicate that the regulation of aquaporin-4 (AQP4) channels is a critical target for therapeutic intervention. The glymphatic system plays a critical role in the pathophysiology of various neurosurgical conditions, influencing brain edema and CSF dynamics. Targeting the regulation of AQP4 channels presents as a significant therapeutic strategy. Although promising, the translation of these findings into clinical practice requires further human studies. Future research should focus on establishing non-invasive biomarkers for glymphatic function and exploring the long-term effects of glymphatic dysfunction.

Impaired glymphatic system revealed by DTI-ALPS in cerebral palsy due to periventricular leukomalacia: relation with brain lesion burden and hand dysfunction.

PURPOSE: Preterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL. METHODS: We retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP. RESULTS: There were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c' = 0.061, P = 0.665), explaining 80% of the effect. CONCLUSION: This study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.

Imaging glymphatic response to glioblastoma.

BACKGROUND: The glymphatic system actively exchanges cerebrospinal fluid (CSF) and interstitial fluid (ISF) to eliminate toxic interstitial waste solutes from the brain parenchyma. Impairment of the glymphatic system has been linked to several neurological conditions. Glioblastoma, also known as Glioblastoma multiforme (GBM) is a highly aggressive form of malignant brain cancer within the glioma category. However, the impact of GBM on the functioning of the glymphatic system has not been investigated. Using dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) and advanced kinetic modeling, we examined the changes in the glymphatic system in rats with GBM. METHODS: Dynamic 3D contrast-enhanced T1-weighted imaging (T1WI) with intra-cisterna magna (ICM) infusion of paramagnetic Gd-DTPA contrast agent was used for MRI glymphatic measurements in both GBM-induced and control rats. Glymphatic flow in the whole brain and the olfactory bulb was analyzed using model-derived parameters of arrival time, infusion rate, clearance rate, and residual that describe the dynamics of CSF tracer over time. RESULTS: 3D dynamic T1WI data identified reduced glymphatic influx and clearance, indicating an impaired glymphatic system due to GBM. Kinetic modeling and quantitative analyses consistently indicated significantly reduced infusion rate, clearance rate, and increased residual of CSF tracer in GBM rats compared to control rats, suggesting restricted glymphatic flow in the brain with GBM. In addition, our results identified compromised perineural pathway along the optic nerves in GBM rats. CONCLUSIONS: Our study demonstrates the presence of GBM-impaired glymphatic response in the rat brain and impaired perineural pathway along the optic nerves. Reduced glymphatic waste clearance may lead to the accumulation of toxic waste solutes and pro-inflammatory signaling molecules which may affect the progression of the GBM.

Decreased DTI-ALPS and choroid plexus enlargement in fibromyalgia: a preliminary multimodal MRI study.

PURPOSE: The glymphatic system is a fluid exchange pathway that clears waste products that is crucial for the maintenance of brain homeostasis. However, the exact role it plays in the emergence of fibromyalgia (FM) is still not fully understood. Here, we explored the changes in non-invasive MRI proxy probably related to the glymphatic function in FM patients, and explored brain-behavior relationships. METHODS: A total of 40 participants, consisting of 20 individuals with FM and 20 healthy controls (HCs), were included in the study. The participants underwent structural T1-weighted MRI, diffusion tensor imaging (DTI), and clinical assessment. The data was obtained from an open access dataset. The study compared non-invasive MRI indices, including choroid plexus (CP) volume and DTI analysis along the perivascular space (ALPS), between the FM and HC groups. Furthermore, correlation analysis was conducted to determine the correlation between clinical parameters and both CP volume and DTI-ALPS index. RESULTS: Patients with FM had significantly higher CP volume and a lower DTI-ALPS index than HCs adjusting for age and intracranial volume. Higher CP volume was associated with lower DTI-ALPS index, and longer disease duration. CONCLUSION: Our findings demonstrate aberrant glymphatic function in FM, and that dysfunction in the brain glymphatic system may play a role in the neural mechanisms underlying FM.

[Perifocal edema and glymphatic system dysfunction: quantitative assessment based on diffusion tensor magnetic resonance imaging]. / Peritumoroznyi otek i disfunktsiya glimfaticheskoi sistemy golovnogo mozga: kolichestvennaya otsenka na osnove diffuzionno-tenzornoi MRT.

BACKGROUND: Pathogenesis of peritumoral cerebral edema is unclear and potentially associated with glymphatic system dysfunction. Diffusion tensor MRI (DT-MRI) with analysis of ALPS (Analysis along the Perivascular Space) index may be valuable for assessment of edema. This approach visualizes fluid flow along perivascular spaces of deep cerebral veins. OBJECTIVE: To assess glymphatic system function in supratentorial tumors and healthy volunteers using DT-MRI. MATERIAL AND METHODS: There were 52 patients (59% men) aged 43 (28-64) years with supratentorial tumors (meningioma - 20, grade 3-4 glioma - 15, metastases - 9, lymphoma - 8). Tumors and perifocal edema did not involve deep cerebral veins. The control group included 6 healthy volunteers aged 34-66 years. MRI protocol (Signa HDxt, 3 T) contained standard T1, T2, T2FLAIR, DWI and post-contrast T1 (3D BRAVO). DT-MRI had the following parameters: TR=10 000 ms, TEmin=102 ms, FOV=240 mm, isotropic voxel size 3×3×3 mm3, 60 directions of diffusion gradients. Measurements were carried out at b-factor 0 and 1000 s/mm2. Analysis was carried out in the ReadyView software. RESULTS: Right- and left-sided ALPS indices were similar in the control group (p=0.917). Perifocal edema (regardless of histological type of tumor) in the ipsilateral hemisphere was accompanied by significantly lower ALPS index (p<0.005), while these values in contralateral (intact) hemisphere were similar in both groups (p=0.7). CONCLUSION: We found significantly lower ALPS index in deep parts of the affected hemisphere in patients with perifocal edema. These data can indicate the role of glymphatic system dysfunction in pathogenesis of this pathology.

Vascular risk factors and astrocytic marker for the glymphatic system activity.

OBJECTIVES: Glymphatic system maintains brain fluid circulation via active transportation of astrocytic aquaporin-4 in perivascular space. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an established method measuring perivascular glymphatic activity, but comprehensive investigations into its influential factors are lacking. METHODS: Community-dwelling older adults underwent brain MRI scans, neuropsychiatric, and multi-domain assessments. Blood biomarker tests included glial fibrillary acidic protein (GFAP) for astrocyte injury. RESULTS: In 71 enrolled participants, the DTI-ALPS index was associated with modifiable factors, including lipid profile (high-density lipoprotein, r = 0.396; very-low-density lipoprotein, r = - 0.342), glucose intolerance (diabetes mellitus, standardized mean difference (SMD) = 0.7662; glycated hemoglobin, r = - 0.324), obesity (body mass index, r = - 0.295; waist, r = - 0.455), metabolic syndrome (SMD = - 0.6068), cigarette-smoking (SMD = - 0.6292), and renal clearance (creatinine, r = - 0.387; blood urea nitrogen, r = - 0.303). Unmodifiable associative factors of DTI-ALPS were age (r = - 0.434) and sex (SMD = 1.0769) (all p < 0.05). A correlation of DTI-ALPS and blood GFAP was noticed (r = - 0.201, one-tailed t-test for the assumption that astrocytic injury impaired glymphatic activity, p = 0.046). Their cognitive correlations diverged, domain-specific for DTI-ALPS (Facial Memory Test, r = 0.272, p = 0.022) but global cognition-related for blood GFAP (MoCA, r = - 0.264, p = 0.026; ADAS-cog, r = 0.304, p = 0.010). CONCLUSION: This correlation analysis revealed multiple modifiable and unmodifiable association factors to the glymphatic image marker. The DTI-ALPS index correlated with various metabolic factors that are known to increase the risk of vascular diseases such as atherosclerosis. Furthermore, the DTI-ALPS index was associated with renal indices, and this connection might be a link of water regulation between the two systems. In addition, the astrocytic biomarker, plasma GFAP, might be a potential marker of the glymphatic system; however, more research is needed to confirm its effectiveness.

Sistema glinfático: aspectos anatómicos, fisiológicos e implicaciones clínicas / Glymphatic system: Anatomo-physiological principles and their clinical implications

Introducción: El sistema glinfático comprende el conjunto de rutas perivasculares tanto arteriales como venosas que se encuentran en estrecha asociación con células astrogliales y que permiten la interacción entre el líquido cefalorraquídeo (LCR) y el líquido intersticial cerebral (LIC), para llevar a cabo procesos como la depuración de los metabolitos de desecho celular, o la distribución de nutrientes, así como contribuir al metabolismo cerebral local, la transmisión de volumen y la señalización paracrina cerebral. Contenidos: Este artículo busca profundizar en los conceptos anatómicos y fisiológicos, hasta el momento descritos, sobre este sistema macroscópico de transporte. Se realiza una búsqueda bibliográfica de revisiones y estudios experimentales sobre la anatomía, la fisiología y las implicaciones fisiopatológicas del sistema glinfático. Conclusiones: La identificación anatómica y funcional del sistema glinfático ha ampliado el conocimiento sobre la regulación del metabolismo cerebral en cuanto a distribución de nutrientes y cascadas de señalización celular. Al establecer una interacción entre el espacio subaracnoideo subyacente y el espacio intersticial cerebral, el sistema glinfático surge como uno de los mecanismos protagonistas de la homeostasis cerebral. La disfunción de esta vía hace parte de los mecanismos fisiopatológicos de múltiples trastornos neurológicos, ya sea por la acumulación de macromoléculas, como ocurre en la enfermedad de Alzheimer, o por la reducción del drenaje de sustancias químicas y citocinas proinflamatorias en patologías como la migraña o el trauma craneoencefálico.

Introduction: The glympathic system comprises the set of perivascular routes, arterials or venous, that are found in close relationship with astroglial cells and allow interaction between the cerebrospinal fluid (CSF) and the interstitial brain fluid (ISF), to carry processes like cell-wasting metabolites depuration, nutrients distribution, as well as make a contribution in the local brain metabolism, volumen transmition and brain paracrine signaling. Contents: This article seeks to deepen in the anatomical and physiological concepts, so far described, about this macroscopic transport system. A bibliographic search of reviews and experimental studies on the anatomy, physiology and pathophysiological implications of the glymphatic system is carried out. Conclusions: Anatomical and functional identification of glympathic system has broaden the knowledge about regulation of brain metabolism on the nutrients distribution and cell signaling cascades. When setting an interaction between the subarachnoid space and the brain interstitial space, the glymphatic system arise as one of the leading mechanisms of brain homeostasis. Disfunction of this pathway makes part of the patophysiological mechanisms of multiple neurological disease, either be by collection of macromolecules as in Alzheimer's disease, or by the reduction of inflammatory cytokines and chemical substances drainage as in migraine or traumatic brain injury (TBI).

Recovery of glymphatic system function in patients with temporal lobe epilepsy after surgery.

OBJECTIVES: To investigate the recovery of human glymphatic system (GS) function in patients with temporal lobe epilepsy (TLE) after successful anterior temporal lobectomy (ATL) using diffusion tensor image analysis along the perivascular space (DTI-ALPS). METHODS: We retrospectively analysed DTI-ALPS index in 13 patients with unilateral TLE before and after ATL, and compared the index with 20 healthy controls (HCs). Two-sample t tests and paired t tests were performed to analyse differences in the DTI-ALPS index between patients and HCs. The Pearson correlation analysis was used to observe the relationship between the disease duration and GS function. RESULTS: The DTI-ALPS index before ATL was significantly lower in the hemisphere ipsilateral to the epileptogenic foci than in the contralateral hemisphere of the patients (p < 0.001, t = - 4.81) and in the ipsilateral hemisphere of the HCs (p = 0.007, t = - 2.90). A significant increase in the DTI-ALPS index was found in the hemisphere ipsilateral to the epileptogenic foci after successful ATL (p = 0.01, t = - 3.01). In addition, the DTI-ALPS index of the lesion side before ATL was significantly correlated with disease duration (p = 0.04, r = - 0.59). CONCLUSIONS: DTI-ALPS may be used as a quantitative biomarker evaluating surgical outcomes and TLE disease duration. DTI-ALPS index may also help localise epileptogenic foci in unilateral TLE. Overall, our study suggests that GS may potentially serve as a new method for the management of TLE and a new direction for investigating the mechanism of epilepsy. KEY POINTS: • DTI-ALPS index may contribute to epileptogenic foci lateralisation in TLE. • DTI-ALPS index is a potential quantitative feature evaluating surgical outcomes and TLE disease duration. • The GS provides a new perspective for the study of TLE.

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method.

BACKGROUND AND OBJECTIVE: Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. MATERIALS AND METHODS: Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16 years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. RESULTS: Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, pFDR-corrected = 0.04) in pediatric ALL. CONCLUSIONS: Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. KEY POINTS: • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, pFDR-corrected = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm.

The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-ß peptide (Aß) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer's disease (AD) defers Aß accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.

Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases.

Emerging evidence suggests that an important function of the sleeping brain is the removal of wastes and toxins from the central nervous system (CNS) due to the activation of the brain waste removal system (BWRS). The meningeal lymphatic vessels (MLVs) are an important part of the BWRS. A decrease in MLV function is associated with Alzheimer's and Parkinson's diseases, intracranial hemorrhages, brain tumors and trauma. Since the BWRS is activated during sleep, a new idea is now being actively discussed in the scientific community: night stimulation of the BWRS might be an innovative and promising strategy for neurorehabilitation medicine. This review highlights new trends in photobiomodulation of the BWRS/MLVs during deep sleep as a breakthrough technology for the effective removal of wastes and unnecessary compounds from the brain in order to increase the neuroprotection of the CNS as well as to prevent or delay various brain diseases.

Neuroimaging findings related to glymphatic system alterations in older adults with metabolic syndrome.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Reduced glymphatic flow has been observed in rat models of type 2 diabetes and hypertension, indicating the role of vascular risk factors in the glymphatic system. However, little is known about how vascular risk factors affect the human glymphatic system. The present study aims to assess the relationships between metabolic syndrome (MetS), a cluster of vascular risk factors, and the glymphatic system function using diffusion magnetic resonance imaging (MRI)-based measures of water diffusivity in the glymphatic compartments, including the brain interstitial space and perivascular spaces around the deep medullary vein. We hypothesized that vascular risk factors are associated with glymphatic dysfunction, leading to cognitive impairment in older adults. METHODS: This cross-sectional study assessed 61 older adults (age range, 65-82 years) who had participated in the Bunkyo Health Study, including 15 healthy controls (mean age, 70.87 ± 4.90 years) and 46 individuals with MetS (mean age, 71.76 ± 4.61 years). Fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. RESULTS: After adjusting for age, sex, years of education, total Fazekas scale, Pittsburgh sleep quality index (PSQI) score, and intracranial volume (ICV), a significantly (P = 0.030; Cohen's d = 1.01) higher FW was observed in individuals with MetS than in the healthy controls. Furthermore, individuals with MetS had a significantly (P = 0.031; Cohen's d = 0.86) lower ALPS index than the healthy controls, with age, sex, years of education, total Fazekas scale, PSQI score, ICV, fractional anisotropy, and mean diffusivity included as confounding factors. Higher FW was significantly associated with lower ALPS index (r = -0.37; P = 0.004). Multiple linear regression (MLR) with backward elimination analyses showed that higher diastolic blood pressure (BP; standardized ß = 0.33, P = 0.005) was independently associated with higher FW, whereas higher fasting plasma glucose levels (standardized ß = -0.63, P = 0.002) or higher Brinkman index of cigarette consumption cumulative amount (standardized ß = -0.27, P = 0.022) were associated with lower ALPS index. The lower ALPS index (standardized ß, 0.28; P = 0.040) was associated with poorer global cognitive performance, which was determined using the Japanese version of the Montreal Cognitive Assessment (MOCA-J) scores. Finally, partial correlation analyses showed a significant correlation between higher FW and lower MOCA-J scores (r = -0.35; P = 0.025) and between higher FW and higher diastolic BP (r = 0.32, P = 0.044). CONCLUSION: The present study shows the changes in diffusion MRI-based measures reflected by the higher FW and lower ALPS index in older adults with MetS, possibly due to the adverse effect of vascular risk factors on the glymphatic system. Our findings also indicate the associations between the diffusion MRI-based measures and elevated diastolic BP, hyperglycemia, smoking habit, and poorer cognitive performance. However, owing to the limitations of this study, the results should be cautiously interpreted.

Extensive widening of Virchow-Robin spaces in the frontal lobe: two case reports and systematic review of the literature.

AIM: To report our experience on giant tumefactive Virchow-Robin spaces (GTVRS) in the frontal lobe and perform a systematic review of previous reports on GTVRS. MATERIALS AND METHODS: This is a retrospective single-center study reporting the clinical manifestations, magnetic resonance (MR) imaging appearance, differential diagnosis, and management of two patients diagnosed with frontal lobe GTVRS at Bahcesehir University School of Medicine Goztepe Hospital in the past 5 years. A systematic literature search was performed in the PubMed and Google Scholar databases, with case selection criteria including Virchow-Robin spaces (VRS) size greater than 1.5 cm, frontal lobe localization, and the presence of MR imaging. The search strategy included only English language keywords. The systematic review was searched between database inception and May 6, 2022. RESULTS: A total of 18 cases were included in the study. Of the 15 cases with known sex, nine were female and six male. The median age was 29.8 with an age range of 4-57. Eleven of the 18 lesions were in the right frontal lobe. The lesions were multilocular in 15 cases and unilocular in three cases. All lesions had signal intensity as cerebrospinal fluid, showed no perifocal edema, and did not enhance. A hyperintensity was noted around the 14 lesions on the FLAIR sequence. Ten lesions showed cortical thinning adjacent to the lesion. No abnormality was detected on DWI, SWI, and MRS. Follow-up imaging was available in ten patients without any interval change. Unnecessary surgical interventions were noted in three cases. CONCLUSIONS: The results of reported cases and the literature review emphasize the role of MR imaging in the diagnosis of frontal lobe GTVRS. Beyond diagnostic consideration, GTVRS may have prognostic value and often indicate a "don't touch lesion" albeit requiring further consideration on a case-to-case basis. Familiarity with this entity improves diagnostic accuracy and, prevents accidental diagnosis of any neoplasm or other diseases.

Dilated Virchow Robin spaces in brainstem.

Virchow Robin spaces are normally found pial-lined perivascular spaces traversing from subarachnoid space to the brain parenchyma. Giant dilated Virchow robin spaces (dVRS) are rare. They do not require any surgical intervention unless they are causing symptoms. Here we report a young boy with an incidentally detected giant dVRS in brainstem which was referred for surgery with an initial impression of glioma. Knowledge about such an entity is important to prevent mismanagement.