[Glymphatic dysfunction and sleep disorders: indirect effects on Alzheimer's disease]. / Glimfaticheskaya disfunktsiya i narusheniya sna: oposredovannoe vliyanie na bolezn' Al'tsgeimera.

Modern research raises the question of the potentially significant role of glymphatic dysfunction in the development of neurodegeneration and pathological aging. The exact molecular mechanisms are not yet fully understood, but there is ample evidence of a link between sleep deprivation and decreased clearance of ß-amyloid and other neurotoxin proteins that are associated with the development of neurodegenerative diseases, particularly Alzheimer's disease. The review analyzes current scientific information in this area of research, describes the latest scientific discoveries of the features of the glymphatic system, and also illustrates studies of markers that presumably indicate a deterioration in the glymphatic system. The relationship between sleep deprivation and pathophysiological mechanisms associated with neurodegenerative diseases is considered, and potential targets that can be used to treat or delay the development of these disorders are noted.

Spaceflight-associated neuro-ocular syndrome: potential etiologies and connections to the glymphatic system.

The etiology of spaceflight-associated neuro-ocular syndrome (SANS) is a developing field of research, with many current hypotheses receiving varying degrees of support. This syndrome affects ∼70% of astronauts both during and after long-duration space missions, resulting in impaired near vision and visual scotomas (blind spots). In this article, three prominent risk factors for SANS including zero gravity conditions, extraterrestrial hypercapnic environments, and individual genetic predisposition are described. These risk factors are then compared and their pathophysiological pathways are divided into five current hypotheses for the development of SANS. Finally, glymphatic system impairment is explored as a potential mutual end point for these pathways in the development of SANS.

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes.

Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Cerebrospinal fluid egress to human parasagittal dura and the impact of sleep deprivation.

Emerging evidence suggests that the glymphatic system and meningeal lymphatic vessels are instrumental for clearance of toxic metabolites from the brain. Animal and human studies suggest that glymphatic circulation is up-regulated during sleep. Meningeal lymphatic clearance may be more efficient in the wake state, as shown in rodents. We have previously shown clearance of cerebrospinal fluid directly from the subarachnoid space to the parasagittal dura, which harbors meningeal lymphatic vessels. Hence, assessing molecular clearance from parasagittal dura provides an opportunity to decipher the role of sleep/sleep deprivation in human lymphatic clearance function. In this study, we applied magnetic resonance imaging to explore whether sleep deprivation modifies molecular clearance from human parasagittal dura, utilizing an intrathecal magnetic resonance imaging contrast agent as tracer. We hypothesized that tracer enhancement in parasagittal dura would differ after sleep deprivation. One group of individuals (n = 7) underwent one night's total sleep deprivation while a control group (n = 9) was allowed unrestricted sleep. There were no sleep restrictions after the 24-hour time point. After one night of sleep deprivation (at 24 h), we found neither evidence for altered tracer enrichment in the parasagittal dura, nor after a day of unrestricted sleep (at 48 h). The hypothesis of altered molecular egress to parasagittal dura after sleep deprivation was not supported by our data. Further studies are required to determine the role of sleep for molecular clearance from cerebrospinal fluid to meningeal lymphatic vessels in humans.

Diffusion along perivascular spaces reveals evidence supportive of glymphatic function impairment in Parkinson disease.

BACKGROUND: Reduced diffusion along perivascular spaces in adults with Alzheimer's-disease-related-dementias has been reported and attributed to reduced glymphatic function. OBJECTIVES: To apply quantitative measures of diffusion along, and orthogonal to, perivascular spaces in a cohort of older adults with and without clinical symptoms of alpha-synuclein related neurodegeneration. METHODS: 181 adults with Parkinson disease (PD) or essential tremor (ET) additionally sub-classified by the presence of cognitive impairment underwent 3 T MRI. Diffusion-tensor-imaging (spatial resolution = 2x2x2 mm; b-value = 1000 s/mm2; directions = 33) measures of diffusion (mm2/s) parallel and orthogonal to perivascular spaces at the level of the medullary veins, and the ratio of these measures (ALPS-index), were calculated. Regions were identified by a board-certified neuroradiologist from T1-weighted and T2-weighted MRI. Evaluations of motor impairment and mild cognitive impairment (MCI) were interpreted by a board-certified neurologist and neuropsychologist, respectively. Multiple regression with false discovery rate correction was applied to understand how diffusion metrics related to (i) disease category (PD vs. ET), (ii) cognition (MCI status), and (iii) white matter disease severity from the Fazekas score. RESULTS: The ALPS-index was reduced in PD compared to ET participants (p = 0.037). No association between the ALPS-index and MCI status, but an inverse association between the ALPS-index and Fazekas score (p = 0.002), was observed. The ALPS-index was inversely associated with age (p = 0.007). CONCLUSION: Diffusion aberrations near perivascular spaces are evident in patients with alpha-synuclein related neurodegenerative disorders, and are related to age and white matter disease severity.

The Glymphatic System (En)during Inflammation.

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

Choroid plexus perfusion in sickle cell disease and moyamoya vasculopathy: Implications for glymphatic flow.

Cerebrospinal fluid (CSF) and interstitial fluid exchange have been shown to increase following pharmacologically-manipulated increases in cerebral arterial pulsatility, consistent with arterial pulsatility improving CSF circulation along perivascular glymphatic pathways. The choroid plexus (CP) complexes produce CSF, and CP activity may provide a centralized indicator of perivascular flow. We tested the primary hypothesis that elevated cortical cerebral blood volume and flow, present in sickle cell disease (SCD), is associated with fractionally-reduced CP perfusion relative to healthy adults, and the supplementary hypothesis that reduced arterial patency, present in moyamoya vasculopathy, is associated with elevated fractional CP perfusion relative to healthy adults. Participants (n = 75) provided informed consent and were scanned using a 3-Tesla arterial-spin-labeling MRI sequence for CP and cerebral gray matter (GM) perfusion quantification. ANOVA was used to calculate differences in CP-to-GM perfusion ratios between groups, and regression analyses applied to evaluate the dependence of the CP-to-GM perfusion ratio on group after co-varying for age and sex. ANOVA yielded significant (p < 0.001) group differences, with CP-to-GM perfusion ratios increasing between SCD (ratio = 0.93 ± 0.28), healthy (ratio = 1.04 ± 0.32), and moyamoya (ratio = 1.29 ± 0.32) participants, which was also consistent with regression analyses. Findings are consistent with CP perfusion being inversely associated with cortical perfusion.

Influence of Virchow-Robin spaces on the electric field distribution in subthalamic nucleus deep brain stimulation.

Patient MRI from DBS implantations in the subthalamic nucleus (STN) were reviewed and it was found that around 10% had Virchow-Robin spaces (VRS). Patient-specific models were developed to evaluate changes in the electric field (EF) around DBS leads. The patients (n = 7) were implanted bilaterally either with the standard voltage-controlled lead 3389 or with the directional current-controlled lead 6180. The EF distribution was evaluated by comparing simulations using patient-specific models with homogeneous models without VRS. The EF, depicted with an isocontour of 0.2 V/mm, showed a deformation in the presence of the VRS around the DBS lead. For patient-specific models, the radial extension of the EF isocontours was enlarged regardless of the operating mode or the DBS lead used. The location of the VRS in relation to the active contact and the stimulation amplitude, determined the changes in the shape and extension of the EF. It is concluded that it is important to take the patients' brain anatomy into account as the high conductivity in VRS will alter the electric field if close to the DBS lead. This can be a cause of unexpected side effects.

Dilated perivascular space is related to reduced free-water in surrounding white matter among healthy adults and elderlies but not in patients with severe cerebral small vessel disease.

Perivascular space facilitates cerebral interstitial water clearance. However, it is unclear how dilated perivascular space (dPVS) affects the interstitial water of surrounding white matter. We aimed to determine the presence and extent of changes in normal-appearing white matter water components around dPVS in different populations. Twenty healthy elderly subjects and 15 elderly subjects with severe cerebral small vessel disease (CSVD, with lacunar infarction 6 months before the scan) were included in our study. And other 28 healthy adult subjects were enrolled under a different scanning parameter to see if the results are comparable. The normal-appearing white matter around dPVS was categorized into 10 layers (1 mm thickness each) based on their distance to dPVS. We evaluated the mean isotropic-diffusing water volume fraction in each layer. We discovered a significantly reduced free-water content in the layers closely adjacent to the dPVS in the healthy elderlies. however, this reduction around dPVS was weaker in the CSVD subjects. We also discovered an elevated free-water content within dPVS. DPVS played different roles in healthy subjects or CSVD subjects. The reduced water content around dPVS in healthy subjects suggests these MR-visible PVSs are not always related to the stagnation of fluid.

Deep white matter hyperintensity is associated with the dilation of perivascular space.

Understanding the pathophysiology of white matter hyperintensity (WMH) is necessary to reduce its harmfulness. Dilated perivascular space (PVS) had been found related to WMH. In the present study, we aimed to examine the topological connections between WMH and PVS, and to investigate whether increased interstitial fluid mediates the correlation between PVS and WMH volumes. One hundred and thirty-six healthy elder subjects were retrospectively included from a prospectively collected community cohort. Sub-millimeter T2 weighted and FLAIR images were acquired for assessing the association between PVS and WMH. Diffusion tensor imaging and free-water (FW) analytical methods were used to quantify white matter free water content, and to explore whether it mediates the PVS-WMH association. We found that most (89%) of the deep WMH lesions were spatially connected with PVS, exhibiting several interesting topological types. PVS and WMH volumes were also significantly correlated (r = 0.222, p < 0.001). FW mediated this association in the whole sample (ß = 0.069, p = 0.037) and in subjects with relatively high WMH load (ß = 0.118, p = 0.006). These findings suggest a tight association between PVS dilation and WMH formation, which might be linked by the impaired glymphatic drainage function and accumulated local interstitial fluid.

Cardiovascular brain impulses in Alzheimer's disease.

Accumulation of amyloid-ß is a key neuropathological feature in brain of Alzheimer's disease patients. Alterations in cerebral haemodynamics, such as arterial impulse propagation driving the (peri)vascular CSF flux, predict future Alzheimer's disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10 Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer's disease. The arrival latency and propagation speed both differed in patients with Alzheimer's disease. Our mapping of arterial territories revealed Alzheimer's disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular CSF impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-ß in Alzheimer's disease.

Glymphatic pathways in the gyrencephalic brain.

Identification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that these folds enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed a PVS influx density 4-fold larger in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.

Espacios de Virchow-Robin mesencefálicos y parkinsonismo: caso clínico y revisión de la literatura / Midbrain Virchow-Robin spaces and Parkinsonism: a case report and literature review

No disponible

Perivascular abnormalities in pediatric encephalopathy with fulminant brain edema.

BACKGROUND: Acute encephalopathy with acute brain swelling (ABS) is a recently proposed disease of unknown etiology, characterized by rapid progression to whole-brain swelling. To our knowledge, we reported the first case of a patient with acute encephalopathy with ABS wherein brain magnetic resonance imaging (MRI) abnormalities were noted prior to the diffuse brain swelling onset. CASE PRESENTATION: An 11-year-old boy was admitted to our unit owing to prolonged disturbance of consciousness following febrile status epilepticus. At the initial visit, the vital signs were within the normal range, except for the body temperature and consciousness level (Glasgow Coma Scale 6; E1V1M4). The initial laboratory results showed elevated inflammatory marker levels and mild hyponatremia. Cerebrospinal fluid analysis revealed albuminocytologic dissociation, whereas the myelin basic protein level was not elevated. Electroencephalography showed diffuse, high-amplitude slow waves. No abnormalities were detected on the initial brain computed tomography (CT) scan. However, at 11 h after the seizure onset, diffuse hyperintense lesions were observed throughout the cerebrum on T2-weighted brain MRI. The patient was diagnosed with acute encephalopathy and received methylprednisolone-pulse therapy (1 g) with high-dose gamma globulin (1 g/kg) administration. At 14 h after the seizure onset, the patient was declared brain-dead; the brain CT findings revealed whole-brain swelling and herniation. CONCLUSION: Our findings were suggestive of a perivascular pathophysiology and may be used for subtyping acute encephalopathy. In cases where such findings are observed, subsequent development of severe diffuse brain swelling should be considered.

Achieving brain clearance and preventing neurodegenerative diseases-A glymphatic perspective.

Age-related neurodegenerative diseases are a growing burden to society, and many are sporadic, meaning that the environment, diet and lifestyle play significant roles. Cerebrospinal fluid (CSF)-mediated clearing of brain waste products via perivascular pathways, named the glymphatic system, is receiving increasing interest, as it offers unexplored perspectives on understanding neurodegenerative diseases. The glymphatic system is involved in clearance of metabolic by-products such as amyloid-ß from the brain, and its function is believed to lower the risk of developing some of the most common neurodegenerative diseases. Here, we present magnetic resonance imaging (MRI) data on the heart cycle's control of CSF flow in humans which corroborates findings from animal studies. We also review the importance of sleep, diet, vascular health for glymphatic clearance and find that these factors are also known players in brain longevity.

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

Putting 'CSF-Shift Edema' Hypothesis to Test: Comparing Cisternal and Parenchymal Pressures After Basal Cisternostomy for Head Injury.

BACKGROUND: Increased brain edema in head injury is due to shift of cerebrospinal fluid (CSF) from cisterns at high pressure to brain parenchyma at low pressure. By opening basal cisterns and decreasing the increased cisternal pressure, basal cisternostomy (BC) results in reversal of CSF shift from parenchyma to cisterns, leading to decreased brain edema. Though the CSF-shift edema hypothesis is based on pressure difference between cisterns and brain parenchyma, the relationship of these pressures has not been studied. METHODS: A prospective clinical study was conducted from November 2018 to March 2020 including adult patients with head injury who were candidates for standard decompressive hemicraniectomy (DHC). All patients had neurological assessment and head computed tomography preoperatively and postoperatively. All patients underwent BC with DHC. Postoperatively, parenchymal and cisternal pressures and neurological condition were monitored hourly for 72 hours. RESULTS: Nine (5 men, 4 women) patients with head injury (mean age, 45.7 years; range, 25-72 years) underwent DHC-BC. Median Glasgow Coma Scale score of patients at admission was 8 (range, 4-14), and median midline shift on computed tomography was 8 mm (range, 7-12 mm). There was a significant difference between opening (25.70 ± 10.48 mm Hg) and closing (11.30 ± 5.95 mm Hg) parenchymal pressures (t9 = 3.963, P = 0.003). Immediate postoperative cisternal pressure was 1-11 mm Hg and was lower than immediate postoperative parenchymal pressure in all except 1 patient. Postoperatively, if cisternal pressure remained low, parenchymal pressure also decreased, and patients showed clinical improvement. Patients showing increased cisternal pressure showed increased parenchymal pressure and clinical worsening. CONCLUSIONS: Our study supports the CSF-shift edema hypothesis. Following DHC-BC, cisternal pressure is lowered to near-atmospheric pressure, and its relationship to parenchymal pressure predicts the future course of patients by reversal or re-reversal of CSF shift.

The Pathogenesis Based on the Glymphatic System, Diagnosis, and Treatment of Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a rare neurological disorder with no clear prevalence factors and is a significant danger to the elderly. The intracranial glymphatic system is the internal environment that maintains brain survival and metabolism, and thus fluid exchange changes in the glymphatic system under various pathological conditions can provide important insights into the pathogenesis and differential diagnosis of many neurodegenerative diseases such as iNPH. iNPH can be diagnosed using a combination of clinical symptoms, imaging findings and history, and cerebrospinal fluid biomarkers due to the glymphatic system disorder. However, only few researchers have linked the two. Shunt surgery can improve the glymphatic system disorders in iNPH patients, and the surgical approach is determined using a combination of clinical diagnosis and trials. Therefore, we have composed this review to provide a future opportunity for elucidating the pathogenesis of iNPH based on the glymphatic system, and link the glymphatic system to the diagnosis and treatment of iNPH. The review will provide new insights into the medical research of iNPH.

D-Glucose uptake and clearance in the tauopathy Alzheimer's disease mouse brain detected by on-resonance variable delay multiple pulse MRI.

In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer's disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%, p = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min-1) compared to their wild-type counterpart (0.56 ± 0.1 min-1, p < 0.001), which suggests the presence of an impaired glucose transporter on both blood-brain and blood-CSF barriers of these AD mice. Clearance of D-glucose was observed in the CSF of wild-type mice but not AD mice, which suggests dysfunction of the glymphatic system in the AD mice. The results in this study indicate that onVDMP MRI could be a cost-effective and widely available method for simultaneously evaluating glucose transporter and glymphatic function of AD. This study also suggests that tau protein affects the D-glucose uptake and glymphatic impairment in AD at a time point preceding neurofibrillary tangle pathology.