Search Results (120)

Neurodegenerative disorders, including Alzheimer’s disease (AD), are a growing problem in aging society. The amyloid cascade hypothesis has recently been questioned, and therapies based on it have not yielded the expected results. However, the role of amyloid-β (Aβ) in AD pathogenesis cannot be rejected. It appears that some of the key players in the pathogenesis of the disease are the soluble amyloid-β oligomers. Soluble amyloid-β oligomers have neurotoxic effects by disrupting intracellular Ca²⁺ homeostasis and impairing mitochondrial function. The glymphatic system is an important pathway for the removal of soluble amyloid forms from the brain. The decline in the activity of this system is observed in aging brains, which is correlated with the occurrence of Alzheimer’s disease, primarily among the elderly population. Therefore, the question arises as to whether the glymphatic system could be another potential target for therapeutic interventions in Alzheimer’s disease. In this regard, it is imperative to pay attention to the factors that contribute to the pathogenesis of Alzheimer’s disease and also impact the glymphatic system, such as sleep, physical activity, alcohol consumption, and supplementation with polyunsaturated fatty acids. The question remains whether the glymphatic system will become the key to treating Alzheimer’s disease. Full article

Although intracranial hypertension (ICH) has traditionally been framed as simply a numerical escalation of intracranial pressure (ICP) and usually dealt with in its clinical form and not in terms of its complex underlying pathophysiology, an emerging body of evidence indicates that ICH is not simply an elevated ICP process but a complex process of molecular dysregulation, glymphatic dysfunction, and neurovascular insufficiency. Our aim in this paper is to provide a complete synthesis of all the new thinking that is occurring in this space, primarily on the intersection of glymphatic dysfunction and cerebral vein physiology. The aspiration is to review how glymphatic dysfunction, largely secondary to aquaporin-4 (AQP4) dysfunction, can lead to delayed cerebrospinal fluid (CSF) clearance and thus the accumulation of extravascular fluid resulting in elevated ICP. A range of other factors such as oxidative stress, endothelin-1, and neuroinflammation seem to significantly impair cerebral autoregulation, making ICH challenging to manage. Combining recent studies, we intend to provide a revised conceptualization of ICH that recognizes the nuance and complexity of ICH that is understated by previous models. We wish to also address novel diagnostics aimed at better capturing the dynamic nature of ICH. Recent advances in non-invasive imaging (i.e., 4D flow MRI and dynamic contrast-enhanced MRI; DCE-MRI) allow for better visualization of dynamic changes to the glymphatic and cerebral blood flow (CBF) system. Finally, wearable ICP monitors and AI-assisted diagnostics will create opportunities for these continuous and real-time assessments, especially in limited resource settings. Our goal is to provide examples of opportunities that exist that might augment early recognition and improve personalized care while ensuring we realize practical challenges and limitations. We also consider what may be therapeutically possible now and in the future. Therapeutic opportunities discussed include CRISPR-based gene editing aimed at restoring AQP4 function, nano-robotics aimed at drug targeting, and bioelectronic devices purposed for ICP modulation. Certainly, these proposals are innovative in nature but will require ethically responsible confirmation of long-term safety and availability, particularly to low- and middle-income countries (LMICs), where the burdens of secondary ICH remain preeminent. Throughout the review, we will be restrained to a balanced pursuit of innovative ideas and ethical considerations to attain global health equity. It is not our intent to provide unequivocal answers, but instead to encourage informed discussions at the intersections of research, clinical practice, and the public health field. We hope this review may stimulate further discussion about ICH and highlight research opportunities to conduct translational research in modern neuroscience with real, approachable, and patient-centered care. Full article

Epidemiological studies identified insufficient and poor-quality sleep as independent risk factors for multiple sclerosis (MS). The glymphatic system, active during slow-wave sleep, clears brain waste through perivascular astrocytic aquaporin-4 (AQP4) channels. The presence of antigens induces a transient, physiological lowering of glymphatic flux as a first step of an inflammatory response. A possible hypothesis linking infection with the Epstein–Barr virus, a well identified causal step in MS, and the development of the disease is that mechanisms such as poor sleep or less functional AQP4 polymorphisms may sustain glymphatic flow reduction. Such chronic glymphatic reduction would trigger a vicious circle in which the persistence of antigens and an inflammatory response maintains glymphatic dysfunction. In addition, viral proteins that persist in demyelinated plaques can depolarize AQP4, further restricting waste elimination and sustaining local inflammation. This review examines the epidemiological evidence connecting sleep and MS risk, and the mechanistic findings showing how poor sleep and other glymphatic modulators heighten inflammatory signaling implicated in MS pathogenesis. Deepening knowledge of glymphatic functioning in MS could open new avenues for personalized prevention and therapy. Full article

Background/Objectives: The glymphatic system plays a crucial role in clearing brain metabolic waste, and its dysfunction has been correlated to various neurological disorders. The Diffusion Tensor Imaging Analysis Along the Perivascular Space (DTI-ALPS) index has been proposed as a non-invasive marker of glymphatic function by measuring diffusivity along perivascular spaces; however, its sensitivity to sleep-related changes in glymphatic activity has not yet been validated. This study aimed to evaluate the feasibility of using the DTI-ALPS index as a quantitative marker of dynamic glymphatic activity during sleep. Methods: Diffusion tensor imaging (DTI) data were obtained from 12 healthy male participants (age = 24.44 ± 2.5 years; Pittsburgh Sleep Quality Index (PSQI) < 5), once while awake and 16 times during sleep, following 24 h sleep deprivation and administration of 10 mg zolpidem. Simultaneous MR-compatible electroencephalography was used to determine whether the subject was asleep or awake. DTI preprocessing included eddy current correction and tensor fitting. The DTI-ALPS index was calculated from nine regions of interest in projection and association areas aligned to standard space. The final analysis included nine participants (age = 24.56 ± 2.74 years; PSQI < 5) who maintained a continuous sleep state for 1 h without awakening. Results: Among nine ROI pairs, three showed significant increases in the DTI-ALPS index during sleep compared to wakefulness (Friedman test; p = 0.027, 0.029, 0.034). These ROIs showed changes at 14, 19, and 25 min after sleep induction, with FDR-corrected p-values of 0.024, 0.018, and 0.018, respectively. Conclusions: This study demonstrated a statistically significant increase in the DTI-ALPS index within 30 min after sleep induction through time-series DTI analysis during wakefulness and sleep, supporting its potential as a biomarker reflecting glymphatic activity. Full article

Cerebral edema is the abnormal accumulation of fluid in any of the tissue compartments of the cerebral parenchyma. It remains a significant challenge in neurotrauma care because it contributes to secondary brain injury, affecting prognosis. This review analyzes the recent literature, including foundational studies, to describe the mechanisms of distinct types of cerebral edema following traumatic brain injury (TBI). Emerging concepts, such as the role of the glymphatic system and heme-derived inflammasomes, offer new insights into new types of edemas, differentiated by pathogenesis and potential treatments. Recent advancements in understanding these molecular mechanisms can improve therapeutic strategies, facilitating a better approach in the era of precision and personalized medicine. Although there has been notable progress, a proposal to customize treatments for diverse types of edemas is necessary to improve outcomes following traumatic brain injury. In this review, we describe the current subtypes of post-traumatic brain edemas and link them to a specific management approach. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

Hydrocephalus is a complex neurological condition marked by abnormal cerebrospinal fluid (CSF) accumulation, often leading to elevated intracranial pressure and structural brain damage. Despite advances in surgical treatment, diagnostic precision and prognosis remain challenging, especially in idiopathic normal pressure hydrocephalus (iNPH). This narrative review aims to synthesize the current knowledge regarding molecular and neuroimaging biomarkers that hold diagnostic, prognostic, and therapeutic significance in hydrocephalus. A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar. The inclusion criteria encompassed peer-reviewed studies involving congenital or acquired hydrocephalus and reporting on mechanistic, diagnostic, or monitoring biomarkers. Both established and emerging biomarkers were included, and preclinical findings were considered when translational relevance was apparent. The review highlights a broad spectrum of molecular markers including aquaporins, vascular endothelial growth factor, neurofilaments, glial fibrillary acidic protein, matrix metalloproteinases, and neuroinflammatory markers. The genetic markers associated with ciliogenesis also show promise in subtyping disease. Parallel to molecular advances, neuroimaging techniques, ranging from classic markers like Evans’ index to advanced modalities such as diffusion tensor imaging (DTI), arterial spin labeling (ASL), and glymphatic MRI, provide functional perspectives on hydrocephalus diagnosis and management, while artificial intelligence may further enhance diagnostic algorithms. Molecular and imaging markers could not only increase diagnostic confidence, but also provide information on disease causes and progression. As research progresses, merging various methodologies may result in more accurate diagnoses. Full article

Background: One of the major contributors to homeostasis at the level of the central nervous system, specifically the brain, is the glymphatic system, which is described as an exchange occurring at the level of and between the interstitial fluid and cerebrospinal fluid that has been linked to neurodegenerative processes. Methods: Fourteen studies were included after PROSPERO registration and a literature search. Screening, reviewing, and data extraction were performed by two reviewers. Quality assessment scales were used. General continuous and subgroup analysis, heterogeneity tests, and random effect models were run using SPSS. Forest plots were constructed based on subgroup analysis. Results: Significant correlations (p < 0.05) were detected between MRI indices and outcomes quantifying neurodegenerative diseases. Studies on Alzheimer’s disease showed a positive correlation between diffusivity indices and cognitive scores. Studies on Parkinson’s disease showed negative correlations between diffusivity indices and disease severity, progression, and motor function (p < 0.05). As for other conditions, the conclusions remain uncertain, yet positive results were detected (p < 0.05). Conclusions: Positive significant correlations were deduced between the ALPS index and cognitive scores, indicating that low cognition is correlated with a low ALPS index and enlarged PVSs. Negative significant correlations were deduced between ALPS indices and UPDRS scores, indicating motor dysfunction is correlated with lower ALPS indices and enlarged PVSs. Finally, MRI parameters may help to deduce disease progression across subgroups. Despite the presence of heterogeneity between studies, significant correlations with moderate to large effect sizes were detected. Glymphatic dysfunction measured through MRI indices is correlated with neurodegenerative changes across various neurological conditions. Full article

Aquaporins (AQPs) are a family of transmembrane water channel proteins facilitating the transport of water and, in some cases, small solutes such as glycerol, lactate, and urea. In the central nervous system (CNS), several aquaporins play crucial roles in maintaining water homeostasis, modulating cerebrospinal fluid (CSF) circulation, regulating energy metabolism, and facilitating neuroprotection under pathological conditions. Among them, AQP2, AQP4, AQP9, and AQP11 have been implicated in traumatic and non-traumatic brain injuries. The most abundant aquaporin (AQP) in the brain, AQP4, is essential for fluid regulation, facilitating water transport across the blood–brain barrier and glymphatic clearance. AQP2 is primarily known for its function in the kidneys, but it is also expressed in brain regions related to vasopressin signaling and CSF dynamics. AQP9 acts as a channel for glycerol and lactate, thus playing a role in metabolic adaptation during brain injury. AQP11, an intracellular aquaporin, is involved in oxidative stress responses and cellular homeostasis, with emerging evidence suggesting its role in neuroprotection. Aquaporins play a dual role in brain injury; while they help maintain homeostasis, their dysregulation can exacerbate cerebral edema, metabolic dysfunction, and inflammation. In traumatic brain injury (TBI), aquaporins regulate the formation and resolution of cerebral edema. In non-traumatic brain injuries, including ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH), and intracerebral hemorrhage (ICH), aquaporins influence fluid balance, energy metabolism, and oxidative stress responses. Understanding the specific roles of AQP2, AQP4, AQP9, and AQP11 in these brain injuries may lead to new therapeutic strategies to mitigate secondary damage and improve neurological outcomes. This review explores the function of the above aquaporins in both traumatic and non-traumatic brain injuries, highlighting their potential and limitations as therapeutic targets for neuroprotection and recovery. Full article

Background/Objectives: Idiopathic normal-pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait disturbance, cognitive impairment, and urinary incontinence. Its pathophysiology involves impaired cerebrospinal fluid (CSF) absorption, and recent research has highlighted the role of the glymphatic and meningeal lymphatic systems in this process. However, the factors that trigger the clinical manifestations of iNPH in subclinical cases remain poorly understood. Case Presentation: Herein, we report two rare cases of iNPH in which clinical symptoms only became apparent following systemic infections. An 82-year-old man presented with transient neurological deficits during a course of sepsis caused by Klebsiella pneumoniae. Neuroimaging revealed periventricular changes and mild ventricular enlargement. Shunting and a tap test led to significant improvements to both his gait and cognition. An 80-year-old man with a history of progressive gait disturbance and cognitive decline developed worsening urinary incontinence and acute cerebral infarction caused by Staphylococcus haemolyticus bacteremia. Magnetic resonance imaging revealed a ventriculomegaly with features of disproportionally enlarged subarachnoid space hydrocephalus and a corona radiata infarct. Clinical improvement was achieved after a ventriculoperitoneal shunt was placed. Conclusions: Our two present cases suggest that systemic inflammatory states may act as catalysts for the manifestation of iNPH in patients with predisposing cerebral ischemia or subclinical abnormalities in CSF flow, highlighting the need for higher clinical awareness of iNPH in older patients who present with neurological deterioration during systemic infections. Early diagnosis and timely shunting after appropriate infection control may facilitate significant functional recovery in such patients. Full article

Stress and sleep share a reciprocal relationship, where chronic stress often leads to sleep disturbances that worsen neurodegenerative and psychiatric conditions. Non-neuronal cells, particularly astrocytes and microglia, play critical roles in the brain’s response to stress and the regulation of sleep. Astrocytes influence sleep architecture by regulating adenosine signaling and glymphatic clearance, both of which can be disrupted by chronic stress, leading to reduced restorative sleep. Microglia, activated under stress conditions, drive neuroinflammatory processes that further impair sleep and exacerbate brain dysfunction. Additionally, the gut–brain axis mediates interactions between stress, sleep, and inflammation, with microbial metabolites influencing neural pathways. Many of these effects converge on the disruption of synaptic processes, such as neurotransmitter balance, synaptic plasticity, and pruning, which in turn contribute to the pathophysiology of neurodegenerative and psychiatric disorders. This review explores how these cellular and systemic mechanisms contribute to stress-induced sleep disturbances and their implications for neurodegenerative and psychiatric disorders, offering insights into potential therapeutic strategies targeting non-neuronal cells and the gut–brain axis. Full article

Background: The brain’s vascular system has recently been shown to provide an important efflux pathway for cerebral waste clearance (CWC). However, little is known about the influence of aging or diabetes on the CWC. The aim of the current study is to investigate the vasculature contribution to CWC under aging and diabetic conditions. Methods: Male Wistar rats under aging and diabetic conditions were evaluated using dynamic intra-cisterna superparamagnetic iron oxide-enhanced susceptibility-weighted imaging (SPIO-SWI). Theoretical analysis of the expected signal intensity using SPIO-SWI was compared with the corresponding dynamic in vivo images. Quantitative susceptibility mapping (QSM) was used to evaluate the iron-based tracer concentration in the venous system. Results: Our data demonstrated that the theoretical analysis predicted the dynamic changes in the signal intensity after SPIO infusion. The distinct hyperintense signals due to the lower concentration of the SPIO over time in cerebrospinal fluid (CSF) and meningeal lymphatic (ML) vessels likely represented the CWC through various efflux pathways, including cerebral vascular and ML vessels. The QSM analysis further revealed reduced CWC from the vasculature in both the aged and diabetic groups compared to the younger group. Conclusions: Our results demonstrated that SPIO-SWI can quantitatively evaluate the CWC efflux contributions from cerebral vascular vessels under aging or diabetic conditions. Full article

Ocular aqueous humor plays an important role in maintaining retinal function. Recent findings indicate that aqueous humor, which flows into the vitreous body, is probably absorbed by Müller cells in the retina, and this process is mediated by aquaporin-4. In this review, we aim to summarize the results of studies on classical aqueous humor circulation and postiridial flow, a pathway proposed in the late 1980s for the inflow of aqueous humor into the vitreous body. In addition, we aim to discuss the retinal glymphatic pathway, inferred by recent findings, with a focus on the anatomical location of aquaporins and barriers that regulate water movement within the tissue. Similarly to the cerebral glymphatic flow, the function of the retinal glymphatic pathway may decline with age, as supported by our findings. In this review, we also discuss age-related ocular diseases that might be associated with the dysfunction of the retinal glymphatic pathway. Full article

An abnormal accumulation of misfolded proteins is a common feature shared by most neurodegenerative disorders. Olfactory dysfunction (OD) is common in the elderly population and is present in 90% of patients with Alzheimer’s or Parkinson’s disease, usually preceding the cognitive and motor symptoms onset by several years. Early Aβ, tau, and α-synuclein protein aggregates deposit in brain structures involved in odor processing (olfactory bulb and tract, piriform cortex, amygdala, entorhinal cortex, and hippocampus) and seem to underly OD. The glymphatic system is a glial-associated fluid transport system that facilitates the movement of brain fluids and removes brain waste during specific sleep stages. Notably, the glymphatic system became less functional in aging and it is impaired in several conditions, including neurodegenerative diseases. As the nasal pathway has been recently described as the main outflow exit of cerebrospinal fluid and solutes, we hypothesized that OD may indeed be a clinical marker of early glymphatic dysfunction through abnormal accumulation of pathological proteins in olfactory structures. This effect may be more pronounced in peri- and postmenopausal women due to the well-documented impact of estrogen loss on the locus coeruleus, which may disrupt multiple mechanisms involved in glymphatic clearance. If this hypothesis is confirmed, olfactory dysfunction might be considered as a clinical proxy of glymphatic failure in neurodegenerative diseases. Full article

The glymphatic system, an analog of the peripheral lymphatic system in the brain, and the meningeal lymphatic system are critical to central nervous system health. The glymphatic system functions to distribute cerebrospinal fluid and important compounds throughout the brain and to remove metabolic waste. The flow of cerebrospinal fluid through this system is affected by changes in cerebral blood flow, intracranial pressure, and vascular tone. Cetaceans experience profound cardiorespiratory alterations while diving that can directly affect cerebrospinal fluid and blood flow and, thus, glymphatic function. Our goal was to investigate glymphatic and lymphatic system structures, including perivascular spaces, aquaporin-4 water channels, meningeal lymphatic, and dural venous sinus vessels in the common dolphin (Delphinus delphis), using immunofluorescent labeling, histochemical staining, and postmortem computed tomography (CT) angiography. We highlight perivascular spaces and aquaporin-4 water channels surrounding blood vessels in the parenchyma and demonstrate evidence of meningeal lymphatic vessels and associated dural venous sinuses. These results demonstrate that common dolphins possess the key anatomical structures required for functional glymphatic and meningeal lymphatic systems. Future studies can build upon these anatomical discoveries to study the function and role of these systems in brain health in this species. Full article