Understanding central nervous system fluid networks: Historical perspectives and a revised model for clinical neurofluid imaging.

The central nervous system (CNS) lacks traditionally defined lymphatic vasculature. However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis. Pathways involved in this system have been under investigation for centuries and continue to be the source of considerable interest and debate. Modern imaging and microscopy technologies have led to important breakthroughs pertaining to various elements of CNS fluid circuitry and exchange over the past decade, thus enhancing knowledge on mechanisms of mammalian CNS maintenance and disease. Yet, to better understand precise anatomical routes, the physiology and clinical significance of these CNS pathways, and potential therapeutic targets in humans, fluid conduits, flow-regulating factors, and tissue effects must be analyzed systematically and in a global manner in persons across age, demographical factors, and disease states. Here, we illustrate the system-wide nature of intermixing CNS fluid networks, summarize historical and clinical studies, and discuss anatomical and physiological similarities and differences that are relevant for translation of evidence from mice to humans. We also review Cushing's classical model of cerebrospinal fluid flow and present a new framework of this "third circulation" that emphasizes previously unexplained complexities of CNS fluid circulation in humans. Finally, we review future directions in the field, including emerging theranostic techniques and MRI studies required in humans.

Profiles of Lifestyle Health Behaviors and Postmortem Dementia-Related Neuropathology.

High engagement in lifestyle health behaviors appears to be protective against cognitive decline in aging. We investigated the association between patterns of modifiable lifestyle health behaviors and common brain neuropathologies of dementia as a possible mechanism. We examined 555 decedents from the Rush Memory and Aging Project, free of dementia at their initial concurrent report of lifestyle health behaviors of interest (physical, social, and cognitive activities, and healthy diet), and who underwent a postmortem neuropathology evaluation. First, we used latent profile analysis to group participants based on baseline behavior patterns. Second, we assessed the associations of profile membership with each neurodegenerative (global Alzheimer's disease [AD] pathology, amyloid-beta load, density of neurofibrillary tangles, and presence of cortical Lewy bodies and TAR DNA-binding protein 43 cytoplasmic inclusions) and neurovascular pathologies (presence of chronic gross or microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), using separate linear or logistic regression models, adjusted for age at death, sex (core model), vascular disease risk factors, and vascular conditions (fully adjusted model). Participants had either consistently lower (N = 224) or consistently higher (N = 331) engagement across 4 lifestyle health behaviors. We generally found no differences in neuropathologies between higher and lower engagement groups in core or fully adjusted models; for example, higher engagement in lifestyle health behaviors was not associated with global AD pathology after core or full adjustment (both p > .8). In conclusion, we found no evidence of associations between patterns of lifestyle health behaviors and neuropathology. Other mechanisms may underlie protective effects of health behaviors against dementia.

Associations of Serum Insulin and Related Measures With Neuropathology and Cognition in Older Persons With and Without Diabetes.

OBJECTIVE: To examine associations of serum insulin and related measures with neuropathology and cognition in older persons. METHODS: We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio. Using adjusted regression analyses, we examined the associations of serum measures with neuropathology of cerebrovascular disease and Alzheimer's disease, and with the level of cognition proximate-to-death. RESULTS: Higher HOMA-IR was associated with the presence of brain infarcts and specifically microinfarcts, and higher HOMA-IR and leptin were each associated with subcortical infarcts. Further, higher leptin levels and lower adiponectin-to-leptin ratios were associated with the presence of moderate-to-severe atherosclerosis. Serum insulin and related measures were not associated with the level of Alzheimer's disease pathology, as assessed by global, as well as amyloid burden or tau tangle density scores. Regarding cognitive outcomes, higher insulin and leptin levels, and lower adiponectin and receptors for advanced glycation-end products levels, respectively, were each associated with lower levels of global cognition. INTERPRETATION: Peripheral insulin resistance indicated by HOMA-IR and related serum measures was associated with a greater burden of cerebrovascular neuropathology and lower cognition. ANN NEUROL 2024;95:665-676.

Giant Arachnoid Granulations: A Systematic Literature Review.

Giant arachnoid granulations (GAGs) are minimally investigated. Here, we systematically review the available data in published reports to better understand their etiologies, nomenclature, and clinical significance. In the literature, 195 GAGs have been documented in 169 persons of varied ages (range, 0.33 to 91 years; mean, 43 ± 20 years; 54% female). Prior reports depict intrasinus (i.e., dural venous sinus, DVS) (84%), extrasinus (i.e., diploic or calvarial) (15%), and mixed (1%) GAG types that exhibit pedunculated, sessile, or vermiform morphologies. GAG size ranged from 0.4 to 6 cm in maximum dimension (mean, 1.9 ± 1.1 cm) and encompassed symptomatic or non-symptomatic enlarged arachnoid granulations (≥1 cm) as well as symptomatic subcentimeter arachnoid granulations. A significant difference was identified in mean GAG size between sex (females, 1.78 cm; males, 3.39 cm; p < 0.05). The signs and symptoms associated with GAGs varied and include headache (19%), sensory change(s) (11%), and intracranial hypertension (2%), among diverse and potentially serious sequelae. Notably, brain herniation was present within 38 GAGs (22%). Among treated individuals, subsets were managed medically (19 persons, 11%), surgically (15 persons, 9%), and/or by endovascular DVS stenting (7 persons, 4%). Histologic workup of 53 (27%) GAG cases depicted internal inflammation (3%), cystic change consistent with fluid accumulation (2%), venous thrombosis (1%), hemorrhage (1%), meningothelial hyperplasia (1%), lymphatic vascular proliferation (1%), and lymphatic vessel obliteration (1%). This review emphasizes heterogeneity in GAG subtypes, morphology, composite, location, symptomatology, and imaging presentations. Additional systematic investigations are needed to better elucidate the pathobiology, clinical effects, and optimal diagnostic and management strategies for enlarged and symptomatic arachnoid granulation subtypes, as different strategies and size thresholds are likely applicable for medical, interventional, and/or surgical treatment of these structures in distinct brain locations.

Giant Arachnoid Granulations: Diagnostic Workup and Characterization in Three Symptomatic Adults.

Giant arachnoid granulations (GAGs) are poorly investigated. Here, we document clinical findings associated with five new GAGs and illustrate the anatomical composition of these structures as well as diagnostic considerations in three symptomatic adults. The GAGs ranged from 1.1 to 3.6 cm (mean, 2.2 cm) in maximum dimension and manifested in middle-aged individuals who presented with long-standing brain mass and/or chronic headache. On imaging examinations, the tissues appeared as irregular parasagittal and/or perisinus structures that demonstrated heterogeneous internal elements. The GAGs abutted dura, extended through calvarial marrow spaces, and impinged on dural venous sinuses, causing their stenosis. The histologic workup of two GAG specimens resected from separate individuals revealed central collagen with pronounced internal vascular proliferation. One specimen additionally exhibited reactive changes within the lesion, including venous thrombosis, hemorrhage, and conspicuous inflammation. The salient immune component consisted of a foam cell-rich infiltrate that obstructed subcapsular and internal sinusoidal GAG spaces. Within this specimen, meningothelial hyperplasia was also appreciated. Notably, proliferated lymphatic vascular elements were additionally observed within the structure, extending into deep central collagen regions and engulfing many extravasated erythrocytes in the subcapsular space. In both surgically treated patients, symptoms resolved completely following resection. This report is the first to definitively depict reactive vascular and immunological changes within GAGs that were clinically associated with headache. The frequency of reactive changes within these meningeal structures is unclear in the literature, as GAGs are rarely sampled and investigated. Further systematic analyses are warranted to elucidate the causes and consequences of GAG genesis and their roles in physiology and disease states.

Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease.

BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD). METHODS: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI. RESULTS: Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant. CONCLUSIONS: FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.

The Vascular-Immune Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating and irreversible neurodegenerative disorder with unknown etiology. While its cause is unclear, a number of theories have been proposed to explain the pathogenesis of AD. In large part, these have centered around potential causes for intracerebral accumulation of beta-amyloid (ßA) and tau aggregates. Yet, persons with AD dementia often exhibit autopsy evidence of mixed brain pathologies including a myriad of vascular changes, vascular brain injuries, complex brain inflammation, and mixed protein inclusions in addition to hallmark neuropathologic lesions of AD, namely insoluble ßA plaques and neurofibrillary tangles (NFTs). Epidemiological data demonstrate that overlapping lesions diminish the ßA plaque and NFT threshold necessary to precipitate clinical dementia. Moreover, a subset of persons who exhibit AD pathology remain resilient to disease while other persons with clinically-defined AD dementia do not exhibit AD-defining neuropathologic lesions. It is increasingly recognized that AD is a pathologically heterogeneous and biologically multifactorial disease with uncharacterized biologic phenomena involved in its genesis and progression. Here, we review the literature with regard to neuropathologic criteria and incipient AD changes, and discuss converging concepts regarding vascular and immune factors in AD.

Neuropathology of the Common Forms of Dementia.

Dementias encompass a range of debilitating neurologic conditions. Here, we summarize the neuropathology of common forms of dementia, focusing on Alzheimer disease (AD) and related dementias. AD is part of a spectrum of neurodegenerative diseases that consists of various protein inclusions (ie, proteinopathies) but other brain abnormalities are also related to dementia. Beta-amyloid and tau aggregates are hallmarks of AD. Other tissue substrates include Lewy bodies, TDP-43 inclusions, vascular brain lesions, and mixed pathologies. This review highlights the complexity of neurodegenerative and other disease substrates and summarizes topography of these lesions and concepts of mixed brain pathologies, resistance, and resilience.

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma.

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology. We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions. The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain-meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified. This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways. These data raise new theories regarding glymphatic-lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease.

Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced ß-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

Association of Traumatic Brain Injury With and Without Loss of Consciousness With Neuropathologic Outcomes in Community-Dwelling Older Persons.

Importance: A history of traumatic brain injury (TBI) has been considered a risk factor for Alzheimer dementia. However, the specific association of TBI, even without loss of consciousness (LOC), with pathologic findings that underlie Alzheimer dementia, including Alzheimer disease (AD), non-AD neurodegenerative, and vascular pathologic findings, remains unclear. Objective: To examine the association between TBI with and without LOC and neuropathologic findings in community-based cohorts. Design, Setting, and Participants: This cross-sectional analysis used neuropathologic data from 1689 participants from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. These studies began enrollment in 1994, 1997, and 2004, respectively. The current study's data set was frozen on April 3, 2021, when the mean (SD) length of follow-up for the participants was 8.7 (5.5) years. Exposure: Traumatic brain injury exposure was assessed using a standardized, self-reported questionnaire at baseline and annual follow-up visits. Participants were categorized into those (1) without TBI exposure (n = 1024), (2) with TBI with LOC (n = 161), or (3) with TBI without LOC (n = 504). Main Outcomes and Measures: Neuropathologic measures of amyloid-ß, paired helical filament tangles, neocortical Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, gross infarcts, and microinfarcts were assessed. Multiple linear regression and logistic regression models were used to determine whether TBI with or without LOC (compared with no TBI exposure as the reference group) was associated with neuropathologic outcomes after adjusting for age at death, sex, and educational level. Whether the apolipoprotein E (APOE) ε4 allele and sex differences modified associations was also examined. Results: A total of 1689 participants (1138 [67%] women and 551 [33%] men; mean [SD] age at death, 89.2 [6.7] years; 80 [5%] Black, 46 [3%] Latino, 1639 [97%] non-Latino, and 1601 [95%] White) participated in the study. Compared with participants without TBI, participants with TBI with LOC had a greater amyloid-ß load (estimate, 0.25; 95% CI, 0.06-0.43; P = .008) and higher odds of having 1 or more gross infarcts (odds ratio [OR], 1.45; 95% CI, 1.04-2.02; P = .02) and 1 or more microinfarcts (OR, 1.70; 95% CI, 1.21-2.38; P = .002), particularly subcortical microinfarcts (OR, 1.85; 95% CI, 1.23-2.79; P = .002). Those with TBI without LOC had higher odds of neocortical Lewy bodies (OR, 1.37; 95% CI, 1.01-1.87; P = .04) and 1 or more cortical microinfarcts (OR, 1.43; 95% CI, 1.09-1.87; P = .008). The association of TBI with and without LOC with vascular pathologic outcomes persisted after controlling for vascular risk factors and vascular disease burden. Traumatic brain injury with or without LOC was not associated with paired helical filament tangles, transactive response DNA-binding protein 43, or hippocampal sclerosis. No interactions occurred with APOE ε4 or sex. Conclusions and Relevance: This cross-sectional analysis suggests that a history of TBI, even without LOC, is associated with age-related neuropathologic outcomes, both neurodegenerative and vascular. The variation in the neuropathologic outcomes in individuals with and without LOC may provide clues to potential mechanisms, diagnoses, and management in persons with TBI.

Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema.

Cerebral oedema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that oedema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of CSF. Oedema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of oedema. Oedema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of oedema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral oedema formation after cardiac arrest.

What is 'Alzheimer's disease'? The neuropathological heterogeneity of clinically defined Alzheimer's dementia.

PURPOSE OF REVIEW: Beta-amyloid with paired helical filaments (PHF)-tau neurofibrillary tangles define hallmark Alzheimer's disease neuropathologic changes (AD-NC). Yet persons with Alzheimer's dementia, defined broadly as an amnestic multidomain progressive dementia, often exhibit postmortem evidence of other neuropathologies including other neurodegenerative (Lewy body disease and transactive response DNA-binding protein disease) and vascular-related brain lesions. Clinicopathologic and epidemiologic analyses demonstrate the significance of these substrates, as coinciding neuropathologies mitigate the threshold for diagnosis of Alzheimer's dementia. In addition, other biologic processes may also independently underlie a progressive amnestic dementia. Advances in research on the relationship between age-related cognitive decline and the underlying neuropathologic substrates indicate that consensus neuropathologic criteria or disease nomenclature may need new considerations or refinement. This review appraises seminal literature as well as mixed pathologies and biological factors that may be determinants of clinical and pathologic disease. RECENT FINDINGS: Cognition in aging (spanning from normal cognition to dementia) represents a clinical continuum. Traditional neuropathologic substrates of dementia however do not explain the variability of cognitive decline. Conversely, not all patients with AD-NC exhibit symptomatology of Alzheimer's dementia. In addition to diagnostic plaques and tangles, other neurodegenerative, cerebrovascular, and perivascular substrates manifest through discrete tissue lesions. Factors related to energetics, neurogenetics, neuroimmunology, resilience, proteinopathies, and waste clearance are increasingly suggested to be general drivers of disease. Recognition of novel neuroimmune pathways and brain-body connections further suggest there may be broader extracranial determinants of person-specific disease. SUMMARY: Alzheimer's dementia is a pathologically heterogeneous and biologically multilayered disease. Recent studies and exercises in nomenclature reveal shortcomings in existing terminologies. Recognizing and overcoming these limitations is required for experts to effectively communicate about and ultimately prevent and treat Alzheimer's dementia.

Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease.

Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-ß plaque burden, improve memory performance, and facilitate delivery of therapeutic agents to the brain. However, physiologic effects of this procedure in humans with Alzheimer disease (AD) require further investigation. Purpose To assess imaging effects of focused ultrasound-induced BBB opening in the hippocampus of human participants with early AD and to evaluate fluid flow patterns after BBB opening by using serial contrast-enhanced MRI. Materials and Methods Study participants with early AD recruited to a Health Insurance Portability and Accountability Act-compliant, prospective, ongoing phase II clinical trial (ClinicalTrials.gov identifier, NCT03671889) underwent three separate focused ultrasound-induced BBB opening procedures that used a 220-kHz transducer with a concomitant intravenous microbubble contrast agent administered at 2-week intervals targeting the hippocampus and entorhinal cortex between October 2018 and May 2019. Posttreatment effects and gadolinium-based contrast agent enhancement patterns were evaluated by using 3.0-T MRI. Results Three women (aged 61, 72, and 73 years) consecutively enrolled in the trial successfully completed repeated focused ultrasound-induced BBB opening of the hippocampus and entorhinal cortex. Postprocedure contrast enhancement was clearly identified within the targeted brain volumes, indicating immediate spatially precise BBB opening. Parenchymal enhancement resolved within 24 hours after all treatments, confirming BBB closure. Transient perivenous enhancement was consistently observed during the acute phase after BBB opening. Notably, contrast enhancement reappeared in the perivenular regions after BBB closure. This imaging marker is consistent with blood-meningeal barrier permeability and persisted for 24-48 hours before spontaneous resolution. No evidence of intracranial hemorrhage or other adverse effect was identified. Conclusion MRI-guided focused ultrasound-induced blood-brain barrier opening was safely performed in the hippocampi of three participants with Alzheimer disease without any adverse effects. Posttreatment MRI reveals a unique spatiotemporal contrast enhancement pattern that suggests a perivenular immunologic healing response downstream from targeted sites. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Klibanov in this issue.

Hydrophilic Polymer Embolism: Implications for Manufacturing, Regulation, and Postmarket Surveillance of Coated Intravascular Medical Devices.

ABSTRACT: Hydrophilic polymers are ubiquitously applied as surface coatings on catheters and intravascular medical technologies. Recent clinical literature has heightened awareness on the complication of hydrophilic polymer embolism, the phenomenon wherein polymer coating layers separate from catheter and device surfaces, and may be affiliated with a range of unanticipated adverse reactions. Significant system barriers have limited and delayed reporting on this iatrogenic complication, the full effects of which remain underrecognized by healthcare providers and manufacturers of various branded devices. In 2015, the United States Food and Drug Administration acknowledged rising clinical concerns and stated that the agency would work with stakeholders to further evaluate gaps that exist in current national and international device standards for coated intravascular medical technologies. The present article reviews current knowledge on this complication as well as factors that played a role in delaying detection and dissemination of information and new knowledge once hazards and clinical risks were identified. Furthermore, organ-specific effects and adverse reaction patterns are summarized, along with implications for device manufacturing, safety assurance, and regulation. Qualitative and quantitative particulate testing are needed to optimize coated intravascular device technologies. Moreover, general enhanced processes for medical device surveillance are required for timely adverse event management and to ensure patient safety.

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed. METHODS: This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline. RESULTS: EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, P=0.0017) and diabetes mellitus (odds ratio=1.73, P=0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, P=0.016) and microscopic infarcts (odds ratio=1.79, P=0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, P=0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, P=0.048) and visuospatial abilities (estimate=-0.11, P=0.016) at the time of death. CONCLUSIONS: EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.

Cerebrospinal fluid influx drives acute ischemic tissue swelling.

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies.

Intrathrombus polymer coating deposition: a pilot study of 91 patients undergoing endovascular therapy for acute large vessel stroke. Part I: Histologic frequency.

BACKGROUND: Polymer coating embolism due to vascular medical device use is an increasingly recognized iatrogenic complication. This phenomenon has been linked with various adverse effects including neuroinflammation, acute ischemic stroke, cerebral hemorrhage, and death. Notably, procedure- and device-specific risks of this complication are poorly investigated. In this study, we evaluate the detectable frequency of intra-arterial polymer coating delamination among patients who underwent endovascular thrombectomy for treatment of acute ischemic stroke due to large vessel occlusion. METHODS: Ninety-two cerebral thrombectomy specimens were retrospectively analyzed for the presence of polymer coating particulates. Histologic findings were correlated with demographic and procedural details and patient outcomes. RESULTS: Evidence of polymer coating deposition was found in 30 of 92 extracted thrombi (33%). No correlation between intrathrombus polymer deposition and use of a specific thrombectomy device such as a stent retriever, aspiration catheter, or guide catheter was found. However, heterogeneous patterns of device use suggest a number of culprit devices. A trend toward longer procedure times and multiple thrombectomy passes was noted in positive cases. Intrathrombus polymer deposition was not associated with adverse clinical outcomes as measured by the 90-day modified Rankin Scale (mRS); however, small sample size and follow-up intervals limit interpretation. Ninety-day outcomes based on mRS may not fully capture the clinical effects of acute and/or delayed intracerebral polymer complications. CONCLUSION: In light of documented adverse neurologic effects, the frequency of intrathrombus polymer particulates indicates the need for consensus testing methods and large-scale long-term prospective clinical device trials, with inclusion of relevant endpoints to better assess biomaterial and device risks to patients.

Expanding the neurodevelopmental phenotype of PURA syndrome.

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.