CSF Volume Research Articles

Quantification of blood and CSF volume to predict outcome after aneurysmal subarachnoid hemorrhage

This study aimed to describe the relationship between blood and CSF volumes in different compartments on baseline CT after aSAH, assess if they independently predict long-term outcome, and explore their interaction with age. CT scans from patients participating in a prospective multicenter randomized controlled trial of patients with aSAH were segmented for blood and CSF volumes. The primary outcomes were the mRS, and the Subarachnoid Hemorrhage Outcome Tool (SAHOT) at day 28 and 180. Univariate regressions were conducted to identify significant predictors of poor outcomes, followed by principal component analysis to explore correlations between imaging variables and WFNS. A multivariate predictive model was then developed and optimized using stepwise regression. CT scans from 97 patients with a median delay from symptom onset of 271 min (131–547) were analyzed. Univariate analysis showed only WFNS, and total blood volume (TBV) were significant predictors of both short and long-term outcome with WFNS more predictive of mRS and TBV more predictive of SAHOT. Principal component analysis showed strong dependencies between the imaging predictors. Multivariate ordinal regression showed models with WFNS alone were most predictive of day 180 mRS and models with TBV alone were most predictive of SAHOT. TBV was the most significant measured imaging predictor of poor long-term outcome after aSAH. All these imaging predictors are correlated, however, and may have multiple complex interactions necessitating larger datasets to detect if they provide any additional predictive value for long-term outcome.

Magnitude and kinetics of a set of neuroanatomic volume and thickness together with white matter hyperintensity is definitive of cognitive status and brain age

Even among the subjects classified as cognitively normal, there exists a subset of individuals at a given chronological age (CA) who harbor white matter hyperintensity (WMH) while another subset presents with low or undetectable WMH. Here, we conducted a comprehensive MRI segmentation of neuroanatomic structures along with WMH quantification in groups of cognitively normal (CN), cognitively impaired (CI) individuals, and individuals with an etiological diagnosis of cognitive impairment owing to Alzheimer’s Disease (CI-AD) across the early (50–64 years), intermediate (65–79 years), and late (≥80 years) age groups from the NACC cohort. Neuroanatomic volumetry quantification revealed that thinning of the parahippocampal gyrus in the early (p = 0.016) and intermediate age groups (p = 0.0001) along with an increase in CSF (p = 0.0009) delineates between CI and CI-AD subjects. Although, a significant loss of ~5–10% in volume of gray matter (p(CN vs CI) < 0.0001, p(CN vs CI-AD) < 0.0001), white matter (p(CN vs CI) = 0.002, p(CN vs CI-AD) = 0.0003) and hippocampus (p(CN vs CI) = 0.007, p(CN vs CI-AD) < 0.0001) was evident at the early age groups in the CI and CI-AD compared to CN but it was not distinct between CI and CI-AD. Using the neuroanatomic and WMH volume, and the supervised decision tree-based ML modeling, we have established that a minimum set of Three brain quantities; Total brain (GM + WM), CSF, and WMH volume, provide the Optimal quantitative features discriminative of cognitive status as CN, CI, and CI-AD. Furthermore, using the volume/thickness of 178 neuroanatomic structures, periventricular and deep WMH volume quantification for the 819 CN subjects, we have developed a quantitative index as ‘Brain Age’ (BA) depictive of neuroanatomic health at a given CA. Subjects with elevated WMH load (5–10 ml) had increased BA ( + 0.6 to +4 years) than the CA. Increased BA in the subjects with elevated WMH is suggestive of WMH-induced vascular insult leading to accelerated and early structural loss than expected for a given CA. Henceforth, this study establishes that quantification of WMH together with an optimal number of neuroanatomic features is mandatory to delve into the biological underpinning of aging and aging-associated cognitive disorders.

CSF dynamics throughout the ventricular system using 4D flow MRI: associations to arterial pulsatility, ventricular volumes, and age

BackgroundCerebrospinal fluid (CSF) dynamics are increasingly studied in aging and neurological disorders. Models of CSF-mediated waste clearance suggest that altered CSF dynamics could play a role in the accumulation of toxic waste in the CNS, with implications for Alzheimer’s disease and other proteinopathies. Therefore, approaches that enable quantitative and volumetric assessment of CSF flow velocities could be of value. In this study we demonstrate the feasibility of 4D flow MRI for simultaneous assessment of CSF dynamics throughout the ventricular system, and evaluate associations to arterial pulsatility, ventricular volumes, and age.MethodsIn a cognitively unimpaired cohort (N = 43; age 41–83 years), cardiac-resolved 4D flow MRI CSF velocities were obtained in the lateral ventricles (LV), foramens of Monro, third and fourth ventricles (V3 and V4), the cerebral aqueduct (CA) and the spinal canal (SC), using a velocity encoding (venc) of 5 cm/s. Cerebral blood flow pulsatility was also assessed with 4D flow (venc = 80 cm/s), and CSF volumes were obtained from T1- and T2-weighted MRI. Multiple linear regression was used to assess effects of age, ventricular volumes, and arterial pulsatility on CSF velocities.ResultsCardiac-driven CSF dynamics were observed in all CSF spaces, with region-averaged velocity range and root-mean-square (RMS) velocity encompassing from very low in the LVs (RMS 0.25 ± 0.08; range 0.85 ± 0.28 mm/s) to relatively high in the CA (RMS 6.29 ± 2.87; range 18.6 ± 15.2 mm/s). In the regression models, CSF velocity was significantly related to age in 5/6 regions, to CSF space volume in 2/3 regions, and to arterial pulsatility in 3/6 regions. Group-averaged waveforms indicated distinct CSF flow propagation delays throughout CSF spaces, particularly between the SC and LVs.ConclusionsOur findings show that 4D flow MRI enables assessment of CSF dynamics throughout the ventricular system, and captures independent effects of age, CSF space morphology, and arterial pulsatility on CSF motion.

Evaluating the interaction between hemorrhagic transformation and cerebral edema on functional outcome after ischemic stroke

BackgroundHemorrhagic transformation (HT) and cerebral edema (CED) are both major complications following ischemic stroke, but few studies have evaluated their overlap. We evaluated the frequency and predictors of CED/HT overlap and whether their co-occurrence impacts functional outcome more than each in isolation. Methods892 stroke patients enrolled in a prospective study had follow-up CT imaging evaluated for HT and CED; the latter was quantified using the ratio of hemispheric CSF volumes (with hemispheric CSF ratio < 0.90 used as the CED threshold). The interaction between HT and CED on functional outcome (using modified Rankin Scale at 3 months) was compared to that for each condition separately. ResultsAmong the 275 (31%) who developed HT, 233 (85%) manifested hemispheric CSF ratio < 0.9 (CED/HT), with this overlap group representing half of the 475 with measurable CED. Higher baseline NIHSS scores and larger infarct volumes were observed in the CED/HT group compared with those with CED or HT alone. Functional outcome was worse in those with CED/HT [median mRS 3 (IQR 2-5)] than those with CED [median 2 (IQR 1-4)] or HT alone [median 1 (IQR 0-2), p < 0.0001]. Overlap of CED/HT independently predicted worse outcome [OR 1.89 (95% CI: 1.12-3.18), p = 0.02] while HT did not; however, CED/HT was no longer associated with worse outcome after adjusting for severity of CED [adjusted OR 0.35 (95% CI: 0.23, 0.51) per 0.21 lower hemispheric CSF ratio, p < 0.001]. ConclusionsMost stroke patients with HT also have measurable CED. The co-occurrence of CED and HT occurs in larger and more severe strokes and is associated with worse functional outcome, although this is driven by greater severity of stroke-related edema in those with HT.

Inflammation-Triggered Enlargement of Choroid Plexus in Subacute COVID-19 Patients with Neurological Symptoms.

To investigate whether choroid plexus volumes in subacute coronavirus disease 2019 (COVID-19) patients with neurological symptoms could indicate inflammatory activation or barrier dysfunction and assess their association with clinical data. Choroid plexus volumes were measured in 28 subacute COVID-19 patients via cerebral magnetic resonance imaging (MRI), compared with those in infection-triggered non-COVID-19 encephalopathy patients (n = 25), asymptomatic individuals after COVID-19 (n = 21), and healthy controls (n = 21). Associations with inflammatory serum markers (peak counts of leukocytes, C-reactive protein [CRP], interleukin 6), an MRI-based marker of barrier dysfunction (CSF volume fraction [V-CSF]), and clinical parameters like olfactory performance and cognitive scores (Montreal Cognitive Assessment) were investigated. COVID-19 patients showed significantly larger choroid plexus volumes than control groups (p < 0.001, η2 = 0.172). These volumes correlated significantly with peak leukocyte levels (p = 0.001, Pearson's r = 0.621) and V-CSF (p = 0.009, Spearman's rho = 0.534), but neither with CRP nor interleukin 6. No significant correlations were found with clinical parameters. In patients with subacute COVID-19, choroid plexus volume is a marker of central nervous system inflammation and barrier dysfunction in the presence of neurologic symptoms. The absence of plexus enlargement in infection-triggered non-COVID-19 encephalopathy suggests a specific severe acute respiratory syndrome coronavirus 2 effect. This study also documents an increase in choroid plexus volume for the first time as a parainfectious event. ANN NEUROL 2024.

Sodium signal intensity of CSF using 1H-guided 23Na-MRI as a potential noninvasive biomarker in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cognitive decline and mnestic deficits. The pathophysiology of AD is not fully understood, which renders the development of accurate tools for early diagnosis and effective therapies exceedingly difficult. In this study, we investigated the use of 23Na-MRI to measure the relative sodium signal intensities (rSSIs) in CSF in patients with AD and healthy controls. We prospectively recruited 11 patients with biomarker-diagnosed early-stage AD, as well as 12 cognitively healthy age-matched controls. All participants underwent 23Na-MRI to measure rSSI. Statistical analyses were performed to compare CSF sodium signal intensities between groups and to evaluate the specificity and sensitivity of the rSSI in the diagnosis of AD. RSSIs in CSF were significantly higher in AD patients (mean=68.6%±7.7%) compared to healthy controls (mean=56.9%±5.5%) (p<.001). There was also a significant negative correlation between rSSI in CSF and hippocampus and amygdala volumes (r=-.54 and -.49, p<.05) as well as a positive correlation with total CSF volumes (r=.81, p<.05). Receiver operating characteristic analysis showed high diagnostic accuracy for rSSI in discriminating between AD patients and healthy controls (area under the curve=.94). Our study provides evidence that rSSI in CSF is increased in AD patients in comparison to healthy controls. rSSI may serve as a potential marker for early detection and monitoring of disease progression. Larger, longitudinal studies are needed to confirm our findings and to investigate the association between rSSI in CSF and the severity of cognitive impairment.

Improved Cerebral Glymphatic Flow after Transvenous Embolization of CSF-Venous Fistula.

Spontaneous intracranial hypotension is characterized by symptoms of low intracranial CSF volume due to various mechanisms of CSF leakage. One such mechanism is a CSF-venous fistula, treatable with transvenous embolization resulting in substantial radiographic and clinical improvement. However, the exact mechanisms underlying these improvements, including the potential involvement of the glymphatic system, remain unclear. To noninvasively assess glymphatic clearance in spontaneous intracranial hypotension, we used an advanced MR imaging technique called the DTI along the perivascular spaces in 3 patients with CSF-venous fistula before and after embolization. All 3 patients with spontaneous intracranial hypotension initially had low glymphatic flow, which improved postembolization. Two patients with symptomatic improvement exhibited a more substantial increase in glymphatic flow compared with a patient with minimal improvement. These findings suggest a possible link between cerebral glymphatics in spontaneous intracranial hypotension pathophysiology and symptomatic improvement, warranting larger studies to explore the role of the glymphatic system in spontaneous intracranial hypotension.

Investigating Sea-Level Brain Predictors for Acute Mountain Sickness: A Multimodal MRI Study before and after High-Altitude Exposure.

Acute mountain sickness is a series of brain-centered symptoms that occur when rapidly ascending to high altitude. Predicting acute mountain sickness before high-altitude exposure is crucial for protecting susceptible individuals. The present study aimed to evaluate the feasibility of predicting acute mountain sickness after high-altitude exposure by using multimodal brain MR imaging features measured at sea level. We recruited 45 healthy sea-level residents who flew to the Qinghai-Tibet Plateau (3650 m). We conducted T1-weighted structural MR imaging, resting-state fMRI, and arterial spin-labeling perfusion MR imaging both at sea level and high altitude. Acute mountain sickness was diagnosed for 5 days using Lake Louise Scoring. Logistic regression with Least Absolute Shrinkage and Selection Operator logistic regression was performed for predicting acute mountain sickness using sea-level MR imaging features. We also validated the predictors by using MR images obtained at high altitude. The incidence rate of acute mountain sickness was 80.0%. The model achieved an area under the receiver operating characteristic curve of 86.4% (sensitivity = 77.8%, specificity = 100.0%, and P < .001) in predicting acute mountain sickness At sea level, valid predictors included fractional amplitude of low-frequency fluctuations (fALFF) and degree centrality from resting-state fMRI, mainly distributed in the somatomotor network. We further learned that the acute mountain sickness group had lower levels of fALFF in the somatomotor network at high altitude, associated with smaller changes in CSF volume and higher Lake Louise Scoring, specifically relating to fatigue and clinical function. Our study found that the somatomotor network function detected by sea-level resting-state fMRI was a crucial predictor for acute mountain sickness and further validated its pathophysiologic impact at high altitude. These findings show promise for pre-exposure prediction, particularly for individuals in need of rapid ascent, and they offer insight into the potential mechanism of acute mountain sickness.

Quantitative noninvasive measurement of cerebrospinal fluid flow in shunted hydrocephalus.

Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients. The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts. The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter. The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.

246 Algorithmic CT Scan Analysis for Prognosticating Brain Injury: A Preliminary Effort

INTRODUCTION: Predicting which trauma patients will progress to brain death is currently based on history, physical examination and radiographic findings. METHODS: 38 trauma subjects, 18 which progressed to brain death (BD), who suffered from high-velocity trauma with presumed diffuse axonal injury, cardiopulmonary/respiratory arrest, and/or found down were included. BLAST-CT was used to identify four lesion types: intraparenchymal hemorrhage, extra-axial hemorrhage, perilesional oedema, and intraventricular hemorrhage. Cerebrospinal fluid volumes were extracted using SimpleITK. These two sets of features were obtained from whole head CT scans and within 117 standardized brain atlas regions. Five ROC curves for classifying BD versus non-BD were generated using a support vector machine trained on (1) BLAST-CT (4 features), (2) Regional BLAST-CT (468 features), (3) Regional CSF volumes (117), (4) BLAST-CT + Regional CSF volumes (121 features), and (5) Regional BLAST-CT + Regional CSF volumes (585 features). RESULTS: For BLAST-CT alone, area under the curve (AUC), sensitivity, specificity, and accuracy in classifying BD were 0.7806, 61.11%, 95.00%, and 78.95% respectively. For regional BLAST CT, they were 0.7611, 55.56%, 100%, and 78.95% respectively. For regional CSF volume, they were 0.7056, 94.44%, 50.00%, and 71.05%. For BLAST-CT + regional CSF volumes, they were 0.8389, 94.44%, 65.00%, and 79.85%. For regional BLAST-CT + regional CSF volumes, they were 0.9083, 83.33%, 100%, 92.11%. CONCLUSIONS: Results indicate that the present model using regional BLAST-CT + regional CSF volumes is able to classify brain death with a large specificity, sensitivity, and accuracy above 90%. Given the clinical value of a tool to assist physicians in predicting progression to BD, additional prospective trials with larger samples and testing cohorts should be conducted.

Longitudinal volumetric analysis of gray matter atrophy in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.

Automatic segmentation of hemispheric CSF on MRI using deep learning: Quantifying cerebral edema following large hemispheric infarction

Background and objectiveCerebral edema (CED) is a serious complication of acute ischemic stroke (AIS), especially in patients with large hemispheric infarction (LHI). Herein, a deep learning-based approach is implemented to extract CSF from T2-Weighted Imaging (T2WI) and evaluate the relationship between quantified cerebrospinal fluid and outcomes. MethodsPatients with acute LHI who underwent magnetic resonance imaging (MRI) were included. We used a deep learning algorithm to segment the CSF from T2WI. The hemispheric CSF ratio was calculated to evaluate its relationship with the degree of brain edema and prognosis in patients with LHI. ResultsFor the 93 included patients, the left and right cerebrospinal fluid regions were automatically extracted with a mean Dice similarity coefficient of 0.830. Receiver operating characteristic analysis indicated that hemispheric CSF ratio was an accurate marker for qualitative severe cerebral edema (area under receiver-operating-characteristic curve 0.867 [95% CI, 0.781–0.929]). Multivariate logistic regression analysis of functional prognosis showed that previous stroke (OR = 5.229, 95% CI 1.013–26.984), ASPECT≤6 (OR = 13.208, 95% CI 1.136–153.540) and low hemispheric CSF ratio (OR = 0.966, 95% CI 0.937–0.997) were significantly associated with higher chances for unfavorable functional outcome in patients with LHI. ConclusionsAutomated assessment of CSF volume provides an objective biomarker of cerebral edema that can be leveraged to quantify the degree of cerebral edema and confirm its predictive effect on outcomes after LHI.

Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis

To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

Mediterranean diet protects against neuroinflammation and degeneration in female nonhuman primates

AbstractBackgroundMediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets in part by protecting against neuroinflammation. In middle‐aged humans that subsequently develop AD, increased cortical thickness precedes atrophy. It is hypothesized that the initial increase in brain volumes may be due to early neuroinflammation that precedes neurodegeneration (Pegueroles et al. Alzheimers Dement 2017). Long term impacts of diet patterns on health are difficult to quantify in human beings. Thus, we addressed this hypothesis in cynomolgus macaques (Macaca fascicularis), a nonhuman primate that undergoes age‐related changes in brain structure and function, and responds to Western diets, like humans.Method38 middle‐aged (mean = 12 years of age) female macaques were fed a Western or Mediterranean diet for 2.5 years in a randomized nonhuman primate trial. Changes from baseline in volumes of total brain, gray, cortical gray, and white matter, cerebrospinal fluid and (CSF), were determined by structural MRI. We also generated thickness‐based AD temporoparietal meta‐ROIs based on the AD clinical literature as previously described (Frye et al., 2021 Alzheimers Dement. 2021;17:733). Transcriptional profiles in the temporal cortex were determined at the end of the study by RNAseq.ResultWestern diet led to increases in temporoparietal cortical thicknesses, total brain and gray matter volumes, and diminished cerebrospinal fluid and white matter volumes. Diet significantly altered expression of seven genes (FDR&lt;0.05). The Mediterranean group had lower expression of CDK14, a proinflammatory regulator, and higher expression of BTN2A1, KATNB1, LFNG, MRC2, SLCA32, and TMEM268, many of which have anti‐inflammatory associations. Several differentially expressed genes were correlated with AD‐relevant brain volumes. CDK14 was positively correlated with total brain, total gray, and cortical gray matter volumes and temporoparietal cortical thickness (Figure, Mediterranean = yellow), and negatively correlated with total white matter and CSF volumes. LFNG, MRC2, and SLCA32 were negatively correlated with total brain, total gray, and cortical gray matter volume, as well as temporoparietal cortical thickness, and positively correlated with CSF volume (all p’s&lt;0.05).ConclusionThese results suggest that the Mediterranean diet protects against, whereas the Western diet promotes, AD‐relevant neuroinflammation associated with early increases in gray matter volumes.

Adjusting for CSF Reference Proteins Improves Biomarker Accuracy

AbstractBackgroundCSF biomarkers are key AD descriptors, but the CSF volume as well as the production and clearance rates of proteins varies in individuals. Adjusting for reference proteins, which reflect these factors, might improve the accuracy of CSF biomarkers, similar to when normalizing CSF Aβ42 levels to Aβ40 levels. For other biomarkers, individual CSF dynamics are seldom adjusted for, which may result in disagreement with other techniques (e.g., PET). Additionally, this may contribute to inaccurate conclusions about CSF protein correlations that mainly exist due to high or low CSF dilution levels. The aim of this work is therefore to establish the use of CSF reference proteins to improve CSF AD biomarker accuracy.MethodWe used measurements of 2944 CSF proteins in the Swedish BioFINDER‐2 cohort (n = 982, 80% train and 20% test). Reference protein candidates (reflecting CSF dilution levels without being related to any disease) were searched for in a data‐driven manner, using t‐distributed stochastic neighbor embedding (t‐SNE) and a semi‐supervised K‐means clustering algorithm. The final candidate proteins were evaluated in logistic regression models, using CSF P‐tau181 and CSF Aβ42 as main predictors of tau‐PET and amyloid‐PET, respectively.ResultMost proteins were associated with an individual dilution level, although at different strengths (Fig 1 and Fig 2e). From the different colorings of the t‐SNE space, proteins of similar expressions were placed nearby, creating areas of extra interest (yellow areas in subfigures 2c‐2h). The semi‐supervised K‐means algorithm highlighted an area (cluster 11) containing proteins with superior reference protein characteristics, from which single reference protein candidates were identified. All examined references (e.g., Aβ40, NTRK3, NTRK2, BLMH,CBLN4, PTPRN2 or PTPRS) outperformed using no reference for both the P‐tau181 and Aβ42 model (Figure 3). For P‐tau181, highest performance was achieved using CBLN4 (AUC = 0.944). For Aβ42, Aβ40 performed best as reference (AUC = 0.992).ConclusionThe individual CSF dilution level affects many CSF proteins. We describe several novel and previously suggested CSF reference proteins, which can significantly improve the accuracy of CSF biomarkers as key AD descriptors.

Use of cortical volume to predict response to temporary CSF drainage in patients with idiopathic normal pressure hydrocephalus.

Temporary drainage of CSF with lumbar puncture or lumbar drainage has a high predictive value for identifying patients with suspected idiopathic normal pressure hydrocephalus (iNPH) who may benefit from ventriculoperitoneal shunt insertion. However, it is unclear what differentiates responders from nonresponders. The authors hypothesized that nonresponders to temporary CSF drainage would have patterns of reduced regional gray matter volume (GMV) as compared with those of responders. The objective of the current investigation was to compare regional GMV between temporary CSF drainage responders and nonresponders. Machine learning using extracted GMV was then used to predict outcomes. This retrospective cohort study included 132 patients with iNPH who underwent temporary CSF drainage and structural MRI. Demographic and clinical variables were examined between groups. Voxel-based morphometry was used to calculate GMV across the brain. Group differences in regional GMV were assessed and correlated with change in results on the Montreal Cognitive Assessment (MoCA) and gait velocity. A support vector machine (SVM) model that used extracted GMV values and was validated with leave-one-out cross-validation was used to predict clinical outcome. There were 87 responders and 45 nonresponders. There were no group differences in terms of age, sex, baseline MoCA score, Evans index, presence of disproportionately enlarged subarachnoid space hydrocephalus, baseline total CSF volume, or baseline white matter T2-weighted hyperintensity volume (p > 0.05). Nonresponders demonstrated decreased GMV in the right supplementary motor area (SMA) and right posterior parietal cortex as compared with responders (p < 0.001, p < 0.05 with false discovery rate cluster correction). GMV in the posterior parietal cortex was associated with change in MoCA (r2 = 0.075, p < 0.05) and gait velocity (r2 = 0.076, p < 0.05). Response status was classified by the SVM with 75.8% accuracy. Decreased GMV in the SMA and posterior parietal cortex may help identify patients with iNPH who are unlikely to benefit from temporary CSF drainage. These patients may have limited capacity for recovery due to atrophy in these regions that are known to be important for motor and cognitive integration. This study represents an important step toward improving patient selection and predicting clinical outcomes in the treatment of iNPH.

Combined endoscopic and microsurgical treatment of Tarlov cysts

Tarlov cysts are a rare condition. While they appear asymptomatic mostly, some patients develop severe clinical symptoms. Tarlov cysts can grow over time and may result from disturbances within the spinal CSF system. Due to the rare character, the disease can be a burden for both patients and physicians. Treat or not to treat, and if yes, how to treat is a relevant question. Here, a retrospective, observational study on 49 patients suffering from symptomatic Tarlov cysts treated with a combined endoscopic-microsurgical approach was performed. The microsurgical resection was combined with thecaloscopy inside the lower lumbosacral subarachnoidal space to improve the CSF flow and pressure regulation capability. The purpose was to prove that the surgical method was able to prevent recurrence and gives a major relief of symptoms. Our data suggest that combined interventional treatment of symptomatic Tarlov Cysts is helpful to treat the long-standing symptoms. In all patients we found signs for inflammatory processes at the level of the lumbar leptomeningeal sheets, involving the pia mater and the arachnoid. We found evidence that patients suffering from a slow inflammatory process within the leptomeninges might have increase risk of developing Tarlov cysts. We hypothesized that local CSF flow and pressure regulation mechanism become invalid by the morphological changes at the arachnoid and lose the capability to regulate CSF pressure down by pressing minimal volumes of CSF out of the dural sac at the nerve root exits.

Abstract 149: The Effect of Lumbar Cerebrospinal Fluid Drainage on Mortality Reduction and Neuro-Prognostic Improvement in Out of Hospital Cardiac Arrest Patients Underwent Targeted Temperature Management

Cerebral edema and increased ICP in post OHCA patients can be harmful due to the brain’s rigid encasement, although the increase is small. Lumbar CSF drainage (LD) may be a valuable treatment for refractory increased ICP in patients with discernible basal cisterns. Furthermore, much of the CSF volume is located in the subarachnoid spaces, which are not accessible for drainage by ventriculostomies. However, there has been no study on the effect of LD in OHCA patients. Therefore, we investigaed whether LD reduces mortality and improves neurological prognosis in OHCA patients who underwent TTM. This was a prospective single-center study conducted from July 2021 to April 2020 (CNUH IRB201907033003, NCT04328974). The target temperature of 33°C was maintained for 24 h, and LD was initiated when ICP exceeded 15 mmHg at the rate of 10 ml per hour via a LD catheter until ICP was less than 15 mmHg. We performed propensity score matching with the CAHP score variables between the group with and without LD. We used the binary logistic regression and the Cox proportional hazard regression with the NULL PLEASE score variables. After propensity score matching, 50 patients were selected in each group (Fig.1, Table 1). Serum levels of NSE and the percentage of brain tissue with ADC value &lt; 650 X 10 -6 mm 2 /s (PV 650 ) obtained 72 h after ROSC were lower in the group with LD (Table 2). The analysis revealed that LD was associated with good neurological prognosis and increased the probability of survival (Table 3, Fig. 2). The subgroup analysis, focusing on OHCA patients with moderate severity based on the rCAST score, yieded consistent results (Table 4, Fig. 2).This study demonstrated that LD significantly improved neurological prognosis and reduced mortality in OHCA patients with moderate severity.

Predictive value of spinal CSF volume in the preoperative assessment of patients with idiopathic normal-pressure hydrocephalus.

The pathophysiology, diagnosis, and management of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Although some prognostic tests recommended in iNPH guidelines should have high sensitivity and high predictive value, there is often no positive clinical response to surgical treatment. In our study, 19 patients with clinical and neuroradiological signs of iNPH were selected for preoperative evaluation and possible further surgical treatment according to the guidelines. MR volumetry of the intracranial and spinal space was performed. Patients were exposed to prolonged external lumbar drainage in excess of 10 ml per hour during 3 days. Clinical response to lumbar drainage was assessed by a walk test and a mini-mental test. Twelve of 19 patients showed a positive clinical response and underwent a shunting procedure. Volumetric values of intracranial space content in responders and non-responders showed no statistically significant difference. Total CSF volume (sum of cranial and spinal CSF volumes) was higher than previously published. No correlation was found between spinal canal length, CSF pressure, and CSF spinal volume. The results show that there is a significantly higher CSF volume in the spinal space in the responder group (n = 12) (120.5 ± 14.9 ml) compared with the non-responder group (103.1 ± 27.4 ml; n = 7). This study demonstrates for the first time that CSF volume in the spinal space may have predictive value in the preoperative assessment of iNPH patients. The results suggest that patients with increased spinal CSF volume have decreased compliance. Additional prospective randomized clinical trials are needed to confirm our results.

Simple methods for cerebrospinal fluid collection in fetal, neonatal, and adult rat

BackgroundCerebrospinal fluid (CSF) collection and its analysis are common medical practices useful in the diagnosis, therapy, and prevention of central nervous system (CNS) disorders. In recent years, several types of research have improved our insight into CSF and its role in health and disease. Yet, many characteristics of this fluid remain to be fully understood. New methodsHere, we describe how to collect CSF from embryonic, postnatal, and adult stages of the rat. In adults, CSF can be collected through simple stereotaxic surgery to expose the membrane overlying the cisterna magna (CM) of an anesthetized rat and collection of CSF through micropipette puncture through the membrane. In embryos and pups, CSF is aspirated, using a fire-polished micro-capillary pipette, from the CM of animals. ResultsApplication of these methods provides the maximum volume of pure, uncontaminated CSF (embryonic day 19: 10–15 microliter, postnatal day 5: 20–30 microliter, adults: 100–200 microliter) with a success rate of approximately 95% in every age. Comparison with existing methodsCompared to the existing protocols, these methods obtain considerable volumes of CSF, which may accelerate the measurement of biological markers in this fluid. Also, these techniques do not require surgical skills and according to the practical points mentioned during sampling, the procedures can be performed in rapid fashion. ConclusionWe describe simple methods for collecting CSF in live rats. These protocols provide clean, uncontaminated CSF for experiments to understand the exact role of this fluid in the development and maintenance of the CNS health.