Low Cerebrospinal Fluid Research Articles

Clinical Features of Cryptococcal Meningoencephalitis in HIV-Positive and -Negative Patients in a Resource-Limited Setting.

Cryptococcal meningoencephalitis is a systemic fungal infection in immunocompromised and immunocompetent individuals. This study investigated the clinical characteristics and factors associated with mortality in HIV-associated and non-HIV-associated cryptococcal meningoencephalitis in a resource-limited setting. This was a retrospective cohort study of patients with cryptococcal meningoencephalitis between January 2009 and December 2019 at a tertiary teaching hospital in Thailand. Overall, 1019 patients with cryptococcal meningoencephalitis were enrolled, and 923 (90.6%) were HIV-positive. The patients with HIV-associated cryptococcal meningoencephalitis were younger than the HIV-negative patients (37 versus 56 years, p < 0.01). The HIV-negative patients were more likely to have underlying conditions (52.1% versus 7.5%; p < 0.01), had a longer median duration of headaches prior to admission (14 days versus 6 days, p < 0.01), and were more likely to have an altered mental status at presentation (36.5% versus 18.6%, p < 0.01) and pulmonary involvement (15.6% versus 0.8%, p < 0.01). The HIV-positive patients had lower cerebrospinal fluid (CSF) white blood cell counts (4 versus 94 cells/mm3; p < 0.01), lower CSF protein (69 versus 157 mg/dL; p < 0.01), higher CSF glucose (38.8 versus 21 mg/dL; p < 0.01), and more frequent cryptococcemia (44.1% versus 20.5%; p < 0.01). The mortality rate was high but not significantly different between the two groups (30.2% versus 33.2%; p = 0.53). The HIV-positive patients with comorbidities, fever, an altered mental status at presentation, a CSF white blood cell count below 20 cell/mm3, fungemia, and positive CSF India ink were independently associated with 30-day mortality. In comparison, an altered mental status at presentation and fungemia were associated with 30-day mortality in HIV-negative patients. In conclusion, HIV-negative patients with cryptococcal meningoencephalitis had more extensive central nervous system inflammation, although the two groups' mortality rates were similar. Unfavorable prognostic factors included comorbidities, fever, an altered mental status at presentation, a low CSF white blood cell count, fungemia, and positive CSF India ink.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache in Patients Undergoing Lower Abdominal Surgeries

Abstract Background Postdural puncture headache (PDPH) is a complication of spinal anesthesia or lumbar puncture and is an unpleasant experience for the patient as well as the anesthetist. It is thought to result from meningeal traction related to low cerebrospinal fluid (CSF) pressure or cerebral vasodilation as an indirect effect of decreased CSF pressure. Neostigmine is a reversible inhibitor of the enzyme cholinesterase, which results in an increased concentration of the neurotransmitter acetylcholine. It produces cholinergic-mediated analgesia and has been used as an adjunct analgesic postoperatively. Neostigmine can pass through the choroid plexus but not the blood–brain barrier, the central effect of both neostigmine and atropine influence both CSF secretion and cerebral vascular tone which are the primary pathophysiological changes in PDPH. Objective Assess the effectiveness of postdural anesthesia with addition of Neostigmine and Atropine versus conventional postdural anesthesia. Patients and Methods A 90 patients were included in our prospective randomized controlled double-blind study that was conducted at Ain Shams University Hospitals for 4 months on patients who fulfilled the inclusion criteria: patients with ASA Grade I &amp; II, aged from (18 to 40) years old and scheduled for cesarean section. All patients aged &amp;gt;18 or &amp;lt;40, body weight &amp;gt;50, ASA III, IV, patients with uncontrolled chronic diseases such as hypertension, cardiac, renal, hepatic, cerebral diseases and peripheral vascular diseases, patients with history of PDPH, chronic headache, cluster headache, migraine, convulsions, cerebrovascular accident, signs of meningismus, preeclampsia, eclampsia coagulopathy, and previous neurological diseases and patients with history of bronchial asthma were excluded. Patients were divided into 2 groups: Group I (experimental group): neostigmine and atropine and Group II (placebo group): Saline placebo. Results The results of this study showed that incidence of postoperative headache was significantly lower among the intervention group, furthermore, VAS was significantly lower in the experimental arm versus placebo one. However, there was no significant difference regarding demographic, vital signs, and need for post-operative analgesia. The presented study showed that there is statistically non-significant difference between the studied groups regarding age, weight, and height and body mass index. There is statistically non-significant difference between the studied groups regarding duration of surgery. Conclusion After demonstrating many management options for post dural puncture headache (PDPH), in this study, we tried to prove the value of the use of neostigmine as a new management option that looks promising to alleviate the symptoms of such distressing condition. The current study results proved that the drug reduced the number of cases that experienced (PDPH) after spinal anesthesia for lower segment caesarean section, and how it prevent &amp;control headache. A combination of neostigmine and atropine are effective in managing PDPH by reducing the associated VAS score and preventing persistence of headache.

Fiber-Specific White Matter Alterations in Parkinson's Disease Patients with GBA Gene Mutations.

Patients with Parkinson's disease (PD) carrying GBA gene mutations (GBA-PD) have a more aggressive disease course than those with idiopathic PD (iPD). The objective of this study was to investigate fiber-specific white matter (WM) differences in nonmedicated patients with early-stage GBA-PD and iPD using fixel-based analysis, a novel technique to assess tract-specific WM microstructural and macrostructural features comprehensively. Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross section (FC), and a combination of FD and FC (FDC), were compared among 30 healthy control subjects, 16 patients with GBA-PD, and 35 patients with iPD. Associations between FDC and clinical evaluations were also explored using multiple linear regression analyses. Patients with GBA-PD showed significantly lower FD in the fornix and superior longitudinal fasciculus than healthy control subjects, and lower FC in the corticospinal tract (CST) and lower FDC in the CST, middle cerebellar peduncle, and striatal-thalamo-cortical pathways than patients with iPD. Contrarily, patients with iPD showed significantly higher FC and FDC in the CST and striatal-thalamo-cortical pathways than healthy control subjects. In addition, lower FDC in patients with GBA-PD was associated with reduced glucocerebrosidase enzyme activity, lower cerebrospinal fluid total α-synuclein levels, lower Montreal Cognitive Assessment scores, lower striatal binding ratio, and higher Unified Parkinson's Disease Rating Scale Part III scores. We report reduced fiber-specific WM density and bundle cross-sectional size in patients with GBA-PD, suggesting neurodegeneration linked to glucocerebrosidase deficiency, α-synuclein accumulation, and poorer cognition and motor functions. Conversely, patients with iPD showed increased fiber bundle size, likely because of WM reorganization. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spontaneous Intracranial Hypotension: An Uncommon Cause of Postural Vestibulocochlear Symptoms.

Spontaneous intracranial hypotension is an uncommon but increasingly recognized condition characterized by an orthostatic headache secondary to low cerebrospinal fluid pressure. Vestibulocochlear symptoms are common but rarely the only presenting feature and can be challenging to differentiate from Meniere's disease. We present a case series that highlights the common vestibulocochlear symptoms and a review of the literature to increase awareness amongst otolaryngologists and highlight the path to diagnosis and management of this condition.

Several dementia subtypes and mild cognitive impairment share brain reduction of neurotransmitter precursor amino acids, impaired energy metabolism, and lipid hyperoxidation.

Dementias and mild cognitive impairment (MCI) are associated with variously combined changes in the neurotransmitter system and signaling, from neurotransmitter synthesis to synaptic binding. The study tested the hypothesis that different dementia subtypes and MCI may share similar reductions of brain availability in amino acid precursors (AAPs) of neurotransmitter synthesis and concomitant similar impairment in energy production and increase of oxidative stress, i.e., two important metabolic alterations that impact neurotransmission. Sixty-five demented patients (Alzheimer's disease, AD, n = 44; frontotemporal disease, FTD, n = 13; vascular disease, VaD, n = 8), 10 subjects with MCI and 15 control subjects (CTRL) were recruited for this study. Cerebrospinal fluid (CSF) and plasma levels of AAPs, energy substrates (lactate, pyruvate), and an oxidative stress marker (malondialdehyde, MDA) were measured in all participants. Demented patients and subjects with MCI were similar for age, anthropometric parameters, biohumoral variables, insulin resistance (HOMA index model), and CSF neuropathology markers. Compared to age-matched CTRL, both demented patients and MCI subjects showed low CSF AAP tyrosine (precursor of dopamine and catecholamines), tryptophan (precursor of serotonin), methionine (precursor of acetylcholine) limited to AD and FTD, and phenylalanine (an essential amino acid largely used for protein synthesis) (p = 0.03 to <0.0001). No significant differences were found among dementia subtypes or between each dementia subtype and MCI subjects. In addition, demented patients and MCI subjects, compared to CTRL, had similar increases in CSF and plasma levels of pyruvate (CSF: p = 0.023 to <0.0001; plasma: p < 0.002 to <0.0001) and MDA (CSF: p < 0.035 to 0.002; plasma: p < 0.0001). Only in AD patients was the CSF level of lactate higher than in CTRL (p = 0.003). Lactate/pyruvate ratios were lower in all experimental groups than in CTRL. AD, FTD, and VaD dementia patients and MCI subjects may share similar deficits in AAPs, partly in energy substrates, and similar increases in oxidative stress. These metabolic alterations may be due to AAP overconsumption following high brain protein turnover (leading to phenylalanine reductions), altered mitochondrial structure and function, and an excess of free radical production. All these metabolic alterations may have a negative impact on synaptic plasticity and activity.

Ventriculosubgaleal shunts in the management of neonatal post-haemorrhagic hydrocephalus: technical note.

Germinal matrix / intraventricular haemorrhage (GMIVH) remains a significant complication of prematurity. The more severe grades are associated with parenchymal haemorrhagic infarction (PHI) and hydrocephalus. A temporising procedure is usually the first line in management of neonatal post-haemorrhagic hydrocephalus (nPHH) as the risk of failure of a permanent cerebrospinal fluid (CSF) diversion is higher in the early stage. Our choice of temporising procedure is a ventriculosubgaleal shunt (VSGS). In this technical note, we describe a modification in technique whereby the pocket of the VSGS is fashioned away from the surgical wound. This resulted in lower CSF leak and subsequent infection rates in our centre. We conducted a retrospective analysis of all patients who underwent insertion of a VSGS between September 2014 and February 2023. Twenty children were included in our study with a mean gestational age of 31 weeks + 4 days. Post-operatively, 10% of patients did not need a tap, and 10%, 20%, 15%, 25% and 20% respectively had 1, 2, 3, 4 and 5 taps. Two patients experienced CSF leak from their wounds. In both these patients, the pocket was deemed too close to the wound. None of the patients without suspected pre-existing CNS infection at the time of insertion of VSGS had a subsequent VSGS-related infection. VSGS conversion to permanent ventriculoperitoneal shunts (VPS) was required in 15 (75%) of the patients with an average interval duration of 72 days. On reviewing the literature, the infection rate following VSGS is quoted up to 13.5%. In our own centre, 13 patients had undergone VSGS insertion between 2005 and 2013 with a 30.8% infection rate which seemed related to increased leak rates. Our modified surgical approach seems to be effective in reducing the risk of infection, which we postulate is a direct result of reduction in the risk of leak from the surgical wound.

White matter hyperintensity volume modifies the association between CSF vascular inflammatory biomarkers and regional FDG-PET along the Alzheimer’s disease continuum

In older adults with abnormal levels of Alzheimer’s disease neuropathology, lower cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF) levels are associated with lower [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) signal, but whether this association is (1) specific to VEGF or broadly driven by vascular inflammation, or (2) modified by vascular risk (e.g., white matter hyperintensities [WMHs]) remains unknown. To address this and build upon our past work, we evaluated whether 5 CSF vascular inflammation biomarkers (vascular cell adhesion molecule 1, VEGF, C-reactive protein, fibrinogen, and von Willebrand factor)—previously associated with CSF amyloid levels—were related to FDG-PET signal and whether WMH volume modified these associations in 158 Alzheimer’s Disease Neuroimaging Initiative participants (55–90 years old, 39 cognitively normal, 80 mild cognitive impairment, 39 Alzheimer’s disease). We defined regions both by cortical boundary and by the 3 major vascular territories: anterior, middle, and posterior cerebral arteries. We found that WMH volume had interactive effects with CSF biomarkers (VEGF and C-reactive protein) on FDG-PET throughout the cortex in both vascular territories and conventionally defined regions of interest.

Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder.

Patients with isolated rapid-eye-movement sleep behavior disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal-fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in patients with iRBD compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson's Disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA)). Patients and controls underwent between 2012 and 2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (β-amyloid42 - Aβ42; total-tau, and phosphorylated tau), and BBB alteration (CSF/serum albumin ratio). All patients with iRBD were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). Thirty-four patients with iRBD (mean age 67.12 ± 8.14) and 33 controls (mean age 64.97 ± 8.91) were included. At follow-up (7.63 ± 3.40 years), eight patients were ncRBD and 33 patients were cRBD: eleven converted to PD, 10 to DLB, and two to MSA. Patients with iRBD showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio [HR] = 1.23, p = 0.032). CSF Aβ42 levels predicted phenoconversion to DLB (HR = 0.67, p = 0.038) and BBB alteration predicted phenoconversion to PD (HR = 1.20, p = 0.038). This study showed that low CSF Aβ42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in patients with iRBD, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers; however, further studies are needed.

Risk factors and cerebrospinal fluid indexes analysis of intracranial infection by Acinetobacter baumannii after neurosurgery

BackgroundIntracranial infection by Acinetobacter baumannii (A. baumannii) after neurosurgery has always been a difficult problem for neurosurgeons. This study analyzed risk factors that discriminated A. baumannii from other bacteria causing intracranial infection after neurosurgery. It also examined the differences in the cerebrospinal fluid (CSF) indexes to explore their value in the early diagnosis of intracranial infection by A. baumannii. MethodsWe retrospectively reviewed ten years (January 2011 to May 2021) of postoperative central nervous system (CNS) infections in the First Hospital of China Medical University. According to the pathogen, CNS infections were divided into A. baumannii group and other species of bacteria group. We collected clinical and laboratory information of patients, and statistical analysis was performed with SPSS 26.0. Risk factors were screened by univariate analysis, and independent risk factors were screened by multiple logistic regression analysis. Finally, CSF-Pro, CSF-Glu, CSF-Cl, CSF-monocytes (%), CSF-multinucleated cells (%) levels, and CSF multinucleated cells%/monocytes% in the different groups were analyzed. ResultsA total of 155 patients were included, 62 cases (40%) of intracranial infection by A. baumannii and 93 cases (60%) by other species of bacteria. The analysis showed that indwelling nasogastric tubes (P＜0.001, OR = 4.231), indwelling peripherally inserted central catheters (PICCs) (P = 0.041, OR = 2.765), and CSF drainage obstruction (P = 0.003, OR = 3.765) were independent risk factors for intracranial infection by A. baumannii after neurosurgery. Indwelling ventriculoperitoneal shunt (VPS) was a protective factor (P = 0.033, OR = 0.22). In addition, compared with other bacterial groups, the A. baumannii group had higher CSF-pro and CSF- multinucleated cells (%) levels and lower CSF-Glu and CSF- monocytes (%) levels, and the difference was statistically significant (P < 0.01). ConclusionsOur results elucidate risk factors and differences in CSF indexes for intracranial infection by A. baumannii after neurosurgery that could be detected and prevented early to reduce mortality.

Mediterranean diet is associated with lower white matter lesion volume in Mediterranean cities and lower cerebrospinal fluid Aβ42 in non-Mediterranean cities in the EPAD LCS cohort

The Mediterranean diet (MedDiet) has been associated with better brain health and reduced incidence of dementia. Few studies have compared the effects of the MedDiet in early Alzheimer’s disease or compared the effects of the diet within and outside of the Mediterranean region. The Mediterranean diet adherence screener (MEDAS) and MEDAS continuous scores were calculated at the baseline visit of the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (n = 1625). The scores were included in linear regression models to test for associations with hippocampal volume, log-transformed white matter lesion volume, cerebrospinal fluid pTau18, and Aβ42. Higher MEDAS scores were associated with lower log-transformed white matter lesion volume (β: −0.07, standard error [SE]: 0.02, p < 0.001). This association was only seen in the Mediterranean region (β: −0.12, SE: 0.03, p < 0.001). In the non-Mediterranean region, higher MEDAS continuous scores were associated with lower cerebrospinal fluid Aβ42 (β: −68.30, SE: 14.32, p < 0.001). More research is needed to understand the differences in the associations seen with the MedDiet and Alzheimer’s disease biomarkers in different European regions.

Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease

BackgroundDespite being twice as likely to get Alzheimer’s disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from African Americans and Caucasians with and without AD to identify both common and divergent AD CSF biomarkers.MethodsMultiplex tandem mass tag-based mass spectrometry (TMT-MS) quantified 1,840 proteins from 105 control and 98 AD patients of which 100 identified as Caucasian while 103 identified as African American. We used differential protein expression and co-expression approaches to assess how changes in the CSF proteome are related to race and AD. Co-expression network analysis organized the CSF proteome into 14 modules associated with brain cell-types and biological pathways. A targeted mass spectrometry method, selected reaction monitoring (SRM), with heavy labeled internal standards was used to measure a panel of CSF module proteins across a subset of African Americans and Caucasians with or without AD. A receiver operating characteristic (ROC) curve analysis assessed the performance of each protein biomarker in differentiating controls and AD by race.ResultsConsistent with previous findings, the increase of Tau levels in AD was greater in Caucasians than in African Americans by both immunoassay and TMT-MS measurements. CSF modules which included 14–3-3 proteins (YWHAZ and YWHAG) demonstrated equivalent disease-related elevations in both African Americans and Caucasians with AD, whereas other modules demonstrated more profound disease changes within race. Modules enriched with proteins involved with glycolysis and neuronal/cytoskeletal proteins, including Tau, were more increased in Caucasians than in African Americans with AD. In contrast, a module enriched with synaptic proteins including VGF, SCG2, and NPTX2 was significantly lower in African Americans than Caucasians with AD. Following SRM and ROC analysis, VGF, SCG2, and NPTX2 were significantly better at classifying African Americans than Caucasians with AD.ConclusionsOur findings provide insight into additional protein biomarkers and pathways reflecting underlying brain pathology that are shared or differ by race.

Intracranial Hypotension and Bilateral Isolated Cortical Vein Thrombosis: A Case Report and Literature Review

Background: Intracranial hypotension (IH) is a clinical manifestation of low cerebrospinal fluid pressure with reports of isolated cortical venous thrombosis (ICVT) rarely described. Case Presentation: A 23-year-old man presented with postural headache followed by blurry vision and horizontal binocular diplopia with extreme gaze. Patient workup showed diffuse thickening and enhancement of the dura suggestive of intracranial hypotension and biparietal superficial cortical vein thrombosis was noted on imaging. The patient was started on folate and therapeutic anticoagulation and his condition improved. Conclusion: Patients with IH are at risk for CVT due to the dilation of the venous sinuses of the brain. Changes in the characteristics of the headache of the patient or the onset of new neurological symptoms should warrant further investigation. Prophylactic systemic anticoagulation might cautiously be indicated in high-risk patients with IH to prevent ICVT.

Lower Cerebrospinal Fluid Amyloid-β42 Predicts Sooner Time to Antipsychotic Use in Alzheimer's Disease.

Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42) and phosphorylated-tau help clinicians accurately diagnose Alzheimer's disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Determine whether CSF biomarker levels aid prognostication of BPSD in AD. This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42, total tau, phosphorylated tau, and amyloid-to-tau index using a survival analysis approach. Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD.

Association between morphologic features of intracranial distal arteries and brain atrophy indexes in cerebral small vessel disease: a voxel-based morphometry study.

Brain atrophy represents a final common pathway for pathological processes in patients with cerebral small vessel disease (CSVD) and is now recognized as a strong independent predictor of clinical status and progression. The mechanism underlying brain atrophy in patients with CSVD is not yet fully comprehended. This study aims to investigate the association of morphologic features of intracranial distal arteries (A2, M2, P2 and more distal) with different brain structures [gray matter volume (GMV), white matter volume (WMV), and cerebrospinal fluid volume (CSFV)]. Furthermore, we also examined whether a correlation existed between these cerebrovascular characteristics and GMV in different brain regions. A total of 39 participants were eventually enrolled. The morphologic features of intracranial distal arteries based on TOF-MRA were extracted and quantified using the intracranial artery feature extraction technique (iCafe). The brain 3D-T1 images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using the "Segment" tool in CAT12 for the voxel-based morphometry (VBM) analysis. Univariable and multivariable linear regression models were used to investigate the relationship between these cerebrovascular features and different brain structures. Partial correlation analysis with a one-tailed method was used to evaluate the relationship between these cerebrovascular features and GMV in different brain regions. Our findings indicate that both distal artery length and density were positively correlated with GM fraction in CSVD patients, regardless of whether univariable or multivariable linear regression analyses were performed. In addition, distal artery length (β = -0.428, p = 0.007) and density (β = -0.337, p = 0.036) were also found to be negative associated with CSF fraction, although this relationship disappeared after adjusting for potential confounders. Additional adjustment for the effect of WMHs volume did not change these results. In subgroup anasysis, we found that participants in the highest distal artery length tertile had significantly higher GM fraction and lower CSF fraction level than participants in the lowest distal artery length tertile. In partial correlation analysis, we also found that these cerebrovascular characteristics associated with regional GMV, especially subcortical nuclear. The morphologic features of intracranial distal arteries, including artery length, density and average tortuosity, measured from 3D-TOF MRA, are associated with generalized or focal atrophy indexes of CSVD.

Disentangling the impact of cerebrospinal fluid formation and neuronal activity on solute clearance from the brain

BackgroundDespite recent attention, pathways and mechanisms of fluid transposition in the brain are still a matter of intense discussion and driving forces underlying waste clearance in the brain remain elusive. Consensus exists that net solute transport is a prerequisite for efficient clearance. The individual impact of neuronal activity and cerebrospinal fluid (CSF) formation, which both vary with brain state and anesthesia, remain unclear.MethodsTo separate conditions with high and low neuronal activity and high and low CSF formation, different anesthetic regimens in naive rat were established, using Isoflurane (ISO), Medetomidine (MED), acetazolamide or combinations thereof. With dynamic contrast-enhanced MRI, after application of low molecular weight contrast agent (CA) Gadobutrol to cisterna magna, tracer distribution was monitored as surrogate for solute clearance. Simultaneous fiber-based Ca2+-recordings informed about the state of neuronal activity under different anesthetic regimen. T2-weighted MRI and diffusion-weighted MRI (DWI) provided size of subarachnoidal space and aqueductal flow as surrogates for CSF formation. Finally, a pathway and mechanism-independent two-compartment model was introduced to provide a measure of efficiency for solute clearance from the brain.ResultsAnatomical imaging, DWI and Ca2+-recordings confirmed that conditions with distinct levels of neuronal activity and CSF formation were achieved. A sleep-resembling condition, with reduced neuronal activity and enhanced CSF formation was achieved using ISO+MED and an awake-like condition with high neuronal activity using MED alone. CA distribution in the brain correlated with the rate of CSF formation. The cortical brain state had major influence on tracer diffusion. Under conditions with low neuronal activity, higher diffusivity suggested enlargement of extracellular space, facilitating a deeper permeation of solutes into brain parenchyma. Under conditions with high neuronal activity, diffusion of solutes into parenchyma was hindered and clearance along paravascular pathways facilitated. Exclusively based on the measured time signal curves, the two-compartment model provided net exchange ratios, which were significantly larger for the sleep-resembling condition than for the awake-like condition.ConclusionsEfficiency of solute clearance in brain changes with alterations in both state of neuronal activity and CSF formation. Our clearance pathway and mechanism agnostic kinetic model informs about net solute transport, solely based on the measured time signal curves. This rather simplifying approach largely accords with preclinical and clinical findings.

Associations of Blood and Cerebrospinal Fluid Aβ and tau Levels with Renal Function.

Amyloid β (Aβ) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aβ and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aβ and tau. However, the effects of deficiency in the clearance of Aβ and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aβ and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aβ40, Aβ42 and total tau (T-tau), lower CSF levels of Aβ40 and Aβ42 and higher levels of CSF T-tau/Aβ42 and phosphorylated tau (P-tau)/Aβ42. Plasma Aβ40, Aβ42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aβ42, and P-tau/Aβ42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.

Day‐to‐day sleep and circadian variability in association with Alzheimer’s Disease biomarkers

AbstractBackgroundIncreasing evidence shows that Alzheimer’s Disease (AD) pathology, i.e., the Aß peptide, tau tangles and the APOEε4 allele, have all been associated with disrupted sleep and change in circadian rhythms. However, objective sleep measurements are often assessed over a single night. Measures of day‐to‐day variability might reveal unstable sleep and circadian rhythms that may reflect neurodegenerative processes. We sought to evaluate the association between AD biomarkers and sleep and circadian variability measured over a week of actigraphy.Method203 dementia‐free participants (age: 68.5±5.4 years, 151 women) from the PREVENT‐AD cohort with known APOEε4 carrier status were tested with a week of actigraphy. Overlapping subsamples were tested for determination of cerebrospinal fluid (CSF) Aß1‐42, total t‐tau and p(181)‐tau (n = 100); CSF apoE protein (n = 69); and plasma Aß1‐42 (n = 144). Day‐to‐day variability in actigraphy circadian and sleep measures were assessed using the standard deviation of individual results. Day‐to‐day variability was compared between APOEε4 carriers were compared to non‐carriers using t‐tests. Linear regressions were performed between day‐to‐day variability with CSF and plasma, adjusted for age, sex, and time interval between measurements. An interaction term for APOEε4 carrier status was additionally tested in regression models.ResultAPOEε4 carriers did not differ meaningfully from non‐carriers regarding sleep and circadian variability. Lower CSF Aß1‐42 was associated with higher day‐to‐day variability of time of morning awakening and nighttime sleep duration (ß = ‐0.263, p = 0.009; b = ‐0.206, p = 0.041). Higher plasma Aß1‐42 was also associated with higher day‐to‐day variability for time in bed, activity counts, sleep onset latency, sleep efficiency, and nighttime sleep duration (ß = 0.160 to 0.242; p = 0.010 to 0.002). Lower CSF apoE protein was associated with increased day‐to‐day variability for time of morning awakening, time in bed, activity counts, and nighttime sleep duration (ß = ‐0.243 to ‐0.420; p = 0.042 to &lt;0.001). Higher CSF t‐tau, and a trend for p(181)‐tau were associated with time of morning awakening day‐to‐day variability inε4 carriers only (interaction p&lt;0.001;ß = 0.330, p = 0.047; b = 0.281, p = 0.094).ConclusionSleep and circadian variability are associated with biomarkers of AD pathology and apoE metabolism. These results may suggest that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep and circadian function.

Sensitive detection of CSF-derived cell-free DNA at the CNV level by shallow whole-genome sequencing for diagnosis and characterization of CNS metastases.

e21185 Background: The cfDNA targeted capture sequencing technology has been gradually applied to research central nervous system (CNS) metastases. But targeted sequencing usually requires at least 5 ng of cfDNA. Due to the limited amount of cerebrospinal fluid (CSF) that can be collected there are not many samples that can meet the requirements of targeted sequencing. Methods: This study assessed the use of shallow whole-genomic sequencing (sWGS) of blood and CSF samples obtained from 35 patients with lung cancer to identify tumor-derived cfDNA. Among them, 6 cases had no intracranial metastasis, 22 had only PMs, and 7 had LMs. Some of these cases underwent irregular follow-up. For blood samples, 5 ng cfDNA was used for library preparation. For CSF samples, try to use trace DNA to prepare libraries, regardless of whether the Qubit assays can quantify the concentration. Cytologic analysis was also performed on CSF samples from the LM cases. A total of 35 peripheral blood samples and 31 cerebrospinal fluid samples were subjected to sWGS tests, and the arm-level CNV and tumor proportion were analyzed.Cytologic analysis was also performed on CSF samples from the LMs. Results: The lowest concentration of cfDNA in 35 plasma samples was 2.20 ng/mL. But when the cfDNA was extracted from the CSF, 50% (6/12) of the LM samples and 70.59% (12/17) of the samples with only PMs could not be quantified by Qubit assays. All libraries were all successfully prepared from the samples that could not quantify cfDNA. For CSF samples from LM cases, the sensitivity of detecting tumor signals by the sWGS test was 90.9% (10/11), higher than 81.8% (9/11) by CSF cytologic analysis. For samples from PM cases, the sensitivity of detecting tumor signals by the sWGS test was 75% (21/28); among them, the detection sensitivity of samples with a total amount of cfDNA not less than 5 ng was 90% (9/10), while the detection sensitivity of samples with the total amount of cfDNA less than 5 ng was 66.67% (12/18). Three patients underwent multiple CSF cfDNA tests, of which one case with RANO evaluation as PR had a decrease in the tumor fraction in CSF cfDNA, while only one of the two cases with RANO SD evaluation had stable tumor fraction in CSF cfDNA. Conclusions: We established a method for detecting CNVs by sWGS using trace amounts of cfDNA. Using the sWGS test improves the sensitivity of the detection of LMs. Compared with targeted capture sequencing, our method reduces the requirement for the amount of cfDNA, which can be more widely used in the detection of CNS metastases, especially in PM-only patients with extremely low CSF cfDNA concentrations.

Lower initial red blood cell count in cerebrospinal fluid predicts good functional outcome in patients with spontaneous subarachnoid haemorrhage.

Red blood cell (RBC) degradation after subarachnoid haemorrhage (SAH) negatively affects functional outcome. Although the detection of RBCs in the cerebrospinal fluid (CSF) is a widely available part of neurological routine diagnostics, the prognostic value as a biomarker remains unclear. This study was undertaken to investigate whether CSF RBC count correlates with established radiological markers of SAH volume and whether the CSF RBC count can predict functional outcome in SAH patients. A total of 121 consecutive spontaneous SAH patients were retrospectively analyzed. CSF was collected from external ventricular drain as part of routine diagnostic procedures. We used multivariable binary logistic regression to investigate associations between CSF RBC counts and functional outcome 3 months after SAH or hospital survival. Good functional outcome was defined as modified Rankin Scale ≤ 2. Patients' age was 60 ± 14 years, and the median admission Hunt & Hess grade (H&H) was 4. CSF samples were collected 2 days after intensive care unit admission. High CSF RBC counts positively correlated with radiological measurements for SAH volume, for example, modified Fisher score (p = 0.002) and Hijdra ventricle score (p = 0.016). Multivariable regression analysis adjusted for age, H&H grade, modified Fisher and Hijdra scores showed that low CSF RBC counts predicted hospital survival (per 100,000 CSF RBCs: adjusted odds ratio [adjOR] = 0.74, 95% confidence interval [CI] = 0.61-0.89, p = 0.001) and good functional outcome after 3 months (per 100,000 CSF RBC: adjOR = 0.76, 95% CI = 0.60-0.96, p = 0.020). CSF RBC counts correlate with radiographic scores quantifying SAH volume and may serve as an early independent biomarker for hospital survival and good functional 3-month outcome in patients requiring ventriculostomy after SAH.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses.MethodsA retrospective observational study was conducted...