Low Cerebrospinal Fluid Research Articles

Association of inflammatory cytokines expression in cerebrospinal fluid with the severity and prognosis of spontaneous intracerebral hemorrhage

ObjectiveTo investigate the potential diagnostic and prognostic implications of inflammatory cytokine levels in the cerebrospinal fluid (CSF) of patients with spontaneous intracerebral hemorrhage (SICH) upon their initial hospital admission.MethodsOur cohort included 100 patients diagnosed with acute SICH, presenting to the Department of Neurosurgery. Additionally, we recruited 50 individuals without central nervous system (CNS) pathology, treated concurrently at our facility, as controls. CSF samples, collected upon hospital entry, were quantitatively assessed for 10 inflammatory cytokines using the Mesoscale Discovery Platform (MSD, Rockville, MD, USA) electrochemiluminescence technology, followed by validation through enzyme-linked immunosorbent assay (ELISA).ResultsWe observed a marked elevation of IL-6, IL-8, IL-10, and TNF-α in the CSF of the SICH subgroup compared to controls. Higher Glasgow Coma Scale (GCS) scores in SICH patients corresponded with lower CSF concentrations of IL-6, IL-8, IL-10, and TNF-α, indicating an inverse relationship. Notably, CSF inflammatory cytokine levels were consistently higher in SICH patients with hydrocephalus than in those without. Increases in IL-6, IL-8, IL-10, and TNF-α in the CSF were notably more pronounced in the poor prognosis group (Glasgow Outcome Scale, GOS 1–3) compared to those with a favorable prognosis (GOS 4–5). The AUC values for these cytokines in predicting SICH prognosis were 0.750, 0.728, 0.717, and 0.743, respectively.ConclusionsInitial CSF levels of IL-6, IL-8, IL-10, and TNF-α upon admission provide significant insights into the severity of neural damage and are robust indicators for prognosis in SICH patients.

Use of Metagenomic Next-Generation Sequencing to Identify Pathogens Involved in Central Nervous System Infections.

Application of metagenomic next-generation sequencing (mNGS) in identifying nosocomial central nervous system (CNS) infections in critical care units remains understudied. We conducted a retrospective analysis of microbiological results through both mNGS and routine examination of cerebrospinal fluid (CSF) samples from patients with nosocomial CNS infections. The aim of this study was to assess the clinical diagnostic effect of nosocomial mNGS in this population. The study included 26 cases of nosocomial CNS infections in total. A total of 69.2% (18/26) of the samples tested positive for mNGS, which is substantially greater than the 7.7% (2/26; p<0.05) detected through conventional techniques. Administration of antibiotics before culture is most likely the cause of the low CSF culture rate. Twenty-five pathogenic strains that were missed by standard testing. Three pathogens that were consistent with the mNGS results were positive by routine tests. Eight cases were negative by mNGS due to low pathogen CSF titres. Compared to traditional testing, mNGS demonstrated 100% sensitivity and 33.3% specificity in diagnosing CNS infections. The thirty-day mortality rate was 26.9% (7/26). Routine microbiologic testing frequently falls short of detecting all neuroinvasive pathogens. Our research suggests that mNGS offers an alternative means of detecting nosocomial CNS infections. By applying mNGS to CSF samples from patients with meningitis or encephalitis, we were able to improve the ability to diagnose nosocomial neurologic infections.

Traumatic Brain Injury and Genetic Risk for Alzheimer's Disease Impact Cerebrospinal Fluid β-Amyloid Levels in Vietnam War Veterans.

Traumatic brain injuries (TBIs) may increase the risk for Alzheimer's disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on β-amyloid (Aβ) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aβ42/40. Data were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aβ42/40 ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aβ42/40. Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino (M age = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aβ42/40 (B = -0.45, 95% CI: -0.86 to -0.05, p = 0.03). This relationship may be stronger with increasing TBI severity (p = 0.05). Overall, TBI was associated with lower Aβ42/40, indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight who may be at increased risk for AD neuropathology following TBI.

Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly.

Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3±5.4; 78males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-β (Aβ)42, and higher plasma p-tau231/Aβ42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography.

Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Association of white matter hyperintensities with cognitive decline and neurodegeneration.

The relationship between white matter hyperintensities (WMH) and the core features of Alzheimer's disease (AD) remains controversial. Further, due to the prevalence of co-pathologies, the precise role of WMH in cognition and neurodegeneration also remains uncertain. Herein, we analyzed 1803 participants with available WMH volume data, extracted from the ADNI database, including 756 cognitively normal controls, 783 patients with mild cognitive impairment (MCI), and 264 patients with dementia. Participants were grouped according to cerebrospinal fluid (CSF) pathology (A/T profile) severity. Linear regression analysis was applied to evaluate the factors associated with WMH volume. Modeled by linear mixed-effects, the increase rates (Δ) of the WMH volume, cognition, and typical neurodegenerative markers were assessed. The predictive effectiveness of WMH volume was subsequently tested using Cox regression analysis, and the relationship between WMH/ΔWMH and other indicators such as cognition was explored through linear regression analyses. Furthermore, we explored the interrelationship among amyloid-β deposition, cognition, and WMH using mediation analysis. Higher WMH volume was associated with older age, lower CSF amyloid-β levels, hypertension, and smoking history (all p ≤ 0.001), as well as cognitive status (MCI, p < 0.001; dementia, p = 0.008), but not with CSF tau levels. These results were further verified in any clinical stage, except hypertension and smoking history in the dementia stage. Although WMH could not predict dementia conversion, its increased levels at baseline were associated with a worse cognitive performance and a more rapid memory decline. Longitudinal analyses showed that baseline dementia and positive amyloid-β status were associated with a greater accrual of WMH volume, and a higher ΔWMH was also correlated with a faster cognitive decline. In contrast, except entorhinal cortex thickness, the WMH volume was not found to be associated with any other neurodegenerative markers. To a lesser extent, WMH mediates the relationship between amyloid-β and cognition. WMH are non-specific lesions that are associated with amyloid-β deposition, cognitive status, and a variety of vascular risk factors. Despite evidence indicating only a weak relationship with neurodegeneration, early intervention to reduce WMH lesions remains a high priority for preserving cognitive function in the elderly.

Correlations between serotonin impairments and clinical indices in multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.

Distinct Effects of Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors on Soluble Biomarkers in Blood and Cerebrospinal Fluid of People With HIV.

Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immunomodulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. Cross-sectional single-center (United States) analysis in 184 PWH on ART with plasma HIV RNA < 200 copies/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and clinical conditions. Participants were mostly middle-aged men, with median CD4+ T cells of 620/µL. In adjusted models, SSRI use was associated with 3 PCs: higher CSF and plasma Aβ42 and CSF CCL2 (aβ=.14, P = .040); lower CSF 8-oxo-dG, total tau, and sCD14 (aβ=-.12, P = .042); and higher plasma sCD14 with lower sCD40L (aβ=.15, P = .042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aβ=.22, P = .004). Statins and ACEIs showed no association. SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation, and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH.

User experience and biomarker associations of remotely administered and unsupervised smartphone‐based cognitive testing in a community sample of older adults

AbstractBackgroundRemotely administered, unsupervised smartphone‐based cognitive tests have the potential for scalable and cost‐effective screening of Alzheimer’s disease (AD) in clinical trials and primary care. Previous work has provided initial evidence for the feasibility and validity of these tools in clinical and community settings. However, more studies investigating the utility of these cognitive tests are warranted, particularly regarding user experience and the association with AD biomarkers.MethodTo date, 198 participants (CDR 0 = 85%, CDR 0.5 = 15%, Mini‐Mental State Examination = 29, average age = 77) have enrolled in this smartphone sub‐study, a part of the Swedish population‐based Gothenburg H70 Birth Cohort Studies. After participating for at least 12 months, the user experience of smartphone‐based cognitive tests (two memory tests, MDT‐OS and ORR‐LDR) was assessed. Furthermore, we investigated their associations with volumetric brain changes based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers (Aβ42/Aβ40 ratio, T‐tau, P‐tau, NFL, and neurogranin). The latter will be analyzed in a subsample (n = 45 for CSF and n = 110 for MRI) of all participants. Voxel‐based analyses are being performed in SPM12.ResultMost study participants found the app easy and enjoyable to use, the instructions easy to understand, and they generally favored performing tests in their home environment. Low CSF Aβ42/Aβ40 ratio at age 70 was associated with worse performance on the ORR‐LDR at age 77 (R = .43, p&lt;.002), while measures of t‐tau, p‐tau, NFL, and neurogranin at age 70 were not. Voxel‐wise associations between smartphone‐based cognitive tests and MRI measures will be reported at the conference.ConclusionOur results suggest that using smartphone‐based cognitive tests in a remote unsupervised setting has the potential to identify aspects of early AD in a community‐based setting. The positive user experience is promising for acceptance of these novel tools for cognition assessment. Next steps include analyses of the relation with neuroimaging‐based biomarkers.

Clinical Manifestations.

The preclinical stage of Alzheimer disease (AD) is a clinically silent period that is detectable through neuroimaging and biofluid biomarkers of amyloid, tau, and neurodegeneration. We evaluated whether performance on cognitively-focused complex daily tasks is associated with cerebrospinal fluid (CSF) biomarkers of brain amyloidosis or tau pathology in cognitively normal (CN) older adults. In this cross-sectional analysis of an ongoing longitudinal cohort study, CN older adults performed three cognitively-focused complex tasks of daily living (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self-Care Skills (PASS) in their home. PASS tasks were scored for independence (cues required to complete task) and adequacy of performance (quality and process, efficiency, redundant actions). Participants also had a CSF sample obtained within two years of completing the PASS. CSF amyloid (Aβ42, Aβ40) and CSF tau phosphorylated at position 181 (p-tau181) were measured with Lumipulse immunoassays. Nonparametric partial correlations were used to examine the associations between task performance and biomarkers of AD (CSF Aβ42/Aβ40 and CSF p-tau181), controlling for age, gender, and level of education. 122 CN participants (mean age 74.4 years, 53% female, 88% white) were included. After controlling for age, gender, and years of education, worse performance on complex daily tasks was associated with lower CSF Aβ42/Aβ40 (more cues required: Spearman rho = -0.213, p = 0.03), and there was a trend towards lower adequacy (rho = 0.161, p = 0.08). There were no significant associations with CSF p-tau181. This study suggests that worse performance on complex daily tasks in CN older adults may be associated with greater amyloid burden. These findings could lead to a better understanding of functional changes that may be associated with amyloidosis prior to the onset of noticeable memory symptoms in AD or related dementias.

CSF Alzheimer’s Disease Biomarker Changes in Veterans with Mild Traumatic Brain Injury

AbstractBackgroundTraumatic brain injury (TBI) has been reported to increase risk of Alzheimer’s dementia (AD). It remains unknown whether mild TBI (mTBI) caused by blast in Veterans confers a similar increase of risk. This study investigated early AD changes defined by cerebrospinal fluid (CSF) AD biomarkers in Veterans with blast mTBI.MethodFifty‐one Veterans with mTBI, 34 non‐mTBI Veterans, and 51 non‐mTBI civilians were recruited from Seattle, Washington. Age‐matched Veteran and civilian non‐mTBI participants had no lifetime history of TBI. All blast‐mTBI Veterans had experienced at least one war zone blast or combined blast/impact exposure, with acute symptoms meeting VA/Department of Defense criteria for mTBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of CSF. CSF biomarkers were measured at the Clinical Neurochemistry Lab in Mölndal, Sweden, using Meso Scale Discovery (MSD) assays for Aβ40 and Aβ42, and Innotest ELISAs for phosphorylated Tau181 (pTau181) and total Tau (tTau).ResultDifferences in all 4 CSF AD biomarkers between participants with and without mTBI were highly age‐dependent and most pronounced in older ages (Figure 1). Both CSF Aβ40 and Aβ42 became lower as age increasing in the mTBI group starting around age 40‐45 years, while they increased with age in the non‐mTBI participants. In contrast, CSF tTau and pTau181 mean levels remained relatively constant with age in participants with mTBI, but increased after age 45 in the non‐mTBI participants. Consequently, for participants aged 50+ years, Veterans with mTBI had lower mean AD biomarkers than the non‐mTBI participants. Similarly, the differences in cognitive performance were age‐dependent, i.e., poorer performance in older Veterans with mTBI than in the non‐mTBI participants. Furthermore, the relationships between CSF Aβ42 and cognitive performance were also age‐dependent; specifically, in participants aged 45+ years, lower CSF Aβ42 level was associated with poorer performance on tests of verbal fluency and memory.ConclusionThe earliest AD biomarker, CSF Aβ42, started to decrease in middle‐aged Veterans with mTBI, more than a decade earlier than those without mTBI in our earlier study, suggesting mTBI may accelerate brain deposition of Aβ and increase risk for AD.

Impact of self‐reported history of head injury on Alzheimer’s disease biomarker profiles

AbstractBackgroundHead injury (HI) as a risk factor for Alzheimer’s disease (AD) has been attracting increased attention thanks to the discovery that concussion is linked to earlier and more severe development of AD (1). HI is prevalent, and a better understanding of how it contributes to AD risk and prognosis is necessary (2). Previous cross‐sectional studies have provided evidence of differences in biomarker levels between individuals with a history of HI and those without (2); this study investigates the effects of a history of HI on longitudinal patterns of AD biomarkers to better understand how HI affects AD risk.MethodUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, we examined longitudinal levels of amyloid β (Aβ), phosphorylated tau (p‐tau), and total tau (t‐tau) in the cerebrospinal fluid (CSF) of 100 individuals with a history of HI and 100 non‐HI controls demographically‐matched on age, sex, race, ethnicity, and years of education. We also analyzed longitudinal levels of blood plasma free plasma (FP) 42, total plasma (TP) 42, pTau181, and NFL.ResultIndividuals with a history of HI had lower CSF Aβ at baseline, lower plasma TP42 at a month 48 follow‐up visit, and lower plasma pTau181 at 72‐ and 96‐month follow‐up visits. There were no differences between the groups on CSF p‐tau or t‐tau levels or plasma FP42 or NFL at any time point.ConclusionLower CSF and plasma amyloid in the HI group may indicate individuals with a history of HI have higher amyloid deposition, given the inverse correlation between CSF/plasma amyloid levels and amyloid deposition on PET (3). The unexpectedly lower plasma pTau in the HI group warrants further analysis. Some of our analyses may be underpowered, as underreporting of HI incidence in ADNI reduces the number of available HI participants. However, despite these limitations, we were able to find significant differences in some biomarkers in individuals with a history of HI. Future studies in expanded samples are needed.1. Fleminger et al. (2003). Journal of Neurology, Neurosurgery &amp; Psychiatry 2. Small et al. (2013). The American Journal of Geriatric Psychiatry 3. Fagan et al. (2006). Annals of Neurology

Memory performance mediates subjective sleep quality associations with cerebrospinal fluid Alzheimer's disease biomarker levels and hippocampal volume among individuals with mild cognitive symptoms.

Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments.

Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease

BackgroundMonoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer’s disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer’s disease.MethodsWe conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer’s disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116.ResultsA total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, –0.31; 95% confidence interval [CI], –0.66 to 0.05; P=0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, –0.19; 95% CI, –0.55 to 0.17; P=0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was –66.44 and –56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%.ConclusionsAmong persons with early Alzheimer’s disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann–La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.)

Cognitive Profile in Parkinson’s Disease Dementia Patients with Low versus Normal Cerebrospinal Fluid Amyloid Beta

Introduction: In patients with Parkinson’s disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer’s disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.

Value of CT in targeted CT-guided epidural blood patching: Predictors for successful epidural punctures

Background and purposeDifferentiating epidural from intrathecal punctures before computed tomography (CT)-guided epidural blood patching (EBP) is subjective, relying on operator experience. This study aimed to investigate CT findings for epidural and intrathecal punctures and identify reliable predictors for successful epidural punctures before targeted CT-guided EBP. Materials and methodsWe included 65 patients with low-cerebrospinal fluid (CSF)-pressure headache receiving targeted CT-guided EBP between January 2021 and October 2022 in this retrospective study. We analyzed clinical data, technical information, and CT features before EBP. Fisher's exact test was used for discrete variables, while Mann–Whitney U test was used for continuous variables. Positive (PLR) and negative likelihood ratios (NLR) were calculated to identify predictors for confirming epidural punctures. ResultsWe confirmed 43 patients as epidural punctures and 22 patients as intrathecal punctures. Before contrast injection, epidural fat at the needle tip in the epidural group was higher than the intrathecal group (37.2 % [16/43] vs. 4.5 % [1/22], p = 0.006). After contrast injection, the “contrast-needle tip connection” sign was mostly observed in the epidural group than the intrathecal group (95.3 % [41/43] vs. 9.1 % [2/22], p < 0.001). Additionally, the epidural group had significantly higher boomerang-shaped contrast morphology than the intrathecal group (65.1 % [28/43] vs. 9.1 % [2/22], p < 0.001). The “contrast-needle tip connection” sign had the highest PLR (10.49) and lowest NLR (0.05). ConclusionIdentifying epidural fat at the needle tip, “contrast-needle tip connection” sign, and boomerang-shaped contrast morphology on CT scans are useful for confirming proper placement of the needle tip within the epidural space.

Prominent cerebral veins on susceptibility-weighted angiography in acute meningoencephalitis.

We have commonly observed prominent cerebral veins on susceptibility-weighted angiography (SWAN) in acute meningoencephalitis. This study aimed to investigate the clinical significance of these findings. Cerebral veins on SWAN of 98 patients with acute meningoencephalitis diagnosed from February 2016 through October 2020 were classified into three groups according to the degree of venous prominence (mild, 23; moderate, 53; and prominent, 22). Clinical variables and laboratory findings were compared between these groups. The influence of variables on the prediction of prominent cerebral veins was measured by random forest (RF) and gradient boosting machine (GBM). As cerebral veins became more prominent, cerebrospinal fluid (CSF) glucose level decreased (69.61±29.05vs. 59.72±22.57vs. 48.36±20.29mg/dL, p=.01) and CSF protein level increased (100.73±82.98vs. 104.73±70.99vs. 159.12±118.15mg/dL, p=.03). The etiology of meningoencephalitis, neurological symptoms, and increased intracranial pressure (ICP) signs differed between groups (p<.05). RF and GBM demonstrated that CSF protein level was the variable with the highest power to predict the prominent cerebral vein (mean decrease in node impurity: 4.19, relative influence: 50.66). The presence of prominent cerebral veins on SWAN in acute meningoencephalitis was significantly associated with a low CSF glucose level and a high CSF protein level, as well as ICP. Thus, the visual grade of the cerebral veins on SWAN may be utilized for the management of patients with acute meningoencephalitis.

Objective Physical Function in the Alzheimer's Disease Continuum: Association with Cerebrospinal Fluid Biomarkers in the ALBION Study.

Cognitive and physical decline, both indicators of aging, seem to be associated with each other. The aim of the present study was to investigate whether physical function parameters (walking time and handgrip strength) are related to cerebrospinal fluid (CSF) biomarkers (amyloid-beta Aβ42, Tau, PhTau) in individuals in the Alzheimer's disease (AD) continuum. The sample was drawn from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study, comprising 163 individuals aged 40-75 years: 112 cognitively normal (CN) and 51 with mild cognitive impairment (MCI). Physical function parameters were measured at baseline, a lumbar puncture was performed the same day and CSF biomarkers were analyzed using automated methods. The association between walking time, handgrip strength and CSF biomarkers was evaluated by linear correlation, followed by multivariate linear regression models adjusted for age, sex, education and APOEe4 genotype. Walking time was inversely related to CSF Aβ42 (lower CSF values correspond to increased brain deposition) in all participants (p < 0.05). Subgroup analysis showed that this association was stronger in individuals with MCI and participants older than 60 years old, a result which remained statistically significant after adjustment for the aforementioned confounding factors. These findings may open new perspectives regarding the role of mobility in the AD continuum.

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression.

We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181 , and NfL. Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury. Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury.

The clinical utility of metagenomic next-generation sequencing for the diagnosis of central nervous system infectious diseases.

To evaluate the clinical utility of metagenomic next-generation sequencing (mNGS) for the diagnosis of central nervous system infections (CNSI). Cerebrospinal fluid (CSF) from 54 patients who were high-level clinical suspicion of CNSI was collected and sent for mNGS and conventional tests from January 2019 to March 2022. Twenty out of 54 patients were diagnosed with CNSI and 34 non-CNSI. Among the 34 non-CNSI, one was false positive by mNGS. Among the 20 CNSI, 11 had presumed viral encephalitis and/or meningitis, 5 had presumed bacterial meningitis, 2 had presumed TMB, 1 had Crytococcus meningitis and 1 had neurosyphilis. The sensitivity of viral encephalitis and/or meningitis was 0.73 (8/11); 10 virus were detected; 9/10 was dsDNA; 1/10 was ssRNA. SSRN ranged from 1 to 13. The accuracy rate was 0.4, the accuracy rate was positively correlated with SSRN (r = 0.738, P = 0.015), SSRN ≥ 1, the accuracy rate was 0.4; SSRN ≥ 3, the accuracy rate was 0.66; SSRN ≥ 4, the accuracy rate was 0.75; SSRN ≥ 6, the accuracy rate was 1. The sensitivity of bacterial meningitis was 1. Seven kinds of bacteria were detected, among which 3/7 were gram positive, 3/7 were gram negative, and 1/7 was infected NTM (nontuberculous mycobacteria). The accuracy rate was 0.43 (3/7). The sensitivity of TBM was 0.66 (2/3), the accuracy rate was 1. The sensitivity of Crytococcus meningitis was 1, the accuracy rate was 0.5. PPV (positive predictive value) of mNGS was 0.94, NPV (negative predictive value) of mNGS was 0.89, specificity was 0.97 and sensitivity was 0.8. The AUG for CSF mNGS diagnosis of CNSI was 0.89 (95% CI = 0.78-0.99) Headache, meningeal irritation sign and image of meninges abnormal were correlated with the sensitivity of mNGS (r = 0.451, 0.313, 0.446; p = 0.001, 0.021, 0.001); CSF Glucose and CSF Chloride were negatively correlated with sensitivity of mNGS (r = -0.395, -0.462; p = 0.003, ＜ 0.001). mNGS is a detection means with high sensitivity, wide coverage and strong timeliness, which can help clinicians to identify the pathogen diagnosis quickly, conduct targeted anti-infection treatment early and reduce antibiotic abuse. The pathogen which causing low CSF Glucose, low CSF Chloride or meninges infections was more likely to be detected by mNGS. It may be related to growth and structural characteristics of the pathogen and blood-brain barrier damage.