Low CSF Research Articles

Association of retinol binding protein and the risk of idiopathic intracranial hypertension: a systematic review and meta-analysis.

Idiopathic Intracranial Hypertension (IIH) is a disease of unknown etiology. Understanding the role of Retinol Binding Protein (RBP) in IIH pathogenesis could provide valuable perceptions into disease mechanisms and potentially identify new therapeutic targets. The study conducted a comprehensive search of electronic databases following PRISMA guidelines. The inclusion criteria involved human studies published in English that reported RBP levels in IIH patients. The New Castle Ottawa scale was used for the quality assessment of the included studies. Analysis was done using the Random Effects Model with 95% Confidence Interval. A total of 4 studies met the inclusion criteria for meta-analysis. The quality score for the included studies ranged from 5 to 6. The pooled analysis indicated significant association of RBP with risk of IIH, with higher serum RBP levels (SMD = 1.56, 95% CI: 0.13 to 2.98, I2 = 93.9) and lower CSF RBP levels (SMD = -0.67, 95% CI: -1.37 to 0.04, I2 = 65.4) as compared to controls. Significant heterogeneity was found in the studies, suggesting variability in study design and methods. Further subgroup analysis by investigation method also showed significant results (SMD = 1.56, 95% CI: 0.13 to 2.98, I2 = 93.9). The findings of this study propose that an elevated level of RBP may contribute to the risk of IIH, potentially through its involvement in retinol transport and metabolism. The study has been registered in PROSPERO (CRD42023436827).

Prospective memory performance and its resting-state functional connectivity correlates in individuals with memory complaints.

This study aimed to investigate prospective memory (PM) in patients with memory complaints but without dementia (PWD) and correlate findings with resting-state functional connectivity (rsFC) alterations. We hypothesized that PM impairment would be evident at a certain relatively early point in the continuum and specific rsFC patterns would be the neuroimaging signature of this impairment. Sixty PWD participated in the study. The Memory Screening Test for Intentions and the Virtual Week were used to assess PM. Using the participants' PM scores as a regressor, the rsFC for PM was analyzed by Network-Based Statistics (NBS). Participants were divided into high and low PM groups (HPMG, LPMG) according to their PM scores and then their neuropsychological scores, rsFC patterns, and CSF biomarker levels were compared. The effect of education on the relationship between connectivity and CSF Aβ42 level was examined by moderation analysis. Compared with HPMG, LPMG was impaired in both event- and time-based PM tasks, but the difference was more distinct in the event-based ones. While HPMG was more successful in event-based tasks than time-based ones, LPMG was not. As a result of NBS analysis, the middle frontal gyrus (MFG), supramarginal gyrus (SMG), and anterior cingulate cortex (ACC) were determined as central seeds. The HPMG's performance and connectivity were higher for most comparisons but had lower CSF Aβ42 than LPMG and therefore was closer to the positivity threshold. When the education level was at the mean and above, there was a negative correlation between CSF Aβ42 level and overall connectivity. The connectivities of MFG, SMG, and ACC play an important role in PM performance in the PWD. In more advanced PM impairment, the impairment of spontaneous processes is more prominent. At the onset of amyloidosis, the cognitive reserve may compensate for cognitive impairment by increasing connectivity.

P-909. Molecular Testing Performance for the Diagnosis of Cryptococcal Meningitis in a Tertiary Care Center

Abstract Background Cryptococcus is the most common cause of fungal meningitis worldwide and delayed diagnosis and treatment can be devastating. Diagnostic modalities include culture, antigen detection (CrAg), direct visualization in CSF and PCR. The reported sensitivity of the FilmArray® meningitis/encephalitis (ME) panel for cryptococcal meningitis compared to culture is 92-96%, and compared to CSF CrAg is 52-83%, with reported specificity of 99%. Lower CSF CrAg levels and lower quantitative growth in culture have been associated with false negative ME panel. Characteristics of samples with false negative ME Panel Methods After IRB approval was obtained, a retrospective chart review of all cases of cryptococcal meningitis established by CSF Culture, CSF CrAg or ME panel from June 2017-June 2020 in a tertiary center was performed. Results Cryptococcus spp. was detected in 18 specimens, by either ME panel (14), CSF CrAg (12) or culture (18). These specimens were obtained from 16 patients. Their mean age was 46 years (24-73). 75% of patients were male. All the patients in this series were immunocompromised. 10 patients had HIV (PWH), half of them had CD4 counts < 40 cells/mm^3, and the mean CD4 count of the rest was 99 cells/mm^3 (41-163). Three patients had a prior solid organ transplant, one had liver cirrhosis and one had idiopathic CD4 lymphopenia. The mean opening pressure was 28.1 (16- >60 cm CSF). Compared to culture, the ME panel detected Cryptococcus spp. in 14/18 specimens. Of those, a total of 14 patients had a simultaneous CSF CrAG performed, 12 of those samples had a detectable CrAG, and ME panel detected the organism in all those samples. Both false negative CSF CrAG had a false negative ME Panel but were later diagnosed with a culture. There were 4 samples with false negative ME Panel. Their cultures were reported as “very light” qualitative growth. Two of them had a bloody sample and CMV detected in the ME panel, suggesting that contamination with large amount of blood can interfere with the performance of this test. This delayed treatment initiation by an average of 2 days. Conclusion Although the ME Panel is an excellent tool to diagnose meningitis, the lack of detection of Cryptococcus sp. in the ME panel in the right clinical context should prompt careful clinical consideration to prevent delays in treatment initiation for patients at risk of this infection. Disclosures All Authors: No reported disclosures

Artificial Intelligence Chatbot and Low CSF Pressure Headaches Decision-Making

Background The potential for inaccuracy while using AI could cause problems for future doctors attempting to pass their board exams, doctors attempting to brush up on a certain topic in a short amount of time, or those trying to make use of AI to for patient care decision-making. Low CSF pressure headaches can be highly disabling for patients and are often misdiagnosed These types of headaches are relatively common, effecting approximately 5 individuals per 100,000 per year. Methods An AI model was selected to examine the neurological scenario through a Neurology expert’s guidance to determine a diagnosis. While some AI models are more developed than others, a free, heavily utilized platform was used in this testing. Results the AI gave direction to order an MRI and consult with other Neurological doctors, but it failed to arrive at the correct differential diagnosis. In the test, the first failure was to request the appropriate tests. It then failed to provide an accurate working diagnosis. Discussion Without understanding an AI model’s limitations, it may lead to negative patient outcomes if used in medical decision-making. This could also prolong the patient’s condition, allowing them to suffer unnecessary pain and potential disability.

Cerebrospinal fluid tau and disease progression in early Parkinson's disease: an 8-year longitudinal study.

To explore whether CSF phosphorylated tau-181 (P-tau181) and total tau (T-tau) are associated with disease progression in early PD patients. We analyzed 8-year longitudinal clinical data from 368 early, drug-naive PD patients and 185 matched controls from the Parkinson's Progression Markers Initiative cohort. CSF P-tau181 and T-tau were measured over 5years, while CSF α-synuclein was measured over 3years. Dopamine transporter (DAT) imaging was performed at baseline and at 1, 2, and 4years. PD patients exhibited significantly lower CSF P-tau181, T-tau and P-tau181/T-tau ratio than controls at each visit. Higher baseline CSF P-tau181 predicted greater increases in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III (estimate: 0.067, P < 0.001) and Montreal Cognitive Assessment (MoCA) scores (estimate: -0.010, P = 0.009). Similarly, higher baseline CSF T-tau predicted greater increases in MDS-UPDRS III (estimate: 0.005, P < 0.001) and MoCA scores (estimate: -0.001, P = 0.013). Higher baseline P-tau181/T-tau ratio predicted greater increases in MDS-UPDRS III (estimate: 0.552, P < 0.001) but was not significantly associated with changes in MoCA scores (estimate: -0.052, P = 0.114). CSF P-tau181 (estimate = 84.889, P < 0.001), T-tau (estimate = 8.297, P < 0.001) and P-tau181/T-tau ratio (estimate = 263.425, P < 0.001) were positively correlated with CSF α-synuclein but not correlated with striatal DAT uptake. Elevated baseline CSF P-tau181, T-tau and P-tau181/T-tau ratio in early PD patients predict accelerated motor deterioration, with P-tau181 and T-tau also predicting cognitive decline, potentially through interactions with α-synuclein. However, the direct role of tau on nigrostriatal dopaminergic degeneration remains uncertain.

Accrual of Alzheimer’s Disease pathology as a function of proximity to parental dementia onset

AbstractBackgroundThere is emerging evidence to substantiate temporal proximity to parental onset (PPO) of dementia as a proxy stage marker in studies of late onset Alzheimer’s Disease (AD). PPO predicts accrual of amyloid pathology cross‐sectionally and longitudinally. However interactions with gender, age, and APOE‐𝜀4 carriage have been inconsistent across datasets and amyloid measures.MethodWe investigated cross‐sectionally a subset of the European Prevention of Alzheimer's Dementia (EPAD) study cohort (n=688) (Table 1). PPO was calculated by substracting a subject’s age from the youngest age of diagnosis of an affected parent. Regressions were used to determine whether PPO predicts CSF fluid Aβ1‐42 in the whole sample or p‐tau in an amyloid‐positive subgroup (n=226). Possible interactions with age, gender, education, APOE‐𝜀 status, family history load, gender of affected parent and CDR score were explored.ResultNearer PPO predicted lower CSF Aβ1‐42 level (p&lt;0.001), interacting significantly with APOE‐𝜀4 carriage only (β=12.683; T=3.295; p=0.001) accounting for effects of age, gender and education level. In APOE‐𝜀4+ subjects, APOE‐𝜀2 provided a protective effect (Figure 1). At least half of APOE‐𝜀4+/APOE‐𝜀2‐ subjects (n=255) within ten years of age of parental onset were amyloid positive (Figure 2). PPO did not predict p‐tau levels in amyloid positive subjects (n=226) (p=0.414).ConclusionIn APOE‐𝜀4+/APOE‐𝜀2‐ individuals, PPO predicts accrual of amyloid but not tau pathology, independently of age. Selectively examining this population as they approach age of parental onset may better elucidate the natural history of preclinical late onset AD.

Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis

Objective To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH). Method CSF levels of NfL, NfM, and pNfH were analyzed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Center in Stockholm, Sweden. NfM levels were analyzed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations. Result Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls. Similarly, higher NfM levels were found in fast compared with slow progressing patients for baseline and longitudinal progression when evaluating both total and subscores of ALSFRS-R. These findings were consistent with the results observed for NfL and pNfH. All three proteins, used individually as well as in combination, showed comparable performance when classifying fast vs slow progressing patients (AUCs 0.78–0.85). For all neurofilaments, higher survival probability was observed for patients with low CSF levels. Conclusion Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. Additional investigations with independent cohorts and longitudinal studies are needed to further assess the potential added value of NfM.

Silent Devastation: Acute Marchiafava-Bignami Disease Unmasked by Chronic Alcoholism in a 24-Year-Old Male: A Case Report

Marchiafava-Bignami disease (MBD) is an uncommon condition that is mainly linked to prolonged alcoholism and nutritional deficits. It is characterised by necrosis and demyelination of the corpus callosum. Due to its rarity and vague clinical signs, this disorder can frequently be misdiagnosed. It manifests as a range of neurological symptoms, from altered awareness to motor impairments. We present a 24-year-old man in this case report who has a history of intravenous drug use, chronic alcohol intake, and recent binge drinking.He presented with a 10-day history of constipation, vomiting, and a high-grade continuous fever. Over two days, the patient’s condition deteriorated into a drowsy state with abdominal pain.On examination, the patient was drowsy but arousable, with stable vital signs except for hypertension. Neurological findings indicated reduced deep tendon reflexes, hypotonia, and neck stiffness. A systemic workup revealed normal brain CT findings, however, diffusion limitation was seen in the corpus callosum's splenium on MRI, along with mild oedema and T2/FLAIR hyperintensity. The lumbar puncture showed lymphocytic predominance, low CSF glucose, and elevated protein levels suggestive of a possible CNS infection. The differential diagnosis included Marchiafava-Bignami disease (MBD) and cytotoxic lesions of the corpus callosum (CLOCCs).The patient was managed with intravenous steroids, empirical antitubercular therapy (ATT), broad-spectrum antibiotics, and supportive care, including airway protection via intubation. Despite the late diagnosis, the clinical history of chronic alcoholism, recent binge, and imaging findings confirmed MBD. Early recognition and treatment of this disorder can improve neurological outcomes. The present study emphasises how crucial it is to take MBD into account when making a differential diagnosis for alcohol-related encephalopathies, especially in individuals who have neurological decline and prolonged alcohol consumption.

Brain age in genetic and idiopathic Parkinson's disease.

The brain-age gap, i.e. the difference between the brain age estimated from structural MRI data and the chronological age of an individual, has been proposed as a summary measure of brain integrity in neurodegenerative diseases. Here, we aimed to determine the brain-age gap in genetic and idiopathic Parkinson's disease and its association with surrogate markers of Alzheimer's disease and Parkinson's disease pathology and with rates of cognitive and motor function decline. We studied 1200 cases from the Parkinson's Progression Markers Initiative cohort, including idiopathic Parkinson's disease, asymptomatic and clinical mutation carriers in the leucine-rich repeat kinase 2 gene (LRRK2) and the glucocerebrosidase gene (GBA), and normal controls using a cohort study design. For comparison, we studied 187 Alzheimer's disease dementia cases and 254 controls from the Alzheimer's Disease Neuroimaging Initiative cohort. We used Bayesian ANOVA to determine associations of the brain-age gap with diagnosis, and baseline measures of motor and cognitive function, dopamine transporter activity and CSF markers of Alzheimer's disease type amyloid-β42 and phosphotau pathology. Associations of brain-age gap with rates of cognitive and motor function decline were determined using Bayesian generalized mixed effect models. The brain-age gap in idiopathic Parkinson's disease patients was 0.7 years compared to controls, but 5.9 years in Alzheimer's disease dementia cases. In contrast, asymptomatic LRRK2 individuals had a 1.1. year younger brain age than controls. Across all cases, the brain-age gap was associated with motor impairment and (in the clinically manifest PD cases) reduced dopamine transporter activity, but less with CSF amyloid-β42 and phosphotau. In idiopathic Parkinson's disease cases, however, the brain-age gap was associated with lower CSF amyloid-β42 levels. In sporadic and genetic Parkinson's disease cases, a higher brain-age gap was associated with faster decline in episodic memory, and executive and motor function, whereas in asymptomatic LRRK2 cases, a smaller brain-age gap was associated with faster cognitive decline. In conclusion, brain age was sensitive to Alzheimer's disease like rather than Parkinson's disease like brain atrophy. Once an individual had idiopathic Parkinson's disease, their brain age was associated with markers of Alzheimer's disease rather than Parkinson's disease. Asymptomatic LRRK2 cases had seemingly younger brains than controls, and in these cases, younger brain age was associated with poorer cognitive outcome. This suggests that the term brain age is misleading when applied to disease stages where reactive brain changes with apparent volume increases rather than atrophy may drive the calculation of the brain age.

Autoimmune and infectious encephalitis: development of a discriminative tool for early diagnosis and initiation of therapy

BackgroundEncephalitis originates from diverse autoimmune and infectious etiologies. Diagnostic challenges arise due to the spectrum of presentation and the frequent absence of specific biomarkers. This study aimed to comprehensively characterize and differentiate autoimmune encephalitis (AE) from infectious encephalitis (IE) in adults, and disentangle clinical, paraclinical, and therapeutic differences.MethodsA cohort study spanning 10 years was conducted across three Austrian tertiary care hospitals. Inclusion criteria comprised adults with probable or definite encephalitis. Demographics, clinical features, technical findings, treatment modalities, and outcomes were collected from the electronic patient files. A follow-up was performed via telephone interviews and clinical visits.ResultsOf 149 patients, 17% had AE, 73% IE, and 10% encephalitis of unknown etiology. Significant differences between AE and IE included the prevalence of acute symptomatic seizures (AE: 85% vs. IE: 20%, p < 0.001), fever (8% vs. 72%, p < 0.001), headache (15% vs. 61%, p < 0.001), and focal neurological deficits (56% vs. 23%, p = 0.004), respectively. Paraclinical differences comprised lower CSF pleocytosis in AE compared to IE (median 6 cells/µl vs. 125 cells/µl, p < 0.001). Epileptic discharges on EEG and MRI lesions were more prevalent in AE than IE (50% vs. 14%, p < 0.001; 50% vs. 28%, p = 0.037). The modified Rankin Scale scores at discharge and last follow-up (median duration 2304 days, IQR 1433–3274) indicated favorable outcomes in both groups.ConclusionThis comprehensive analysis provides insights into the epidemiology, clinical, paraclinical, and therapeutic aspects and the outcomes of AE and IE in adults. We developed a diagnostic tool that facilitates early differentiation between AE and IE, aiding in timely therapeutic decision-making.

APOE contributes to longitudinal impulse control disorders progression in Parkinson’s disease

BackgroundImpulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area.ObjectiveWe aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD.MethodsThis study included 287 PD patients from the Parkinson’s Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses.Results44.3% (31/70) patients with APOE ɛ4 and 32.3% (70/217) patients without APOE ɛ4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE ɛ4 group showed significantly lower CSF Aβ42 and CSF α-syn level than patients without APOE ɛ4 group at baseline. In patients with APOE ɛ4 group, the “low α-syn level” group and the “low ptau/tau ratio” group had a significantly higher incidence of ICDs, respectively.ConclusionsThis study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail.

Clinical predictors of poor outcome of bacterial meningitis in infants less than 90 days: a systematic review

Backgroundbacterial meningitis (BM) is more common in infants than at any other time in life and remains a devastating disease with considerable risk of death and morbidity. This article aims to gather the currently available evidence to perform a systematic review of clinical factors that may predict or be associated with BM death and/or sequelae in infants &amp;lt; 90 days of age.MethodsThe Medline/PubMed, Cochrane Library and Embase databases were systematically searched for prognostic studies that described risk factors for mortality and sequelae in infants aged &amp;lt;90d with BM. The databases were searched from the beginning of the database to December 31st, 2022.The quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). The quality of cross-section studies was assessed by the Agency for Healthcare Research and Quality (AHRQ). A systematic review was undertaken to ascertain the prognostic factors proven to be noteworthy.ResultsOf the 1,431 studies retrieved, 20 were eligible for the final analysis including 11 cohort and 9 cross-sectional studies were identified. Four risk factors predicting poor outcome were mentioned mostly in those studies, including prematurity or low birth weight (LBW), seizures, coma, and elevated CSF protein. But only preterm, coma and elevated CSF protein were identified by multivariate analyses in more than one study.ConclusionsThis study demonstrates several potential predictive factors to the poor outcomes of BM in infant. But with large heterogeneity, these predictors should be evaluated by further well-designed prospective studies.Systematic Review Registrationhttps://www.crd.york.ac.uk/, identifier CRD42017074949.

Diagnostic Dilemma between Scrub Typhus Meningoencephalitis and Dengue Encephalopathy Resolved! - A Novel Prediction Score.

Scrub typhus and dengue, common etiologies of acute encephalitis syndrome, present with similar clinico-laboratory profiles but differ in management protocol. We aimed to devise a score differentiating between scrub typhus meningoencephalitis (STM) and dengue encephalopathy (DE). A prospective cohort of 204 children, (aged 6 months to 14 years) presenting with acute encephalitis syndrome in a public teaching hospital in northern India was subjected to standardized workup including serum IgM against Orientia tsutsugamushi and Dengue virus. Clinico-laboratory features were compared between STM and DE using univariate and multivariate analysis. Area under the receiver operating characteristic (ROC) curve (AUROC) for the score derived from independent predictors and its sensitivity, specificity, predictive values was calculated at cutoffs. STM and DE IgM ELISA were positive in 38 (18.6%) and 41 (20.1%) children, respectively. Longer duration of fever, prodromal stage, respiratory complaints and pneumonia were significantly frequent in STM; however, swelling, petechiae and myalgia were significantly prevalent in DE. STM had higher blood total leukocyte count (TLC), higher CSF protein and lower CSF sugar compared to DE. At admission, TLC >10,000/mm3, pneumonia, absence of myalgia and petechiae were independent predictors for differentiating STM from DE. AUROC of novel score (range: -5 to 5) was 0.879 (95% CI: 0.805-0.952). Score at cutoff ≥5 had 100% specificity and 100% PPV for differentiating STM from DE. Prediction score may benefit physicians to differentiate between these two infections and treat them accordingly.

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

Hemorrhagic 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. 892 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. Among 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]. Most 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.

Hormone therapy is associated with lower Alzheimer’s disease tau biomarkers in post-menopausal females -evidence from two independent cohorts

BackgroundFemales represent approximately 70% of the Alzheimer’s disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum.MethodsThis cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET.ResultsHT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges’ g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges’ g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges’ g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau181 (P < 0.001) and plasma p-tau181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aβ and is associated with lower regional NFT load.ConclusionsOverall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression.

Isolated Psychiatric Symptoms in Children With Anti-N-Methyl-d Aspartate Receptor Encephalitis

Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12=92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.

A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease

BackgroundAmyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.MethodsDouble-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.ResultsFrom June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.ConclusionsPosiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.Trial registrationNCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Thermodynamic modeling of CsF with LiF-NaF-KF for molten fluoride-fueled reactors

Thermodynamic modeling of CsF with LiF-NaF-KF for molten fluoride-fueled reactors

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.

CSF β-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury.

Moderate-to-severe traumatic brain injuries (TBI) have been reported to increase the risk of Alzheimer disease (AD). Whether mild TBI (mTBI) in veterans confers a similar increased risk of AD is less known. This study investigated early AD changes using CSF biomarkers in veterans with blast mTBI. This was a cross-sectional case-control study of veterans with mTBI and non-mTBI veterans and civilians from 2 study sources. Blast-mTBI veterans had at least 1 war zone blast or combined blast/impact mTBI meeting Veterans Affairs (VA) and Department of Defense (DoD) criteria for mTBI. Non-mTBI participants had no lifetime history of TBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of the CSF. CSF biomarkers were measured using MesoScale Discovery assays for Aβ40 and Aβ42 and INNOTEST ELISAs for phosphorylated tau181 (p-tau181) and total tau (t-tau). Our sample comprised 51 participants with mTBI and 85 non-mTBI participants with mean (SD) ages 34.0 (10.1) and 33.5 years (8.9), respectively. All participants but 1 (99%) were male. Differences in CSF AD biomarkers between mTBI and non-mTBI groups were age dependent and most pronounced at older ages (omnibus test p ≤ 0.08). At age 50 years, the mTBI group had lower mean [95% CI] CSF Aβ42 and Aβ40 than the non-mTBI group by 154 [-12 to 319] and 1864 [610-3,118] pg/mL, respectively. By contrast, CSF p-tau181 and t-tau mean levels remained relatively constant with age in participants with mTBI, while tending to be higher at older ages for the non-mTBI group. The mTBI group also demonstrated poorer cognitive performance at older ages (omnibus p < 0.08): at age 50 years, the mean TMT-B time was higher by 34 seconds [10-58] and the mean CVLT-II short-delay recall was lower by 4.2 points [1.9-6.6]. Poorer verbal memory and verbal fluency performance were associated with lower CSF Aβ42 (p ≤ 0.05) in older participants. CSF Aβ levels decreased in middle-aged veterans with blast-related mTBI. These data suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes known to portend AD onset, thus raising concern that veterans with blast-related mTBI may develop a dementing disorder later in life.