Cerebrospinal Spinal Fluid Research Articles

Psychotropic Polypharmacy Leading to Reversible Dementia: A Case Report.

Psychotropic polypharmacy presents a diagnostic challenge that may be further complicated by inadequate medication history and underappreciation of the cognitive effects of such polypharmacy. Here we present the case of a 57-year-old man who presented to our memory clinic with progressive cognitive decline and a prior neuropsychological evaluation supporting the diagnosis of a neurodegenerative disorder. He was taking multiple psychotropic medications at the time, but the exact dosages were unclear due to a lack of collateral history. He was also taking prescribed opioids and a combination of buprenorphine and naloxone for pain relief, again with unclear dosages at the time of presentation. Brain imaging and cerebrospinal spinal fluid biomarker testing were negative for Alzheimer pathophysiologic processes. Months later, the patient was taken to the emergency room after an overdose caused by overuse of opioid medications. Once he was taken off all psychoactive medications, the patient's cognitive impairment completely reversed, and he became independent in activities of daily living. Psychotropic polypharmacy can have a myriad of cognitive manifestations which need to be better recognized by clinicians. Deprescription of such medications should be attempted whenever clinically appropriate.

A Retrospective Study of Pediatric Posterior Fossa Tumors: Was the Outcome Different in Patients Undergoing Elective versus Emergency Surgery?

Abstract Background: Pediatric posterior fossa tumors (pPFTs) may present acutely with features of increased intracranial pressure that need urgent intervention or with stable symptoms requiring elective management. In this article, we have analyzed the outcomes of pPFTs managed under three arms: (1) emergency tumor resection (A), (2) elective tumor resection (B), and (3) pre-resection cerebrospinal spinal fluid (CSF) diversion followed by elective tumor resection (C). Materials and Methods: We retrospectively reviewed our database from July 2012 to March 2020 for pediatric patients (age ≤16 years) with PFTs. The patients were classified into three groups based on the timing and type of intervention. Their result was assessed as the primary (postoperative complications) and secondary outcomes (post-resection CSF diversion, CSF diversion failure, residual tumor, and survival). A P value < 0.05 was considered significant (SPSS version 22.0, IBM, New York). Results: A total of 154 patients (M:F = 2.42:1) were included with a mean age of 8.1 (SD ± 4.2)-years (range 1–16). Group B (n = 72/46.8%) had a significantly higher number of patients as compared to the group A (n = 40/26%) and group C (n = 42/27.3%) (χ2 test, P value = 0.02). The primary outcomes were comparable between group A and group B. A higher incidence of preoperative external ventricular drain insertion and post-resection CSF diversion failure was noted in group A as compared to group B (P value < 0.01). Group C had a significantly higher proportion of patients with residual tumor (n = 19/48.7%) as compared to group A (n = 11/29.7%, P value = 0.09) and group B (n = 20/ 29.4%,P value < 0.05). The post-resection CSF diversion failure rate was significantly higher in group C than in the other two groups (P value < 0.05). Conclusion: The pre-resection CSF diversion subgroup had a poorer outcome as compared to elective and emergency tumor resection. The outcomes of elective and emergency resection of pPFTs were comparable, except for the higher risk of shunt failure in the emergency cohort.

Diagnostic value of EBV-DNA in CSF for PCNSL in AIDS patients with focal brain lesions: A meta-analysis of diagnostic test

Epstein-Barr virus (EBV) infection plays a crucial role in the progression of acquired immunodeficiency syndrome related primary central nervous system lymphoma (AR-PCNSL). This study aimed at evaluating the diagnostic value of cerebrospinal spinal fluid (CSF) EBV-deoxyribonucleic acid (DNA) for PCNSL in patients with infection of human immunodeficiency (HIV) virus through a meta-analysis of diagnostic test. A systematic search in PubMed, Embase, Web of Science, Wanfang, Chinese Biomedical Database and Chinese National Knowledge Infrastructure was conducted before May 10, 2022. Heterogeneity among the studies was assessed using Q test and I2 statistics. Publication bias was assessed using the Deek's funnel plot asymmetry test. Statistical analyses were performed using Stata 16.0 software. The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratios (DOR) and 95% confidence intervals (CI) were caculated to evaluate the diagnostic value. A symmetric receiver operating characteristic (SROC) curve and the area under the SROC curve (AUC) were constructed to evaluate the test-performance. Twelve studies were included in the final analyses, with a total of 141 patients with AR-PCNSL and 590 controls. The pooled diagnostic values were sensitivity of 0.83 (95% CI: 0.73-0.90), specificity of 0.95 (95%CI: 0.89-0.98), PLR of 17.8 (95%CI: 6.8-46.1), NLR of 0.17 (95%CI: 0.10-0.30), DOR of 102 (95%CI: 28-379), and AUC of 0.94 (95%CI: 0.91-0.96). In summary the overall diagnostic value of CSF EBV-DNA is very high and it can be a reliable diagnostic biomarker for AR-PCNSL.

Insomnia symptoms and markers of preclinical Alzheimer’s disease in the community

AbstractBackgroundAmyloid production increases during wakefulness before being cleared during sleep. Insomnia is one of the commonest sleep disorders, yet its relationship to core markers of preclinical Alzheimer’s disease remains unknown. We investigated the cross‐sectional relationship between insomnia symptom severity, APOE e4 carriage, and cerebrospinal spinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a non‐demented community‐sample aged 43‐67 years.Method66 participants from the Healthy Brain Project Biomarker Sub‐study (age = 58±6 years; MMSE = 29±7; 68% women) completed a lumbar puncture, two weeks of actigraphy to measure sleep and wake patterns, and the Insomnia Severity Index (ISI) to measure insomnia symptom severity over the past two weeks. The ISI was split into two groups (normal vs. high [>7]) based on established cut‐off values (42% of the sample were high). Two core insomnia features were captured: Difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (high wake after sleep onset (WASO) duration and number of awakenings), with each variable classified as the top 25th percentile versus the remainder of the sample. Analysis of covariance was used to compare CSF amyloid‐beta 42 (Aβ42), phosphorylated tau 181 (p‐tau181), total‐tau, and neurofilament light chain protein (NfL) across each of the sleep groups, adjusting for age and sex.ResultPersons with high insomnia symptom severity had higher CSF Aβ42 levels (p=0.033, d=0.58). Difficulty maintaining sleep (both high WASO and number of awakenings) was also associated with higher Aβ42 levels (p=0.023, d=0.77 for WASO; p=0.013, d=0.92 for awakenings), whereas difficulty initiating sleep was not (p= 0.776, d=0.08). The sleep variables were not associated with p‐tau181, total‐tau, or NfL levels (p>0.05). APOE e4 modified the association between WASO and Aβ42. The strength of the relationship between higher WASO (versus normal) and Aβ42 was stronger in e4 carriers, compared to non‐carriers (F(df) = 6.94 (1, 44), p=0.012).ConclusionIn this relatively young sample, symptoms and features of insomnia were associated with higher CSF Aβ42 levels. These findings may reflect increased amyloid production due to acute sleep disruption. Longitudinal studies are needed to determine whether sustained sleep disruption associates with amyloid accumulation over time.

Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis.

Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau181 in ALS. Patients were clinically or pathologically diagnosed with ALS (n=130) or AD (n=79), or were healthy non-impaired controls (n=26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss. A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W=2,600, p=0.000015), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC=0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W=827, p=0.0072), thoracic (W=469, p=0.00025), and lumbosacral regions (W=851, p=0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho=0.46, p=0.017), but not in the motor cortex (p=0.41). Cerebrospinal spinal fluid p-tau181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818.

Outcome of acute bacterial meningitis among children in Tertiary care hospital.

Objective: To determine the frequency of Hemophilus Influenzae type b, streptococcus pneumonia and Niesseria Meningitidis and outcome in culture proven meningitis in children 6 months to 24 months of age admitted in children ward. Study Design: Cross Sectional Analytical study. Setting: Pediatric Medical Unit of Bahawal Victoria Hospital, Bahawalpur. Period: January 2019 to December 2019. Material & Methods: A total of 220 children of either sex with culture proven meningitis, aged 6 months to 24 months, were included in the study. Demographic characteristics, duration of fever, history of seizures, weight of child, vaccination status and bacteria isolated from Cerebrospinal Spinal Fluid (CSF) and outcome were analyzed. Confidentiality of data was maintained and it was assured that no harm to the participants will be done. The outcome in the form of mortality was noted during the first 10 days of hospital stay. There was no conflict of interest among the authors and study was self-funded. Results: Amongst a total of 220 children, 123 (55.9%) were male. There were 130 (59.1%) children who were less than or equal to 1 year of age. There were 154 (70.0%) children who were having a weight of 7 to 10 kg. Vaccination status showed that, 111 (50.5%) were fully vaccinated, 59 (26.8%) partially vaccinated and 50 (22.7%) not vaccinated. Duration of fever revealed that, 141 (64.1%) had fever for more than 5 days. There were 139 (63.2%) children who had a history of seizures. Streptococcus pneumonia was the commonest bacteria found in 110 (50%) children followed by Neisseria meningitides 53 (24.1%), H. Influenza 37 (16.8%). Overall mortality was noted in 34 (15.5%) children. Conclusion: In children with bacterial meningitis, mortality was high and most common bacteria were found to be S.pneumoniae followed by H.influenzae.

RNase A Inhibits Formation of Neutrophil Extracellular Traps in Subarachnoid Hemorrhage.

Background: Subarachnoid hemorrhage (SAH) caused by rupture of an intracranial aneurysm, is a life-threatening emergency that is associated with substantial morbidity and mortality. Emerging evidence suggests involvement of the innate immune response in secondary brain injury, and a potential role of neutrophil extracellular traps (NETs) for SAH-associated neuroinflammation. In this study, we investigated the spatiotemporal patterns of NETs in SAH and the potential role of the RNase A (the bovine equivalent to human RNase 1) application on NET burden.Methods: A total number of n=81 male C57Bl/6 mice were operated utilizing a filament perforation model to induce SAH, and Sham operation was performed for the corresponding control groups. To confirm the bleeding and exclude stroke and intracerebral hemorrhage, the animals received MRI after 24h. Mice were treated with intravenous injection of RNase A (42μg/kg body weight) or saline solution for the control groups, respectively. Quadruple-immunofluorescence (IF) staining for cell nuclei (DAPI), F-actin (phalloidin), citrullinated H3, and neurons (NeuN) was analyzed by confocal imaging and used to quantify NET abundance in the subarachnoid space (SAS) and brain parenchyma. To quantify NETs in human SAH patients, cerebrospinal spinal fluid (CSF) and blood samples from day 1, 2, 7, and 14 after bleeding onset were analyzed for double-stranded DNA (dsDNA) via Sytox Green.Results: Neutrophil extracellular traps are released upon subarachnoid hemorrhage in the SAS on the ipsilateral bleeding site 24h after ictus. Over time, NETs showed progressive increase in the parenchyma on both ipsi- and contralateral site, peaking on day 14 in periventricular localization. In CSF and blood samples of patients with aneurysmal SAH, NETs also increased gradually over time with a peak on day 7. RNase application significantly reduced NET accumulation in basal, cortical, and periventricular areas.Conclusion: Neutrophil extracellular trap formation following SAH originates in the ipsilateral SAS of the bleeding site and spreads gradually over time to basal, cortical, and periventricular areas in the parenchyma within 14days. Intravenous RNase application abrogates NET burden significantly in the brain parenchyma, underpinning a potential role in modulation of the innate immune activation after SAH.

Development of Reverse Phase Ultra-fast Liquid Chromatography Using Ion-pairing Reagent for Quantitative Assessment of Ceftriaxone in Rat Serum and Cerebrospinal Fluid

Background:In case of meningitis, the meninges are inflamed and the blood brain barrier is distorted, therefore, there is no hindrance to drug penetration. The problem arises when the disease is at the verge of cure, the meninges become uninflamed and the permeability of the drug is reduced to such extend that it becomes nearly impossible to maintain the minimum inhibitory concentration of drug at the site of infection. This problem was overcome by formulating ceftriaxone loaded NLCs and administrating it through intraperitoneal route to Wistar Albino rat. For quantitative assessment of drugs in rat serum and cerebrospinal spinal fluid, a new RP-UFLC (reverse-phase ultra-fast liquid chromatography) method has been developed and validated. Objective:Development and validation of RP-UFLC (using ion-pairing reagent) method for accurate estimation of ceftriaxone in rat serum and CSF. Methods:Method validation is done according to the ICH Guidelines (Q2) for the estimation of ceftriaxone in rat serum and its CSF (cerebrospinal fluid) by the RP-UFLC method. The blood was collected from the rat tail vein and CSF was collected carefully from cisterna magna of the rats by a 23G syringe. The mobile phase was used in a ratio of 70:30%v/v of phosphate buffer with ion-pairing reagent and acetonitrile with a pH of 8.0 Results:Limit of detection and limit of quantification of ceftriaxone in rat serum was 1.08 μg/ml and 3.84 μg/ml, respectively. Similarly, the limit of detection and limit of quantification of ceftriaxone in CSF of rats was 0.94 μg/ml and 2.84 μg/ml, respectively. In both cases, the R2 value was more than 0.99 and showed 99% accuracy. Conclusion:The experimental result suggests that the new RP-UFLC method developed and validated can be effectively used to assess ceftriaxone in preclinical studies in rats.

Safety and Success of Lumbar Puncture in Young Infants: A Prospective Observational Study.

Objective: This study aims to evaluate safety and success rates of lumbar puncture (LP) and to identify factors associated with adverse events or failure of LP in infants.Methods: This two-center prospective observational study investigated infants younger than 90 days of age who underwent LP. Need for resuscitation oxygen desaturation (SpO2 < 90%), bradycardia and intraventricular hemorrhage were considered adverse events. LP failed if cerebrospinal spinal fluid was not collected or had traces of blood. Logistic regression analysis was used to evaluate whether corrected gestational age (GA), body weight at LP, position, and any respiratory support during LP affected SpO2 desaturation or failure of LP.Results: Among 204 LPs, 134 were performed in full-term and 70 in pre-term born infants. SpO2 desaturations occurred during 45 (22.4%) LPs. At multivariate analysis, lower GA at LP (p < 0.001), non-invasive respiratory support (p 0.007) and mechanical ventilation (p 0.004) were associated with SpO2 desaturations. Transient, self-resolving bradycardia occurred in 7 (3.4%) infants. Two infants had intraventricular hemorrhage detected within 72 h of LP. No further adverse events were registered. Failure of LP occurred in 38.2% of cases and was not associated with any of the factors evaluated.Conclusions: LP was safe in most infants. Body weight or GA at LP did not affect LP failure. These data are useful to clinicians, providing information on the safety of the procedure.

Cerebrospinal fluid metabolomics uniquely identifies pathways suggesting risk for anesthesia reactions during electroconvulsive therapy for bipolar disorder.

In this case report, we describe the results of next generation non-targeted cerebrospinal spinal fluid (CSF) metabolomics in a patient presenting with a prolonged delirium and elevated serum ammonia after standard electroconvulsive therapy treatment. These studies subsequently, in part, revealed abnormalities in the citric acid cycle, a finding previously reported in the bipolar literature. The patient subsequently has had a sustained response to pioglitazone, a mitochondrially targeted agent, in contrast to established medical and interventional therapies.

The relationship between CSF biomarkers and cerebral metabolism in early-onset Alzheimer's disease.

One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. Three clusters emerged. The "Aβ42" cluster contained 32 patients with low levels of Aβ42, while tau and p-tau remained within the normal range. The "Aβ42 + tau" cluster contained 41 patients with low levels of Aβ42 and high levels of tau and p-tau. Lastly, the "tau" cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aβ42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The "Aβ42 + tau" and "tau" clusters displayed more marked frontal hypometabolism than the "Aβ42" cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The "Aβ42" and "Aβ42 + tau" clusters displayed more marked hypometabolism in the left occipitotemporal region than the "tau" cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aβ42 level. The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.

Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates.

The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma. We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against β-secretase 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys. Animals infused with anti-BACE1 i.c.v. showed a robust and sustained reduction (~70%) of CSF amyloid-β (Aβ) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40nM, resulting in a ~50% reduction of Aβ in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical Aβ levels and had a low (~0.6nM) antibody concentration in the brain. I.c.v. administration of anti-BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS Aβ concentrations, due to enhanced brain exposure to antibody.

PP05.15 – 2915: A case of neonatal onset leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with rapid progression

Objective To present a case of LBSL with neonatal onset and with rapid progression and to review the literature focused on LBSL with early onset (before one year of age). Methods We report a case of an infant admitted at our Child Neurology Unit in November 2014 with LBSL, investigated with blood and cerebrospinal spinal fluid (CSF) tests, brain and spinal magnetic resonance imaging (MRI). Results The patient was admitted at our hospital at 2 months of age because of severe hypotonia. She had regular antenatal and perinatal story. At birth physical and neurological examination were normal. At two weeks of age nystagmus was noticed and after few weeks, she started to be hyporeactive and hypotonic. At our examination she had severe and diffuse hypotonia, brisk reflex at legs and nystagmus. CSF examination showed an increased lactate (7.4 mmol/L, range 1.2–2.2 mmol/L). Cerebral (including spectroscopy) and spinal MRI showed changes in white matter consistent with LBSL. Two weeks later she developed respiratory arrest and needed mechanical ventilatory support. Steroid therapy was administered without results. Genetic test is in progress. Conclusion LBSL is a rare disease described for the first time in 2003 by Van der Knaap et al. as a mild disorder with childhood and adolescent onset and slow progression. In the Literature we found two cases with neonatal onset, rapid deterioration and death respectively at 2 and 3 year of age and 16 cases with onset before 12 months (mean 8 months) and early death in 6/16 cases. We add to the pertinent literature a new case of LBSL with neonatal onset having a rapid and deteriorating course. This condition should be suspected in neonates or infants with leukoencephalopathy on brain MRI and lactic acidosis in CSF. Spinal MRI and specific genetic tests are needed to confirm the diagnosis.

Affinity proteomic profiling of plasma, cerebrospinal fluid, and brain tissue within multiple sclerosis.

The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.

Analysis of l-serine-O-phosphate in cerebrospinal spinal fluid by derivatization–liquid chromatography/mass spectrometry

l-Serine-O-phosphate (l-SOP), the precursor of l-serine, is a potent agonist against the group III metabotropic glutamate receptors (mGluRs) and, thus, is of interest as a potential biomarker for monitoring modulation of neurotransmitter release. So far, no reports are available on the analysis of l-SOP in cerebrospinal fluid (CSF). Here a novel method is presented to determine l-SOP levels in CSF employing precolumn derivatization with (5-N-succinimidoxy-5-oxopentyl)triphenylphosphonium bromide (SPTPP) coupled to liquid chromatography/mass spectrometry (derivatization–LC/MS, d-LC/MS).

Trypanosoma brucei gambiense infection in vervet monkeys: a potential model for early‐stage disease

Non-human primates are important experimental models for human African trypanosomiasis. Six monkeys were intravenously inoculated with 10(5) trypanosomes of Trypanosoma brucei gambiense IL 3253. They were monitored for 180 days for parasitemia, hematology, clinical and biochemical profiles. The pre-patent period was 2-3 days. From 33 to 123 dpi, the parasitemia was low and only detectable by the hematocrit centrifugation technique. Thereafter, to the end of the experimental period, the parasitemia was undetectable by parasitological methods. Clinical signs observed were lymphadenopathy and splenomegaly. Hematological changes included a decline in hemoglobin occurring between 14 and 56 dpi and a significant decline in platelet counts after infection. The levels of total protein, albumin and globulins increased from 26 dpi for the rest of the experimental period. No parasites were detected in cerebrospinal spinal fluid, and no brain pathology was observed. This vervet monkey model can only be used for early-stage disease Gambian sleeping sickness.

Fatal Influenza A(H1N1)pdm09 Encephalopathy in Immunocompetent Man

We report an immunocompetent patient who had fatal encephalopathy after mild influenza. He rapidly died after unusual symptoms related to intracerebral thrombosis and hemorrhage. A brain biopsy specimen was positive for influenza A(H1N1)pdm09 virus RNA, but a lung biopsy specimen and cerebrospinal spinal fluid samples were negative.

Histology of the Parapapillary Region in High Myopia

To examine histomorphometrically the parapapillary region in highly myopic eyes. Retrospective laboratory investigation. We examined a highly myopic glaucomatous group (36 human globes; axial length >26.5 mm) and a non-highly myopic group (28 globes with secondary angle-closure glaucoma; 17 eyes with malignant choroidal melanoma). Using light microscopy, pupil-optic nerve sections were assessed. The length of the scleral flange (sclera between optic nerve border and optic nerve dura mater) increased with axial length (P < .001; correlation coefficient r = 0.70) and decreased with its thickness (P < .001; r = 0.75). In all highly myopic eyes (n = 15) with a distance of >0.5 mm between optic nerve border and beginning of Bruch membrane, the parapapillary region consisted of an elongated parapapillary scleral flange associated with a scleral flange thinning and a retrobulbar cerebrospinal fluid space extended into the retroparapapillary region. The parapapillary retina was composed of retinal nerve fiber layer (or its remnants) only, without elements of any other retinal layer, without underlying Bruch membrane or choroid. These histologic features were not detected in any of the non-highly myopic eyes. Since parapapillary scleral thickness influences the lamina cribrosa biomechanics, the findings may partially explain the increased glaucoma susceptibility in highly myopic eyes. The implications of an absence of Bruch membrane and choroid in the highly myopic parapapillary region, and the implications of the retrobulbar parapapillary extension of the cerebrospinal spinal fluid space for the pathophysiology of the optic nerve head, have to be elucidated.

Down syndrome with and without dementia: An in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

TROSPIUM CHLORIDE IS UNDETECTABLE IN THE OLDER HUMAN CENTRAL NERVOUS SYSTEM

To the Editor: Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) affects.1, 2 Memory deficits with oxybutynin and tolterodine have been reported.3-5 The available agents for the treatment of OAB are relatively lipophilic tertiary amines, which may be partially unionized at physiological pH. An exception is trospium chloride, which is a quaternary ammonium compound, which confers a permanent cationic charge at physiological pH. The resulting hydrophilicity limits the ability of trospium to cross the lipid cell membranes.6, 7 Hence, it would not be expected to penetrate into the human CNS.8, 9 An institutional review board–approved clinical trial (NCT00863551) was performed to determine whether trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. Twelve cognitively intact older adults (aged ≥65–75; median age 69) with OAB and stable comorbidities were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardized memory testing (Hopkins Verbal Learning Test Revised and Brief Visuospatial Memory Test Revised) was performed before and after the 10-day period.10 Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on Day 10 and assayed for trospium chloride. Predose (Day 0) and postdose (Day 10) results on the memory tests were compared using a reliable change index to assess meaningful change in learning or memory. Trospium chloride levels in the CSF samples of all participants were assay undetectable (<40 pg/mL) on Day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values (Figure 1). Repeat memory testing revealed no significant net drug effect on learning or recall. Plasma and cerebrospinal fluid (CSF) trospium concentration-time profiles on Day 10 after once-daily multiple dose oral administration of 60-mg extended-release trospium chloride capsules in older adult subjects (n=12). This is the first study to investigate the presence of an orally dosed OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures in older adults. Specifically, extended-release trospium chloride was not assay detectable in human CSF concurrent with peak steady-state plasma concentration, and participants concomitantly showed no decline in performance on tests of learning and memory over a 10-day period. The results of pharmacological and memory tests support the hypothesis of a lack of significant CNS penetration for the quaternary amine trospium chloride. Based on the quaternary amine structure and the corresponding cationic charge, it has been predicted that trospium chloride would not be able to cross the human blood–brain barrier (BBB).6-9 Because of the complexities of the aging human BBB, this concept required human clinical trial validation. This study is the first to support the lack of trospium chloride penetration in older adults with OAB and stable comorbid disease who are at risk for drug penetration across the BBB. The correlation of this pharmacokinetic finding with the memory test findings supports the pharmacodynamic antimuscarinic hypothesis; if an antimuscarinic does not cross the BBB, it should not cause cognitive impairment. Larger comparator trials are a logical next step in the evaluation and interpretation of these preliminary findings. Conflict of Interest: Funding provided by Allergan, LLC. Staskin: Received honorarium from and consultant for Allergan, Astella, Pfizer, and Watson; speakers' forum at Allergen, Astella, and Pfizer. Kay: Consultant for Allergan on study design, test administration, evaluation of CNS effects of antimuscarinics, and publications; received honoraria for consulting and training speakers. Consultant and speaker for Pfizer, Novartis. Consultant for Watson. Tannenbaum: Speaker and consultant for Allergan. Goldman: speaker for Pfizer, Astellas, Novartis, and Watson; consultant for Johnson and Johnson, Pfizer, and Allergan; investigator for Allergan. Bhashi and Ling: employees of Allergan, LLC, Pharmacology. Oefelein: employee of Allergan, LLC, Urology. Author Contributions: Staskin: study concept and design, analysis and interpretation of data, preparation of manuscript. Kay: study design, training of site staff to administer memory tests, quality assurance of collected data, interpretation of results, development of manuscript. Tannenbaum: analysis and interpretation of data, preparation of manuscript. Goldman: study design, data analysis, manuscript preparation. Oefelein: study design, conduct, monitoring, analysis of data, manuscript preparation. Bashsi and Ling: pharmacokinetics, bioanalytics, preparation of manuscript. Sponsor's Role: None.