Decrease In Cerebrospinal Fluid Research Articles

Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis.

Neuroinfection is associated with the deposition of amyloid-beta (Aβ) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aβ peptides in the brain is unreported. We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aβ1-42 (cAβ1-42), Aβ1-40 (cAβ1-40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis. NMDAR-E patients had lower cAβ1-42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAβ1-42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAβ1-42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAβ1-42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAβ1-42 levels and high levels of several blood parameters. cAβ1-42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAβ1-42 and some inflammatory indicators. cAβ1-42 was decreased in NMDAR-E patients. cAβ1-42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAβ1-42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E.

Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy.

Novel therapies for Hurler syndrome aim to cross the blood-brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain-targeting therapies. We compared pre-transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non-BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182-1186.

Serial Neuroendoscopic Lavage for the Treatment of Elevated Cerebrospinal Fluid Protein Levels in Infants with Gram-Negative Rod Ventriculitis

Introduction: Gram-negative rod (GNR) bacterial ventriculitis is a rare complication of shunt-dependent hydrocephalus, often requiring an extended and invasive treatment course. Accumulation of purulent material, as well as empyema and septation formation, limits circulation of antibiotics and infection clearance. Supplementation of standard care with neuroendoscopic-guided intraventricular lavage with lactated Ringer solution and fenestration of septations may facilitate infection clearance and simplify the eventual shunt construct required. Here, the utility of serial lavage for ventriculitis is described in a population of shunt-dependent neonates and infants at high risk for morbidity and mortality. Methods: Five infants with shunt-dependent hydrocephalus and subsequent GNR ventriculitis were treated with standard care measures with the addition of serial neuroendoscopic lavage. A retrospective chart review was performed to collect patient characteristics, shunt dependency, and shunt revisions within a year of ventriculitis resolution. Results: Patients demonstrated a mean 74% decrease in cerebrospinal fluid (CSF) protein following each neuroendoscopic lavage and trended toward a shorter time to infection clearance in comparison to previously published literature. Patients required 0–2 shunt revisions at 1-year follow-up following hospitalization for shunt-related ventriculitis (mean 0.8 +/− 0.8). Conclusions: Serial neuroendoscopic lavage is an effective technique, used alone or in combination with fenestration of septations, to reduce the CSF protein and bacterial load in the treatment of ventriculitis, decreasing time until eradication of infection. Serial lavage may reduce the risk of future shunt malfunction, simplify the future shunt construct, and decrease duration of infection.

Clinical pathology of primary central nervous system lymphoma in HIV-positive patients-a 41 Chinese patients retrospective study

ObjectivesThe purpose of this study was to investigate the clinicopathological characteristics of primary central nervous system lymphoma (PCNSL). MethodsWe collected 41 PCNSL formalin-fixed, paraffin-embedded (FFPE) samples from human immunodeficiency virus (HIV)-positive patients and performed HE (haematoxylin-eosin) staining, immunohistochemistry (IHC) staining, in situ hybridization, fluorescence in situ hybridization (FISH). Real-time quantitative polymerase chain reaction (RT-qPCR) was performed in 9 cases of FFPE samples. Meanwhile, we analysed the clinical pathological significance of the results. ResultsSeven patients had diffuse large B-cell lymphoma (DLBCL) with germinal centre B-cell (GCB)-like DLBCL, 32 had activated B-cell (ABC)-like DLBCL, and 2 had Burkitt lymphoma (BL). GCB-like DLBCL patients were older at onset (P = 0.040).A lower CD4+ T-cell count and a decrease in cerebrospinal fluid (CSF) glucose content were more frequent in ABC-like DLBCL (P = 0.012, P = 0.006). Overexpression of P53 was more in ABC-like DLBCL (P = 0.041). 73.2 % cases were Epstein–Barr encoding region (EBER) positive, which was more likely in ABC-like DLBCL patients (P = 0.037). EBV DNA were detected in 5/7 EBER-negative DLBCL cases and none (0/2) of the BL cases. All the cases were negative for HHV8 staining. None of the 7 Double expressor lymphoma (DEL) cases had BCL2, BCL6, or c-MYC genetic rearrangements. ConclusionsHIV-related PCNSL showed unique clinical pathological significance. None of EBV detected in HIV-related BL and without HHV8 infectious are new sights in our single-center study of Chinese HIV-related PCNSL patients.

Modern approaches to the diagnosis and treatment of spontaneous intracranial hypotension (a literature review)

The aim of this review is to analyze and summarize the existing evidence regarding the diagnosis and treatment of spontaneous intracranial hypotension. Spontaneous intracranial hypotension occurs due to a decrease in cerebrospinal fluid (CSF) volume as a result of its spontaneous leakage and has a variety of clinical and neuroimaging features, sometimes different from CSF hypotension after a lumbar puncture. Anatomical changes in spontaneous CSF leakage are complex and are often associated with structural disorders of the connective tissue, weakness of certain areas of the dura mater and its diverticulosis. One consequence of decreased CSF volume is brain descent. This leads to traction of pain-sensitive brain structures and, therefore, to headaches that are orthostatic or with some orthostatic features. The methods of choice to identify the site of CSF leak are CT-myelography and radioisotope cisternography. Epidural blood patch is the main treatment in most cases. Conclusions. The study on the most informative and minimally invasive methods to locate the site of CSF leak, conservative and surgical methods of treatment efficacy evaluation depending on the etiological factors of spontaneous intracranial hypotension are extremely important and promising scientific fields requiring further research with the development of personalized approaches considering the individual characteristics of each patient.

Cerebrospinal fluid A beta 1\u201340 peptides increase in Alzheimer\u2019s disease and are highly correlated with phospho-tau in control individuals

BackgroundAmyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1–42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1–40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results.MethodsHere, we analyzed the levels of Aβ1–40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1–42 and Aβ1–40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular).ResultsRegardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1–40 and p-tau (181) in CSF, particularly in control patients.ConclusionsThese results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

Iron Concentration Does Not Differ in Blood but Tends to Decrease in Cerebrospinal Fluid in Parkinson's Disease.

BackgroundIron accumulation in the substantia nigra in PD patients was acknowledged, but the studies on alteration of iron levels in blood and cerebrospinal fluids (CSF) reported inconsistent results.ObjectiveTo determinate the alterations of blood and CSF levels of iron in PD patients, a case-control study and a meta-analysis both in blood and CSF were conducted.MethodsIn the case-control study, 43 PD patients and 33 controls were recruited to test iron metabolism, 15 normal and 12 PD patients donated CSF. Levels in iron were quantified by inductively coupled atomic emission spectrometry. Iron metabolism was analyzed by routine blood tests. In the meta-analysis, a comprehensive literature search was performed on relevant studies published from Jan 1980 to Dec 2018 in PubMed, Web of Science and EMBASE databases. The pooled standard mean difference (SMD) with random effects model was selected to estimate the association between iron levels and PD.ResultsIn the case-control study, the iron level in serum in the controls and PD patients were 110.00 ± 48.75 μg/dl and 107.21 ± 34.25 μg/dl, respectively, no significant difference was found between them (p = 0.850), with a small effect size (Cohen’s d: 0.12; 95% CI: 0.08–0.17). Ferritin level in PD patients was lower than controls (p = 0.014). The CSF levels of iron in control and the PD patients were 20.14 ± 3.35 ng/dl and 16.26 ± 4.82 ng/dl, respectively. CSF levels of iron were lower in PD compared with that of controls (p = 0.021), with a moderate effect size (Cohen’s d: 0.51; 95% CI: 0.43–0.65). In the meta-analysis, 22 eligible studies and a total of 3607 participants were identified. Blood levels of iron did not differ significant between PD patients and the controls [SMD (95% CI): −0.03 (−0.30, 0.24)], but CSF iron levels tended to be lower in PD patients compared with that in the controls [SMD (95% CI): −0.33 (−0.65, −0.00)].ConclusionIron homeostasis may be disturbed in CSF, but not in the peripheral blood in PD.

A blood-based signature of cerebrospinal fluid A\u03b21\u201342 status

It is increasingly recognized that Alzheimer’s disease (AD) exists before dementia is present and that shifts in amyloid beta occur long before clinical symptoms can be detected. Early detection of these molecular changes is a key aspect for the success of interventions aimed at slowing down rates of cognitive decline. Recent evidence indicates that of the two established methods for measuring amyloid, a decrease in cerebrospinal fluid (CSF) amyloid β1−42 (Aβ1−42) may be an earlier indicator of Alzheimer’s disease risk than measures of amyloid obtained from Positron Emission Tomography (PET). However, CSF collection is highly invasive and expensive. In contrast, blood collection is routinely performed, minimally invasive and cheap. In this work, we develop a blood-based signature that can provide a cheap and minimally invasive estimation of an individual’s CSF amyloid status using a machine learning approach. We show that a Random Forest model derived from plasma analytes can accurately predict subjects as having abnormal (low) CSF Aβ1−42 levels indicative of AD risk (0.84 AUC, 0.78 sensitivity, and 0.73 specificity). Refinement of the modeling indicates that only APOEε4 carrier status and four plasma analytes (CGA, Aβ1−42, Eotaxin 3, APOE) are required to achieve a high level of accuracy. Furthermore, we show across an independent validation cohort that individuals with predicted abnormal CSF Aβ1−42 levels transitioned to an AD diagnosis over 120 months significantly faster than those with predicted normal CSF Aβ1−42 levels and that the resulting model also validates reasonably across PET Aβ1−42 status (0.78 AUC). This is the first study to show that a machine learning approach, using plasma protein levels, age and APOEε4 carrier status, is able to predict CSF Aβ1−42 status, the earliest risk indicator for AD, with high accuracy.

Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease.

IntroductionThe negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures.MethodsThe study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient.ResultsAssignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau.ConclusionThese findings may inform future studies of drugs targeting secretases involved in Aβ generation.Trial registrationClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-015-0121-6) contains supplementary material, which is available to authorized users.

Hearing loss following ventriculoperitoneal shunt in communicating hydrocephalus patients: A pilot study

Hearing loss can be associated with a decrease in cerebrospinal fluid (CSF) pressure because changes in CSF pressure induce changes in perilymph pressure. Hearing loss after neurosurgical procedures have been reported, but clinical information on hearing loss after the placement of ventriculoperitoneal (VP) shunts, the most commonly used CSF shunt for hydrocephalus patients, is limited. This study is aimed to show the relationship between VP shunt and hearing loss. Prospective study. Pure tone threshold and electrocochleography were preoperatively performed in nine patients (18 ears) undergoing elective VP shunt placement. Five-day and 1-month post-shunt placement hearing thresholds were compared with baseline data. A correlation analysis was conducted between the threshold and summating potential/action potential (SP/AP) ratio changes at 5 days and 1 month after shunt placement. Cochlear aqueduct dimensions measured by high-resolution CT were compared between ears with and without hearing loss. About 40% of subject ears showed hearing loss with a threshold elevation of at least 15 dB in one or more frequencies. After VP shunt placement, the mean threshold of all ears showed a significant increase in most frequencies and the pure tone average. The change in the SP/AP ratios was significantly correlated with the change in the pure tone average at both 5 days and 1 month after shunt placement. Cochlear aqueduct dimensions were not correlated with hearing loss occurrence. Hearing thresholds may increase following VP shunt placement, possibly due to secondary endolymphatic hydrops.

Mortality in HIV-Infected Patients with Cryptococcal Meningitis

Cryptococcal meningitis (CM) remains a common, life-threatening infection in HIV-infected individuals in many world regions despite increasing availability of antiretroviral therapy (ART) and antifungal medications. Researchers recently explored factors associated with mortality in nine trials among HIV-infected patients with CM in Africa and Asia. All trials used early fungicidal activity (i.e., rate of decrease in cerebrospinal fluid [CSF]) cryptococcal log colony–forming units/mL) as the primary outcome. The study involved 501 ART-naive patients with first-episode CM (median age, 34; 52% …

Decrease in prosaposin in the Dystrophic mdx mouse brain.

BackgroundDuchenne muscular dystrophy caused by a mutation in the X-linked dystrophin gene induces metabolic and structural disorders in the brain. A lack of dystrophin in brain structures is involved in impaired cognitive function. Prosaposin (PS), a neurotrophic factor, is abundant in the choroid plexus and various brain regions. We investigated whether PS serves as a link between dystrophin loss and gross and/or ultrastructural brain abnormalities.Methodology/Principal FindingsThe distribution of PS in the brains of juvenile and adult mdx mice was investigated by immunochemistry, Western blotting, and in situ hybridization. Immunochemistry revealed lower levels of PS in the cytoplasm of neurons of the cerebral cortex, hippocampus, cerebellum, and choroid plexus in mdx mice. Western blotting confirmed that PS levels were lower in these brain regions in both juveniles and adults. Even with low PS production in the choroids plexus, there was no significant PS decrease in cerebrospinal fluid (CSF). In situ hybridization revealed that the primary form of PS mRNA in both normal and mdx mice was Pro+9, a secretory-type PS, and the hybridization signals for Pro+9 in the above-mentioned brain regions were weaker in mdx mice than in normal mice. We also investigated mitogen-activated protein kinase signalling. Stronger activation of ERK1/2 was observed in mdx mice, ERK1/2 activity was positively correlated with PS activity, and exogenous PS18 stimulated both p-ERK1/2 and PS in SH-SY5Y cells.Conclusions/SignificanceLow levels of PS and its receptors suggest the participation of PS in some pathological changes in the brains of mdx mice.

Altered CSF Orexin and α-Synuclein Levels in Dementia Patients

Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.

Alzheimer's Disease and Vascular Deficiency: Lessons from Imaging Studies and Down Syndrome

Down syndrome (DS) individuals are at high risk for developing Alzheimer's disease (AD) and consequently provide a unique opportunity to examine the factors leading to the onset of AD. This paper focuses on the neglected vascular parallels between AD and DS that can readily be examined in DS. Several recent AD studies provide evidence that internal jugular vein (IJV) reflux may result in white matter lesions and a 30% decrease in cerebrospinal fluid (CSF) clearance of amyloid-β. At the same time, studies analyzing the synthesis of amyloid-β in DS showed greater than expected amounts of Aβ than would be predicted by the increase in gene dosage, perhaps due to slower clearance. These studies are discussed along with the possibility that the venous and CSF dysfunction found in AD patients may be present early in life in persons with DS, leaving them particularly vulnerable to early onset AD. Studying IJV function in DS provides an opportunity to understand the role of vascular function in the initiation of AD.

Carcinomatous meningitis related to patients with breast cancer patients: A new approach of an individual treatment regimen with liposomal cytarabine.

e11532 Background: Carcinomatous meningitis occurs in 5 % of patients with breast cancer. The median survival amounts from 4 to 6 months and only 15% of patients survive more than 1 year. The best result of carcinomatous meningitis treatment is achieved by the use of the combined systemic and intrathecal chemotherapy accompanied by the spinal and whole brain radiotherapy. The patients with carcinomatous meningitis are treated with intrathecal methotrexate as the initial therapy. However the results of methotrexate treatment are not satisfactory. It seems that liposomal cytarabine treatment might be promising for the patients with carcinomatous meningitis. Therefore this therapy was investigated. Methods: In year 2010, 8 patients of Breast Cancer Department in Cancer Center in Warsaw with carcinomatous meningitis received the intrathecal chemotherapy with liposomal cytarabine. The diagnosis was based on the presence of cancer cells in cerebro-spinal fluid and/or cerebrospinal MRI. Liposomal cytarabine was administered in the intrathecal injection of 50 mg, every 2 weeks for 5 cycles followed by 5 cycles of 50 mg every 4 weeks. Results: Generally the liposomal cytarabine therapy was well tolerated. No serious adverse events were observed. The regimen of the treatment was more convenient than weekly administering of methothrexate. Intrathecal liposomal cytarabine treatment results in the rapid cancer cells count decrease in cerebrospinal fluid. It does not seem to correspond with clinical benefits. The progression of the disease was observed in each case after two weeks after drug administration Conclusions: The results suggest that liposomal cytarabine intrathecal chemotherapy is well tolerated. The clarification of cerebrospinal fluid from cancer cells can not to be the factor of the termination of the liposomal cytarabine intrathecal treatment. It seems that the better results could be achieved by the change of the used regimen of treatment, as the every 4 weeks treatment is not efficacious and the progression of disease occurrs after two weeks. The individual timetable of the treatment scheme should be considered in every case according to the clinical status.

Antiamyloid Drugs May Offer Hope for AD

Antiamyloid Drugs May Offer Hope for AD

Intraoperative ultrasonography used to determine the extent of surgery necessary during posterior fossa decompression in children with Chiari malformation Type I

In this retrospective analysis, the authors report a prospective study in which intraoperative ultrasonography was used to determine the extent of surgery necessary during posterior fossa decompression surgery for Chiari malformation Type I (CM-I) in children. Between 1995 and 2003, posterior fossa decompression was performed in 149 patients (mean 5.9 years of age, range 9 months-18 years of age) with CM-I. Of these, 130 underwent intraoperative ultrasonographic evaluation of the craniocervical junction (CCJ) and 15 did not. Four patients with craniosynostosis were excluded from the study. Duraplasty and tonsillar shrinkage were performed when ultrasonographic evidence showed significant decreases in cerebrospinal fluid (CSF) or abnormal tonsillar piston action. Surgical success was determined on the basis of clinical outcome and need for reoperation. One hundred and twenty-four (95.5%) of the children had successful outcomes following surgery and six (4.5%) experienced continued or worsening symptoms requiring reoperation. Forty patients did not undergo duraplasty because the ultrasonography evidence showed adequate decompression with bone removal alone. Of 90 patients with significant compression, decreased CSF dynamics, and/or abnormal tonsillar piston-like action at the CCJ, 85 underwent duraplasty and tonsillar shrinkage and five did not for various reasons. One patient in whom the dura mater was violated accidentally during bone decompression subsequently underwent duraplasty. Hospital stays lasted 6.4 +/- 3.9 days (mean +/- standard deviation) when duraplasty was performed compared with 4.3 +/- 1.1 days when it was not (p < 0.0003). After bone decompression alone, no patient experienced complications. After duraplasty, 12 patients experienced complications and had headaches, nausea, and pain more often than patients who underwent bone decompression alone. Mean tonsillar descent was 11 +/- 4 mm after bone decompression only and 13.9 +/- 4.9 mm after duraplasty, with tonsillar shrinkage (p < 0.0003) seen on magnetic resonance imaging. In patients who undergo decompressive surgery for CM-I, intraoperative ultrasonography may be a useful tool to aid the surgeon in deciding whether to opt for bone removal only or bone removal plus duraplasty and tonsillar shrinkage.

Can chronic increased intracranial pressure or exposure to repetitive intermittent intracranial pressure elevations raise your risk for Alzheimer’s disease?

Over a decade ago, I formulated the hypothesis that cumulative effects of exposure to high intracranial pressure (ICP) may contribute to the development of Alzheimer’s disease (AD), though not necessarily in an exclusive way. In addition to individual ICP characteristics (high ‘physiological’ ICP) and diseases causing ICP elevation, various activities with significant Valsalva effort, such as weightlifting and wind instrument playing, can generate very high ICPs. Recent studies of normal-pressure hydrocephalus (NPH), glaucoma and Alzheimer’s disease provide supportive evidence for this hypothesis. A number of studies have shown a high incidence of AD related lesions in patients with NPH, which is known to be associated with prolonged elevation of ICP in a majority of cases. In both NPH and AD, an important decrease in cerebrospinal fluid (CSF) production was calculated. According to researchers in the US, the resulting CSF stagnation with impaired clearance and accumulation of neurotoxic substances may play an important role in the onset and progression of AD. They tested the hypothesis that improving CSF turnover by means of an investigational low-flow ventriculoperitoneal shunt will delay the progression of dementia in patients with Alzheimer’s disease. With regard to the observed decrease in CSF production in patients suffering from NPH, it was postulated that chronic increased ICP causes downregulation of CSF production. It is hypothesized here that repetitive intermittent ICP elevations also may lead to downregulation of CSF production due to long-term cumulative effects. If the latter proves to be true, then both chronic increased ICP and repeated exposures to increased ICP (e.g., repetitive Valsalva maneuvers) may cause a similar cascade of CSF circulatory failure events leading to AD over time. Furthermore, AD may be causally related to increased ICP through other pathomechanisms. Additional supportive evidence for the role of a pressure factor in the pathogenesis of AD comes from studies concerning glaucoma. Elevated intraocular pressure (IOP) is a hallmark of glaucoma. Recently, similarities in pathophysiology between glaucoma and AD have been noted, with increased processing of amyloid precursor protein (APP) and up-regulation of β-amyloid protein expression in retinal ganglion cells (RGCs). Given this link between AD and glaucoma, evidence for a causal relationship between repetitive intermittent ICP elevations and AD is gained from research indicating that high resistance wind instrument playing raises IOP and may result in glaucomatous damage. To test the validity of the hypothesis that exposure to repetitive but nonsustained ICP elevations may predispose to AD a non-invasive, epidemiological study is proposed in this paper.

Cerebrospinal fluid levels of antiretroviral medications: abstract and commentary.

BackgroundTreatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people.Methods28 antiretroviral-naive individuals with CD4 cell counts of 200/µL or more and plasma HIV-1-RNA concentrations of 10000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n=17) or zidovudine (n=11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid.FindingsAll 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r=0.18, p=0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine.InterpretationThe two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine

Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. 28 antiretroviral-naive individuals with CD4 cell counts of 200/microL or more and plasma HIV-1-RNA concentrations of 10,000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n = 17) or zidovudine (n = 11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r = 0.18, p = 0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.