Cerebrospinal Fluid Of Subjects Research Articles

The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.

Microbiota markers level in the blood and cerebrospinal fluid of patients with different types of multiple sclerosis and radiologically isolated syndrome

To assess the level of microbiota markers in the blood and cerebrospinal fluid (CSF) of patients with different types of multiple sclerosis (MS), people with radiologically isolated syndrome (RIS) and control subjects. We used gas chromatography-mass spectrometry (GC-MS) to evaluate the levels of microbiota markers in 69 patients with different types of MS (27 patients in the acute stage, 35 patients with MS in remission, 7 patients with primary-progressive MS), 10 people with RIS, and 47 control subjects (different diseases of the nervous system of a non-autoimmune or inflammatory nature). We showed a statistically significant increase in the content of various microbiota markers in the CSF of patients with MS compared with the control group. We found no change in the content of these markers in blood of patients with MS. This suggests a change of markers of microbial load at the level of the central nervous system, but not at the level of the whole organism. The greatest number of statistically significant differences with the control group was found in the content of markers in CSF of patients with MS in remission. In the acute stage, on the contrary, we found no statistically significant differences compared to the control group. In particular, in CSF of patients with MS in remission, a statistically significant increase in the content of bacterial plasmalogen (4.5 times), and increase in the level of microbial markers specific to Peptostreptococcus anaerobius, Pseudomonas aeruginosa, Eubacterium, Bifidobacterium, Butirivibrio, Moraxella, Acinetobacter, Propionibacterium acnes, as well as an increase of markers of the Epstein-Barr virus were found. In addition, there was an increase of campesterol, the likely source of which is campesterol-producing microfungi. In the CSF of subjects with RIS there were a statistically significant increase in the level of markers of the Epstein-Barr virus, Propionibacterium acnes, as well as Pseudomonas, Moraxella, and Acinetobacter. An association of MS with polymicrobial infection is possible. It is also likely that there is a certain pattern of increase of microbiota markers in the CSF of patients with MS, but not in blood.

Translational potential of synaptic alterations in Alzheimer's disease patients and amyloid precursor protein knock-in mice.

Synaptic dysfunction is an early event in Alzheimer's disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimer's disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (n = 18) and Alzheimer's disease (n = 18) and compared the levels to cognitively and neurologically healthy controls (n = 18) by using ELISA assay. In addition, we aimed to assess the translational potential of these synaptic proteins in two established amyloid precursor protein knock-in Alzheimer's disease mouse models by assessing the cerebrospinal fluid, hippocampal and cortical synaptic protein concentrations. Using ELISA, we measured in parallel these three proteins in cerebrospinal fluid and/or brain of 12- and 24-month-old AppNL-F and AppNL-G-F knock-in mice and AppWt control mice. The regional distribution and expression of these proteins were explored upon aging of the App knock-in models by quantitative immunofluorescence microscopy. Notably, we found a significant increase in concentrations of zinc transporter protein 3 and AMPA glutamate receptor 3 in cerebrospinal fluid of both patient groups compared with cognitively healthy controls. Dynamin1 concentration was significantly higher in Alzheimer's disease patients. Remarkably, patients with mild cognitive impairment who converted to Alzheimer's disease (n = 7) within 2 years exhibited elevated baseline cerebrospinal fluid zinc transporter protein 3 concentrations compared with mild cognitive impairment patients who did not convert (n = 11). Interestingly, similar to the alterations in Alzheimer's disease subjects, cerebrospinal fluid AMPA glutamate receptor 3 concentration was significantly higher in AppNL-G-F knock-in mice when compared with wild-type controls. Furthermore, we have detected age and brain regional specific changes of the three synaptic proteins in the hippocampus and prefrontal cortex of both AppNL-F and AppNL-G-F knock-in mice. Notably, all the three cerebrospinal fluid synaptic protein concentrations correlated negatively with concentrations in hippocampal lysates. The elevated zinc transporter protein 3 concentrations in the cerebrospinal fluid of converter versus non-converter mild cognitive impairment patients suggests a prospective role of zinc transporter 3 in differentiating dementia patients of the biological continuum of Alzheimer's disease. The increased cerebrospinal fluid concentrations of synaptic proteins in both patient groups, potentially reflecting synaptic alterations in the brain, were similarly observed in the amyloid precursor protein knock-in mouse models highlighting the translational potential of these proteins as markers for synaptic alterations. These synaptic markers could potentially help reduce the current disparities between human and animal model-based studies aiding the translation of preclinical discoveries of pathophysiological changes into clinical research.

Levels of the synaptic proteins PSD‐95, SNAP‐25, and neurogranin are selectively increased in the cerebrospinal fluid of patients with Alzheimer’s disease

AbstractBackgroundSynaptic dysfunction and loss occur early in Alzheimer’s Disease (AD) dementia and are closely linked to cognitive decline. Levels of both pre‐ and post‐synaptic proteins are reduced in AD brains while recent studies have shown increased levels of synaptic proteins in the cerebrospinal fluid (CSF) already in the early stages of AD, presumably due to release from degenerating synapses. We measured CSF levels of the novel post‐synaptic marker PSD‐95 together with levels of SNAP‐25 (pre‐synaptic) and neurogranin (post‐synaptic), two emerging synaptic biomarkers, in subjects with AD, other neurodegenerative diseases (OND), and controls.MethodCSF samples from 158 patients undergoing diagnostic lumbar punctures were selected from banked samples. Clinical diagnoses were established by chart review and AD status was verified by CSF ATN biomarkers. 30 subjects had mild cognitive impairment or dementia due to AD, 69 had OND, and 59 were neurological controls (NC). In addition, 30 CSF samples were obtained from healthy subjects (HC) participating in a research study. Levels of PSD‐95 and SNAP‐25 were measured by Quanterix SIMOA assays and neurogranin by an automated Euroimmun ELISA assay.ResultAll subjects had detectable CSF levels of PSD‐95, SNAP‐25, and neurogranin. Levels of all three synaptic markers were higher in AD subjects compared to subjects with OND (p=0.04, p<0.001, and p<0.001, respectively) and both control groups, while levels of SNAP‐25 and neurogranin were lower in OND subjects compared to NC (p=0.005, and p=0.025, respectively). There were tight correlations between levels of PSD‐95, SNAP‐25, and neurogranin with the strongest correlation between SNAP‐25 and neurogranin (r=0.87; r2=0.76; p<0.0001).ConclusionOur data suggest that PSD‐95 and other emerging synaptic markers are selectively increased in the CSF of subjects with AD and that levels of both pre‐ and post‐synaptic markers are tightly correlated. Specific biomarkers for AD‐associated synaptic pathology may hold promise to discriminate AD from other neurodegenerative disorders, to correlate with cognitive decline, and to monitor responses to disease‐modifying drugs reducing synaptic degeneration.

Alterations of mesenchymal stromal cells in cerebrospinal fluid: insights from transcriptomics and an ALS clinical trial

BackgroundMesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases.MethodsIn this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS).ResultsOur results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs.ConclusionsOverall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.

PP 3.13 - CXCR4-usage HIV-1 strains isolated from blood and cerebrospinal fluid in subjects on suppressive antiretroviral therapy

PP 3.13 - CXCR4-usage HIV-1 strains isolated from blood and cerebrospinal fluid in subjects on suppressive antiretroviral therapy

Changes in Cerebrospinal Fluid Tau and β-Amyloid Levels in Diabetic and Prediabetic Patients: A Meta-Analysis.

Increased risks for Alzheimer's disease (AD) are a well-recognized consequence of diabetes, insulin resistance (IR), and hyperinsulinemia. Since cerebrospinal fluid (CSF) is surrounding the central nervous system, alterations of β-amyloid (Aβ) and tau protein in the CSF may be indicative of AD-type degenerations in the brain. Current laboratory diagnosis of AD uses three biomarkers in CSF: Aβ1-42, total tau (t-Tau), and phosphorylated tau (p-Tau). However, changes in these biomarkers in diabetic and prediabetic patients are scattered and variable in literature. Thus, we attempt to perform a systematical analysis of these available data. MEDLINE, EMBASE, the Cochrane Central database, China National Knowledge Infrastructure (CNKI), and Wanfang Data electronic databases were searched to gather published studies that have evaluated the AD-type biomarkers in the CSF of subjects with diabetes, IR, or hyperinsulinemia in comparison with respective controls. Overall analysis of the published data showed no significant differences in Aβ1-42, t-Tau, and p-Tau levels in the CSF between the (pre)diabetic subjects and controls. However, subgroup analysis suggested that (pre)diabetic conditions might accelerate decrease of Aβ1-42, but increase of t-Tau levels in the CSF of subjects with cognitive impairment, and the association with p-Tau in the CSF was stronger (P = 0.001) for diabetes than those of prediabetes (P = 0.61). Our analyses reveal that the relationship between (pre)diabetic conditions and AD-type biomarker status in the CSF was subjective to clinical characteristics.

Virome definition in cerebrospinal fluid of patients with neurological complications after hematopoietic stem cell transplantation

BackgroundNeurological complications (NC) in allogeneic hematopoietic stem cell transplant (HSCT) recipients lead to long-term sequelae and result in significant morbidity and mortality. Since risk factors for NC include viral infection or reactivation, virome inspection after HSCT might be helpful to the clinical management of patients after HSCT. Objectives and study designIn this study we investigated whether any viruses are found in association with NC after HSCT. For this purpose, unbiased next generation sequencing (NGS) was used to characterize nucleic acid (NA) content in cerebrospinal fluid (CSF) taken at time of NC in 35 HSCT patients. Virome definition in CSF from non-transplanted subjects (controls) was also tested to define the commensal flora. Results and conclusionsA higher number of reads/contigs mapped to viruses in patients compared to the controls (7,626 vs 235). Besides bacteriophages, Torque teno virus (TTV) was also identified in both controls and patients. Interestingly, a significantly higher number of TTV-like sequences was detected in the patient samples (7,236 vs 9), showing similarities to distinct genotypes; 3/2,575, 2/1,692 and 2/2,969 contigs/reads mapped to TTV11, TTV13 and Torque teno midi virus, respectively.In conclusion, unbiased NGS demonstrated to be a suitable approach to characterize the virome in samples containing limiting amounts of NA. The higher TTV levels and genetic diversity found in CSF of subjects with NC after HSCT might suggest a possible association between TTV reactivation and the disorder. However, further studies are needed to evaluate the possible role of TTV on NC in HSCT patients.

Adaptive lymphocyte profiles correlate to brain A\u03b2 burden in patients with mild cognitive impairment

BackgroundWe previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment.MethodsCerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66 ± 6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)ε, and quantification of cytokine and immunoglobin levels. Amyloid (A)β deposition was determined by 18F-florbetapir positron emission tomography. Spearman rank order correlations were performed to assess simple linear correlation for parameters including amyloid imaging, central and peripheral immune cell populations, and protein cytokine levels.ResultsSoluble Aβ42 in the cerebrospinal fluid declined as Aβ deposition increased overall and in the precuneous and posterior cingulate cortices. Lymphocyte profiling revealed a significant decline in T cell populations in the cerebrospinal fluid, specifically CD4+ T cells, as Aβ deposition in the posterior cingulate cortex increased. In contrast, increased Aβ burden correlated positively with increased memory B cells in the cerebrospinal fluid, which was exacerbated in APOε4 carriers. For peripheral circulating lymphocytes, only B cell populations decreased with Aβ deposition in the precuneous cortex, as peripheral T cell populations did not correlate with changes in brain amyloid burden.ConclusionsElevations in brain Aβ burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during Aβ accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, Aβ dysregulation during memory decline on a larger cohort collected at multiple centers.Trial registrationAETMCI NCT01146717

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment

BackgroundIncreased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer’s disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. MethodsSeventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. ResultsCompared with healthy control subjects, plasma BACE1 activity (Vmax) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. ConclusionsPlasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.

Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis.

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

Early cost-utility analysis of general and cerebrospinal fluid-specific Alzheimer's disease biomarkers for hypothetical disease-modifying treatment decision in mild cognitive impairment

IntroductionThe study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. MethodsA decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. ResultsThe simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. DiscussionThe results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions.

Correlations between mini-mental state examination score, cerebrospinal fluid biomarkers, and pathology observed in brain biopsies of patients with normal-pressure hydrocephalus.

Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal-pressure hydrocephalus. Alzheimer disease hallmark lesions-β-amyloid (Aβ) and hyperphosphorylated tau (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini-mental state examination scores. Concomitant Aβ and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between Aβ-immunostained area fraction in tissue and Aβ42 (42-amino-acid form of Aβ) in cerebrospinal fluid (CSF). Levels of Aβ42 were significantly lower in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of Aβ (Aβ42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus.

Thyroid Autoantibodies in the Cerebrospinal Fluid of Subjects with and without Thyroid Disease: Implications for Hashimoto's Encephalopathy.

Introduction. Plasma antithyroid peroxidase (anti-TPO) and anti-thyroglobulin antibodies (anti-Tg) are widely used in the diagnosis of autoimmune thyroiditis. No research has compared anti-TPO and anti-Tg both in plasma and cerebrospinal fluid (CSF) of healthy individuals vis-à-vis patients with thyroid disease. Methods. We measured anti-TPO and anti-Tg antibodies in plasma and CSF in nine subjects (mean age ± SD: 73 ± 6 years) with hypothyroidism and nine subjects (mean age ± SD: 73 ± 8 years) without thyroid disease. Results. The concentration of anti-TPO autoantibodies in CSF was very low compared to plasma in both subjects with thyroid and without thyroid disease (P = 0.007). CSF anti-Tg autoantibodies titers were very low compared to the plasma in subjects with thyroid disease (P = 0.004), whereas, in subjects without thyroid disease, this difference did not reach statistical significance (P = 0.063). Conclusions. Thyroid autoantibodies levels were low in plasma and CSF; we did not observe any transfer of thyroid autoantibodies from the peripheral blood to the CSF. Therefore, regarding Hashimoto's encephalopathy, where elevated antithyroid autoantibodies are often measured in blood, it is more likely that thyroiditis and encephalopathy represent nonspecific, but distinct, events of an aggressive immune system.

Flt3 ligand does not differentiate between Parkinsonian disorders.

Differential diagnosis of parkinsonian disorders is challenging because of overlapping symptoms, especially during early stages of disease. No validated biomarkers are available for early and accurate diagnosis of multiple system atrophy and other parkinsonian disorders. It has been reported that flt3 ligand levels in cerebrospinal fluid could clearly differentiate patients with Parkinson's disease from patients with multiple system atrophy, with 99% sensitivity and 95% specificity. We measured flt3 ligand levels in cerebrospinal fluid of subjects with Parkinson's disease (n = 37), multiple system atrophy (n = 30), and progressive supranuclear palsy (n = 19). In our cohort, no significant difference was found in flt3 ligand levels between Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Our results suggest that cerebrospinal fluid flt3 ligand levels do not differentiate between parkinsonian disorders.

Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline

The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.

Anxiety is related to Alzheimer's disease markers in cerebrospinal fluid of subjects with mild cognitive impairment

in both anterior temporal lobes while FDG PET scan showed posterior hypofixation atypical for AD. The CSF of tau-protein (600 pg/ml), phosphorylated tau (87 pg/ml) were increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (480 pg/ml) according to our cut-off (Dumurgier et al.) suggesting AD CSF profile. Conclusions: Among different clinical AD phenotype, FTD clinical presentation must not be misdiagnosed. CSF biomarkers are helpful to diagnose these patients, establish an accurate diagnosis and introduce a specific treatment.

Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury

Objectives: Head injury frequently results in increased intracranial pressure and brain edema. Investigators have demonstrated that ischemic injury causes an increase in cerebrospinal fluid (CSF) levels of antidiuretic hormone (ADH); increased CSF ADH levels exacerbate cerebral edema, and inhibition of the ADH system with specific ADH antagonists reduces cerebral edema. The current study was designed to test the hypothesis that elevated levels of ADH are present in the CSF of subjects with head injury.Methods: Ventricular CSF and blood samples were taken from 11 subjects with head injury and 12 subjects with no known head trauma or injury. ADH levels were analyzed using radioimmunoassay. Severity of increased intracranial pressure (ICP) was rated in head-injured subjects using a four-point ordinal scale, based on which treatments were necessary to reduce ICP.Results: Subjects with head injury had higher CSF (3.2 versus 1.2 pg/ml; P<0.02) and plasma (4.1 versus 1.4 pg/ml; P<0.02) levels of ADH than did control subjects. In head-injured subjects, CSF ADH levels positively correlated with severity of ICP.Discussion: The results of this study suggest that ADH plays a role in brain edema associated with closed head injury.

HIV‐1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

Striatal Alterations of Secretogranin-1, Somatostatin, Prodynorphin, and Cholecystokinin Peptides in an Experimental Mouse Model of Parkinson Disease

The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain. The information regarding the expression of neuropeptides in parkinsonism is very limited. Here we have elucidated striatal neuropeptide mechanisms in experimental parkinsonism using the unilateral 6-hydroxydopamine model to degenerate dopamine neurons. A thoroughly controlled sample preparation technique together with a peptidomics approach and targeted neuropeptide sequence collections enabled sensitive detection, identification, and relative quantitation of a great number of endogenous neuropeptides. Previously not recognized alterations in neuropeptide levels were identified in the unilateral lesioned mice with or without subchronic 3,4-dihydroxy-L-phenylalanine administration, the conventional treatment of Parkinson disease. Several of these peptides originated from the same precursor such as secretogranin-1, somatostatin, prodynorphin, and cholecystokinin. Disease-related biotransformation of precursors into individual peptides was observed in the experimental model of Parkinson disease. Several previously unreported potentially biologically active peptides were also identified from the striatal samples. This study provides further evidence that neuropeptides take part in mediating the central nervous system failure associated with Parkinson disease.