Reduction In Cerebrospinal Fluid Research Articles

Novel device for sealing perforations following dural puncture

Unintentional dural puncture can lead to post-dural puncture headache. Garcia-Vitoria et al examined the efficacy of a new device that allows sealing a dural puncture. The authors performed their study...

Amyloid-\u03b21\u201343 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

BackgroundAlzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1–42. However, a direct effect on Aβ1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.MethodsN = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1–42 and Aβ1–40 CSF levels.The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.ResultsA known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1–43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1–43 levels positively correlated with CSF Aβ1–42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1–43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1–43 and Aβ1–42 levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations.ConclusionThis is the first time that Aβ1–43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1–43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1–43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

Brain Shuttle Neprilysin reduces central Amyloid-β levels.

Reducing Amyloid β (Aβ) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer`s disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key Aβ-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central Aβ. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading Aβ in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial Aβ reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an Aβ degrading enzyme across the blood-brain barriers to efficiently reduce Aβ levels in both CSF and brain.

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition. APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain. CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies. This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

Predictive value of typical cataplexy+ DQB1*0602 positive to hypocretin-1 reduction in cerebrospinal fluid in patients with narcolepsy

Objective: To discusses the predictive value of typical cataplexy+ HLA-DQB1*0602 positive to hypocretin-1 (HCRT-1) reduction in cerebrospinal fluid (CSF) in patients with narcolepsy. Methods: A total of 165 narcoleptic patients, who were diagnosed at the Sleep Center of Peking University People's Hospital and Peking University International Hospital from March 2003 to March 2017, were recruited. The CSF HCRT-1 level and DQB1*0602 were measured in all the subjects. The narcoleptic patients were divided into two groups: typical cataplexy+ DQB1*0602 positive were CH group, and others who were not typical cataplexy and DQB1*0602 positive simultaneously were NCH group. The HCRT-1 level in CSF was declared to have a serious reduction when HCRT-1≤110 ng/L. According to this standard, the CH group and NCH group were subdivided into sub-groups and the data was analyzed to investigate the predictive value of typical cataplexy+ HLA-DQB1*0602 positive to HCRT-1 reduction. Results: There were 142 patients in CH group, including 137 patients with HCRT-1 reduction and 5 patients without. There were 23 patients in NCH group, including 15 patients with HCRT-1 reduction and 8 patients without. The positive predictive value of typical cataplexy+ DQB1*0602 positive for the reduction of HCRT-1 in CSF was 96.5%. Typical cataplexy+ DQB1*0602 positive had a good consistency with the HCRT-1 reduction in CSF (χ(2)=26.7, P<0.001). Conclusion: Typical cataplexy+ DQB1*0602 positive has a good predictive value to the HCRT-1 reduction in CSF in patients with narcolepsy.

Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer\u2019s disease: randomized, double-blind, placebo-controlled study

Backgroundβ-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer’s disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia.MethodsIn two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6–8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1–40 [Aβ1–40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated.ResultsIn both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1–40 levels from baseline at day 28 in both the 10-mg (67–68%) and 50-mg (87–90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were − 69.37 (− 72.25; − 61.50) and − 92.74 (− 100.08; − 85.39), and for Japanese with preclinical AD, they were − 62.48 (− 78.32; − 46.64) and − 80.81 (− 96.13; − 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60–70% and 90% Aβ1–40 reductions, respectively. The trend of the reduction was similar across the Aβ1–37, Aβ1–38, and Aβ1–42 fragments in both atabecestat dose groups, consistent with Aβ1–40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period.ConclusionsJNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1–40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults.Trial registrationALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013.ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.

Rapid increase of 'brain-type' transferrin in cerebrospinal fluid after shunt surgery for idiopathic normal pressure hydrocephalus: a prognosis marker for cognitive recovery.

Idiopathic normal pressure hydrocephalus (iNPH) is a dementia-inducing disorder. Primary cause of iNPH is speculated to be a reduction of cerebrospinal fluid (CSF) absorption, which secondarily induces hydrocephalus, compression of brain, and reduction of CSF production. Patients are treated by surgically inserting a shunt to deliver excess CSF to the abdominal cavity. The prognosis for cognitive improvement after shunt surgery has been difficult to predict. We therefore investigated various CSF proteins, hoping to find a biomarker predictive of cognitive performance one to two years after shunt surgery. CSF proteins of 34 iNPH and 15 non-iNPH patients were analysed by Western blotting, revealing two glycan isoforms of transferrin (Tf); 'brain-type' Tf with N-acetylglucosaminylated glycans and 'serum-type' Tf with α2, 6-sialylated glycans. Brain-type Tf levels decreased in iNPH but rapidly returned to normal levels within 1-3 months after shunt surgery. This change was positively correlated with recovery from dementia, per Mini-Mental State Examination and Frontal Assessment Battery scores at 11.8 ± 7.7 months post-operation, suggesting that brain-type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH. Histochemical staining with anti-Tf antibody and an N-acetylglucosamine-binding lectin suggests that brain-type Tf is secreted from choroid plexus, CSF-producing tissue.

Investigating the Relationship between Cerebrospinal Fluid and Magnetic Induction Phase Shift in Rabbit Intracerebral hematoma expansion Monitoring by MRI

In a prior study of intracerebral hemorrhage monitoring using magnetic induction phase shift (MIPS), we found that MIPS signal changes occurred prior to those seen with intracranial pressure. However, the characteristic MIPS alert is not yet fully explained. Combining the brain physiology and MIPS theory, we propose that cerebrospinal fluid (CSF) may be the primary factor that leads to hematoma expansion being alerted by MIPS earlier than with intracranial pressure monitoring. This paper investigates the relationship between CSF and MIPS in monitoring of rabbit intracerebral hemorrhage models, which is based on the MIPS measurements data, the quantified data on CSF from medical images and the amount of injected blood in the rabbit intracerebral hemorrhage model. In the investigated results, a R value of 0.792 with a significance of 0.019 is observed between the MIPS and CSF, which is closer than MIPS and injected blood. Before the reversal point of MIPS, CSF is the leading factor in MIPS signal changing in an early hematoma expansion stage. Under CSF compensation, CSF reduction compensates for hematoma expansion in the brain to keep intracranial pressure stable. MIPS decrease results from the reducing CSF volume. This enables MIPS to detect hematoma expansion earlier than intracranial pressure.

Supratentorial acute subdural haematoma during microvascular decompression surgery: report of three cases

Supratentoiral haemorrhage during posterior fossa surgery is very rare. Authors report three cases of acute subdural haematoma occurred during microvascular decompression (MVD). Bleeding was observed in the suboccipital surgical area during operation but the origin of the bleeding was not confirmed intraoperatively in all cases. Decompression procedure was completed and immediate postoperative computed tomography revealed supratentorial subdural haematoma. This complication was observed during MVD in healthy young patients with hemifacial spasm in our cases. Flexion of the head with reduction of cerebrospinal fluid may have induced rotational movement of the cerebrum resulting in rupture of bridging veins, but no definitive mechanism that fulfils the clinical characteristics was clearly determined.

Marizomib for CNS-Multiple Myeloma

Marizomib, a natural marine product, is an irreversible proteasome inhibitor (PI) that has distinct advantages over the currently approved PIs in that it irreversibly inhibits all three enzymatic activities of the proteasome and has been demonstrated to cross the blood brain barrier. Several studies have demonstrated that marizomib (MRZ) penetrates and can be retained in the CNS and that it substantially inhibits proteasome activity in the brain; radiolabeled MRZ showed 30% CNS biodistribution compared with blood levels in rats; it elicits a significant anti-tumor effect in a rodent model of malignant glioma; and pharmacological inhibition of proteasome activity has been observed in primate brains. MRZ is currently under clinical investigation in relapsed-refractory multiple myeloma and grade IV malignant glioma. CNS-multiple myeloma (MM) is a rare manifestation of extra-medullary disease with very limited therapeutic options. Its prevalence is increasing as anti-myeloma therapies become more effective at treating systemic disease, resulting in the CNS becoming a sanctuary site for the disease further highlighting the urgent unmet clinical need in this patient population. MRZ has demonstrated encouraging activity in non-CNS-MM, and has emerging clinical activity in glioma making it a potentially promising CNS-MM therapeutic intervention.To date 3 patients have been treated under compassionate use protocol with MRZ for CNS-involved MM. Two of these patients have received sufficient doses of MRZ in combination with DEX to evaluate its activity in this indication. MRZ was dosed initially at 0.5mg/m2 and then increased to 0.7mg/m2once tolerability had been established on the schedule currently in use on the glioma study (days 1, 8, and 15 of a 28 day cycle as a 10 minute infusion). Both patients, who had received prior cranio-spinal radiotherapy and intrathecal chemotherapy with no response, have tolerated MRZ well with no unexpected adverse events. The first patient had an 89% reduction in cerebrospinal fluid (CSF) plasmacytosis and 77% serum LDH reduction. After 5 months daratumumab was added to MRZ and further clinical improvement was observed (resolution of double vision and becoming fully ambulatory). Six months after MRZ initiation the patient progressed clinically and stopped treatment. Clinical symptoms disappeared in the second patient in the second month of MRZ with complete resolution of CSF plasmacytosis and CSF monoclonal spike. The patient is currently undergoing the 4th cycle of treatment with sustained resolution of saddle anesthesia and no further signs of cauda equina symptoms. Collectively, these cases provide preliminary evidence that MRZ may have utility as a therapeutic for CNS-MM and also demonstrate that combination of MRZ and daratumumab may provide benefit in this indication. Follow up is ongoing on the second patient and more mature data will be presented on this patient and any additional patients subsequently treated under compassionate use for CNS-MM. DisclosuresMacLaren:Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Parameswaran:Takeda: Consultancy.

Reconstruction Following EEA: A 0.5% CSF Leak Rate in 200 Consecutive Cases

Introduction: Reconstruction of the ventral skull base after the Expanded Endonasal Approach (EEA) remains a controversial issue. The development of the pedicled nasoseptal flap (NSF) has been a seminal event in the maturation of EEA, resulting in a marked reduction in cerebrospinal fluid (CSF) leak rates after the procedure. However, other reconstructive options exist, including the use of non-vascularized tissue such as autografts of fat or fascia lata, homografts and tissue adhesives. In addition, many centers now use a hybrid approach, reserving the use of the NSF for high risk cases, and using non-vascularized reconstructions for low risk situations or when the NSF is unavailable because of previous resections or tumor involvement. Our group has routinely used the NSF when available for all EEA cases, with resections of the nasopharynx and drainage of skull base infections and cholesterol granulomas being the most notable exceptions. In addition, we have used other vascularized reconstructions (including the lateral vault flap and, in one case, free tissue transfer) in situations where the NSF is unavailable. This paper will report on our protocol for ventral skull base reconstruction after EEA and examine our CSF leak rate over our last 200 consecutive cases.

The Levels and Duration of Sensory and Motor Blockades of Spinal Anesthesia in Obese Patients That Underwent Urological Operations in the Lithotomy Position.

Obesity has a significant effect on the cephalic spread of a spinal block (SB) due to a reduction in cerebrospinal fluid (CSF). SB is controlled by the tissue blood flow in addition to the CSF. Some positions and techniques of surgery used can cause changes in hemodynamics. We investigated effects of hemodynamic changes that may occur during Transurethral prostate resection (TUR-P) and lithotomy position (LP) at the SB level in obese versus nonobese individuals. Sixty patients who had undergone TUR-P operation under spinal anesthesia were divided into a nonobese (BMI < 25 kg/m2, Group N) or obese (BMI ≥ 30 kg/m2, Group O) group. SB assessments were recorded afterthe LP. SB at 6 and 120 min and the peak SB level were compared between two groups. Hemodynamics were recorded after LP. Peak and 6 min SB levels were similar between the groups, while 120 min SB levels were significantly higher for Group O (P < 0.05). Blood pressure (BP) after the LP was significantly higher for Group N (P < 0.05). LP and TUR-P increased the BP in Group N when compared to Group O. The increase in hemodynamics enhances the blood flow in the spinal cord and may form similar SB levels in nonobese patients to those in obese patients. However, SB time may be longer in obese patients.

Optic Neuropathy Induced by Experimentally Reduced Cerebrospinal Fluid Pressure in Monkeys

To examine the influence of experimentally reduced cerebrospinal fluid pressure (CSFP) on retinal nerve fiber layer (RNFL) thickness and neuroretinal rim area of the optic nerve head. This experimental study included nine monkeys that underwent implantation of a lumbar-peritoneal cerebrospinal fluid (CSF) shunt. In the study group (n = 4 monkeys), the shunt was opened to achieve a CSF of approximately 40 mm H2O, while the shunt remained closed in the control group (n = 5 monkeys). At baseline and in monthly intervals thereafter, optical coherence tomographic and photographic images of the optic nerve head and RNFL were taken of all monkeys. Two out of four monkeys in the study group showed bilaterally a progressive reduction in RNFL thickness between 12% and 30%, reduction in neuroretinal rim area and volume, and increase in cup-to-disc area ratios. A third monkey developed a splinter-like disc hemorrhage in one eye. The fourth monkey in the study group did not develop morphologic changes during follow-up, nor did any monkey in the control group. Experimental and chronic reduction in CSF in monkeys was associated with the development of an optic neuropathy in some monkeys.

Characterization of plasma β‐secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease

Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho-thr181 tau consistently differentiate between Alzheimer's disease (AD) and age-matched control subjects. In contrast, CSF β-site APP-cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age-matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1-specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ-secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age-matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies.

Resorbable Plate Cranioplasty After the Translabyrinthine Approach

To determine the safety of resorbable plate cranioplasty after translabyrinthine cerebellopontine angle tumor excision and to determine efficacy of this technique in the reduction of cerebrospinal fluid (CSF) leaks compared with fat grafting alone. Prospective clinical trial with matched, historic case controls. University tertiary referral center. Seventy-one patients with tumors of the cerebellopontine angle undergoing a translabyrinthine approach had the temporal bone defect repaired by a fat graft secured with a resorbable fixation plate. This cranioplasty technique was designed to improve pressure on the fat graft to block the egress of CSF. Historic controls included 149 consecutive patients undergoing a translabyrinthine approach who were closed with fat cranioplasty only. Resorbable plate cranioplasty versus fat graft cranioplasty. Wound complication rate, incidence of postoperative CSF leak, treatment required, and length of hospitalization. There were no surgical site infections in either group. The incidence of postoperative CSF leak was 12.7% (9/71) in the study group and 13.4% (20/149) in the controls (p = 0.88). There was no significant difference in the rate of lumbar drain placement or surgical revision requirement between the groups. There were no short- or long-term complications attributable to the placement of the plate, and additional operative time for the procedure averaged 7 minutes. Cranioplasty with a resorbable plate after translabyrinthine craniotomy is safe. This technique results in a CSF leak rate equivalent to fat grafting alone.

Remote Cerebellar Hemorrhage after Spinal Surgery

This report details a case of a 56-year-old woman who presented with a herniated lumbar disc at L4-5 with congenital spondylolisthesis (grade II) and developed remote cerebellar hemorrhage following an iatrogenic acute reduction in cerebrospinal fluid (CSF) pressure during spinal interbody fusion. Possible mechanisms are discussed: however, pathological events leading to this complication are unclear. Intracranial hemorrhage (ICH) must be considered in patient presenting with unexplained neurological deterioration not attributable to the spinal surgery, especially when the dura has been opened followed by significant CSF loss. (J Kor Neurotraumatol Soc 2010;6:162-164)

Contribution of memory and naïve B cells to myelin specific T cell function in relapsing remitting multiple sclerosis (99.8)

Abstract B cell depletion therapy reduces numbers of B and T cells within the cerebrospinal fluid (CSF) of relapsing remitting multiple sclerosis (RRMS) patients, suggesting that reduction of CSF B cells modulates the T cell pool in RRMS. We hypothesized that T-B cell interactions are required in order for myelin reactive T cells to proliferate and secrete cytokines optimally, and that memory B cells would be more effective APCs than naïve B cells, because of their higher expression of co-stimulatory molecules and high affinity B cell receptors. To test this hypothesis, we sorted naïve (CD19+CD27-) and memory (CD19+CD27+) B cells from the peripheral blood of 12 treatment naïve RRMS patients, incubated them with autologous purified T cells in the presence of myelin-derived proteins or control recall antigens, and measured T cell proliferation and cytokine production. Both naïve and memory B cells elicited CD4+ and CD8+ T cell proliferation and IFN-gamma secretion to recall antigens, although memory B cells from these patients elicited greater myelin specific CD4+ T cell proliferation than naïve B cells. These data suggest that in a subset of RRMS patients, the memory B cell pool has an enhanced ability to induce activation of myelin specific T cells, most likely because the memory B cell pool is enriched for B cells that have undergone myelin specific affinity driven maturation. This work was supported by Teva Neuroscience.

Reduction of cerebrospinal fluid and plasma serotonin in patients with post-stroke depression: A preliminary report

To investigate the plasma and cerebrospinal fluid (CSF) concentrations of serotonin in patients with post-stroke depression (PSD). Serotonin was measured in 30 PSD patients and 30 controls on day 15 and day 30 following stroke. There was a good correlation between the plasma and the CSF serotonin concentrations in both PSD (r = 0.641, P = 0.001) and control patients (0.852, P = 0.001) 30 days following the stroke. The average plasma and CSF serotonin concentrations in the PSD patients were lower than in the control group on day 15 (CSF: 0.24+/-0.27 vs 0.82+/-0.48 micromol/L, P < 0.01; plasma, 0.32+/-0.25 vs 0.83+/-0.45micromol/L, P < 0.01) and day 30 (CSF: 0.29+/-0.23 vs 0.78+/-0.47 micromol/L, P < 0.01; plasma, 0.31+/-0.33 vs 0.89+/-0.67 micromol/L, P < 0.01). Reduction of plasma serotonin was found in 90.0% of the PSD group and 13.3% of the control group patients (P < 0.01). Reduction in CSF serotonin in the PSD and control group was 80.0% and 6.7% respectively (P < 0.01%). Plasma serotonin levels may be used to represent the CSF serotonin levels in depressed and non-depressed patients following stroke. There is a reduction in the plasma or CSF serotonin concentrations in patients with PSD. Serotonin deficiency may be one of the factors leading to depression following stroke.

B and T cell imbalances in CSF of patients with Hu-antibody associated PNS

In paraneoplastic neurological syndromes associated with Hu-antibodies (Hu-PNS) an important role for cellular immunity is hypothesized. We characterized the cerebrospinal fluid (CSF) pleocytosis in Hu-PNS patients by assessing the major lymphocyte subsets by flow cytometry. The B cell subset in the CSF of Hu-PNS patients showed a significant absolute (~ 20×) and relative (~ 3×) expansion, while the numbers of CD4+ T cells, CD8+ T cells and NK cells only showed an absolute expansion (~ 4–7×) compared to the controls. On the other hand, the NKT cell subset showed a significant relative reduction in CSF and in blood of Hu-PNS patients. The relative B cell expansion is consistent with the intrathecal synthesis of Hu-antibodies, while the increased number of T and NK cells supports an additional role for cellular immunity in the pathogenesis of Hu-PNS. In addition, the autoimmune hypothesis of Hu-PNS is supported by the relative NKT cell deficiency.

Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients

Effects of B cell depletion by rituximab, a monoclonal antibody to CD20, were studied in patients with relapsing MS that had not responded optimally to standard immunomodulatory therapies. Flow cytometry demonstrated reduced cerebrospinal fluid (CSF) B cells and T cells in most patients at 6 months post-treatment. ELISAs demonstrated modest reductions in serum antibodies to myelin oligodendrocyte glycoprotein and myelin basic protein in some subjects. Beta-interferon neutralizing antibodies were reduced in three subjects, but developed anew after treatment in three others, suggesting caution in considering rituximab as a means to eliminate NABs. In summary, rituximab depleted B cells from CSF at 24 weeks after initial treatment, and this B cell depletion was associated with a reduction in CSF T cells as well.