High CSF Research Articles

TH-C-L100J-03: Optimized Voxel Based Morphometry Investigation and Region of Interest Study in Alzheimer's Disease

Purpose: Optimized Voxel based morphometry (VBM) has been increasingly applied to investigate differences in brain morphology between a group of patients and control subjects. VBM permits comparison of gray matter (GM) volume at voxel‐level from the entire brain, thus is an efficient method for assessing regional differences. The purpose of this study was to assess the regional GM volume loss measured by VBM in Alzheimer's disease (AD) compared to controls, and to measure hippocampal volume using manually delineated volumetry and compare the results to VBM findings. Method and Materials: Twenty‐three AD (mean age 70 ± 8y; m/f= 7/16, Mini‐Mental State Exam [MMSE]= 22.2) and 20 cognitively normal elderly control subjects (mean age 69 ± 4y; m/f= 10/10) were included in this study. The 20 sets of images were first normalized and create the probability maps for segmentation. Normalized hippocampal volume to the intracranial volume was compared between AD and control groups. Results: The AD group had a lower GM %, and a higher CSF% compared to controls. The total intracranial volumes analyzed using SPM and our own ROITOOL program were very close (p<0.0001). The hippocampal volume of AD patients was significantly lower than that of controls (P<0.001). The region includes parahippocampal gyrus, cingulate, insula, frontal lobe and middle temporal complex. Despite the high significance in manual ROI analysis, hippocampus was not revealed in the VBM. Conclusions: We found that the hippocampal volume in AD was significantly smaller than in controls using ROI‐based volumetry. However, although our VBM results demonstrated that AD patients had a significant atrophy in middle temporal lobe, parahippocampus and insula, the hippocampus was not revealed. While VBM can be applied to assess global atrophy efficiently, manual volumetry is needed to study irregularly‐shaped subcortical structures.

High Pneumococcal DNA Loads Are Associated With Mortality in Malawian Children With Invasive Pneumococcal Disease

In bacteremia owing to Streptococcus pneumoniae, high bacterial counts at presentation have been shown to be predictive of the development of serious invasive disease. Using real-time PCR, we aimed to determine pneumococcal DNA loads in blood and CSF, and their relationship to cytokine concentrations, clinical presentation and outcome. Children with confirmed meningitis (n = 82) or pneumonia (n = 13) were prospectively recruited, and blood and CSF samples taken for pneumococcal bacterial DNA loads and cytokine determination. At the time of admission, the median bacterial load in blood was 1.6 x 10 DNA copies/mL (range 0.00-1.54 x 10) and in CSF it was 5.77 x 10 DNA copies/mL (range 4.42 x 10 to 6.15 x 10). Median blood and CSF bacterial loads (log DNA copies/mL) were significantly higher in nonsurvivors than in survivors; blood (3.80 vs. 2.97, P = 0.003), CSF (8.17 vs. 7.50, P = 0.03). In HIV-infected children (n = 59), blood and CSF loads and plasma tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6 and IL-10 were all significantly higher in nonsurvivors than in survivors, but in HIV-uninfected children (n = 36) this difference was not significant. Blood bacterial loads and plasma cytokine concentrations were significantly associated, and were all significantly higher in children with meningitis than in those with pneumonia. In children with meningitis, median CSF cytokine concentrations were significantly higher than median plasma cytokine concentrations (P < 0.001) and CSF bacterial loads were significantly associated with CSF IL-1beta (P = 0.002) and IL-10 (P = 0.001) concentrations. Pneumococcal DNA loads are associated with plasma cytokine concentrations, and are higher in meningitis than in pneumonia. High blood and CSF pneumococcal DNA loads are associated with a fatal outcome.

High CSF neurofilament heavy chain levels in neuromyelitis optica

The neurofilament heavy chain (NfHSMI35), a biomarker of axonal damage in the CSF, was measured in patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). Significantly high CSF NfHSMI35 levels (>0.73 ng/mL) were found in 6 of 24 (25%) of the patients with NMO but none of the patients with MS (0/24). This finding suggests that axonal damage is more severe in NMO than in MS.

CSF Neurofilaments in Frontotemporal Dementia Compared with Early Onset Alzheimer’s Disease and Controls

Background: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer’s disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-β(1–42), tau and tau phosphorylated at threonine-181. Methods: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. Results: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. Conclusion: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.

High CSF Tau-Protein Concentration in Delirium Induced by High dose Psychiatric Medication

High CSF Tau-Protein Concentration in Delirium Induced by High dose Psychiatric Medication

High CSF Tau-protein concentration in delirium induced by high dose psychiatric medication

High CSF Tau-protein concentration in delirium induced by high dose psychiatric medication

CSF neurofilament levels: A potential prognostic marker in Guillain–Barré syndrome

Long-term morbidity from Guillain-Barré syndrome (GBS) is caused by axonal damage. This prospective study demonstrated that neurofilaments (NfHs), a biomarker for axonal damage, were of prognostic value in GBS. CSF NfH levels correlated with the F score and Medical Research Council summed score and were higher in patients with neurophysiologic evidence of axonal degeneration compared to those without. Pathologically high CSF NfH levels (>0.73 ng/mL) predicted worse motor and functional outcome.

IC-P-054: Relationship between in vivo amyloid imaging with 11C-PIB and CSF Aβ42

Abundant evidence supports a central role for amyloid–β (Aβ) and its conversion from soluble to insoluble forms (e.g., fibrils or oligomers) in the pathogenesis of Alzheimer's disease (AD). Potential disease–modifying therapies targeting Aβ and its metabolism are currently being developed and will ultimately provide the definitive test of this hypothesis. In order for therapies to have the greatest clinical impact, it will be necessary to identify individuals with AD pathology prior to marked cognitive symptoms and neuronal cell loss (i.e., ‘preclinical’ or very early stage DAT). We recently investigated the relationship between the in vivo amyloid load (via PET imaging of the amyloid–binding compound, 11C–PIB) and various CSF measures in a small (n=24) research cohort (age 48–83 years) that included both cognitively normal individuals and those diagnosed with very mild or mild DAT (Fagan et al., 2006, Ann. Neurol.). We observed a striking inverse relation between mean cortical amyloid load and CSF Aβ42 (but not other CSF markers); those with positive PIB–binding had low CSF Aβ42 levels and those with negative PIB–binding had high CSF Aβ42 levels, with no overlap between the two groups. Importantly, this pattern was observed in a subset of subjects who were cognitively normal, suggesting the presence of amyloid pathology in the absence of cognitive symptoms (“preclinical AD”). These findings suggest that brain amyloid deposition results in low CSF Aβ42, and that amyloid imaging and CSF Aβ42 may potentially be useful as antecedent biomarkers of (preclinical) AD. We have since expanded our cohort size and will provide an update of our findings, including the consistency of this pattern in this larger sample, the degree to which it is maintained in individuals exhibiting a relatively low level of brain amyloid, and whether analyses of regional PIB binding offer additional discriminatory power. These additional analyses will provide important information regarding the potential utility of these measures as diagnostic and/or antecedent biomarkers of AD and may also offer insights into possible mechanism(s) of amyloid deposition in the AD brain.

Removing the Effects of CSF Partial Voluming on Fitted CBF and Arterial Transit Times Using FAIR, a Pulsed Arterial Spin Labelling Technique

FAIR, an arterial spin labelling technique, provides non-invasive, quantitative CBF values and arterial transit times deltat. This paper focuses on the negative impact of CSF partial voluming on FAIR results. To understand and solve this problem, we performed a theoretical analysis and a range of simulations. We then acquired FAIR data from a volunteer to illustrate our findings. We found that the determinant effect of CSF is a delayed zero-crossing during inversion recovery. The subtraction of magnitude inversion recovery data in FAIR generates erroneous negative data and distorted fit results: we simulated that for CSF percentages of 0-40%, CBF and deltat will be progressively overestimated by up to 50%. For higher CSF percentages the errors were found to increase steeply. We explored a straightforward solution: taking the magnitude of the FAIR data before fitting. This provided a remarkably strong antidote against the effects of CSF partial voluming: for CSF percentages of 0-40%, simulations now gave CBF values accurate within 1%, and deltat within 5%. The fit remained robust for high CSF fractions. Our analysis and simulations demonstrate that using magnitude FAIR data minimises the detrimental effects of CSF partial voluming. Data from a healthy volunteer illustrate these results.

SU‐FF‐I‐100: Investigate Between the Voxel Based Morphometry and Region of Interest Study in Alzheimer's Disease

Purpose: Voxel based morphometry (VBM) has been increasingly applied to investigate differences in brain morphology between a group of patients and control subjects. VBM permits comparison of gray matter (GM) volume at voxel‐level from the entire brain, thus is an efficient method for assessing regional differences. The purpose of this study was to assess the regional GM volume loss measured by VBM in Alzheimer's disease (AD) compared to controls, and to measure hippocampal volume using manually delineated volumetry and compare the results to VBM findings. Method and Materials: Twenty‐three AD (mean age 70 ± 8y; m/f= 7/16, Mini‐Mental State Exam [MMSE]= 22.2) and 20 cognitively normal elderly control subjects (mean age 69 ± 4y; m/f= 10/10) were included in this study. The 20 sets of images were first normalized and create the probability maps for segmentation. Normalized hippocampal volume to the intracranial volume was compared between AD and control groups. Results: The AD group had a lower GM %, and a higher CSF% compared to controls. The total intracranial volumes analyzed using SPM and our own ROITOOL program were very close (p&lt;0.0001). The hippocampal volume of AD patients was significantly lower than that of controls (P&lt;0.001). The region includes parahippocampal gyrus, cingulate, insula, frontal lobe and middle temporal complex. Despite the high significance in manual ROI analysis, hippocampus was not revealed in the VBM. Conclusions: We found that the hippocampal volume in AD was significantly smaller than in controls using ROI‐based volumetry. However, although our VBM results demonstrated that AD patients had a significant atrophy in middle temporal lobe, parahippocampus and insula, the hippocampus was not revealed. While VBM can be applied to assess global atrophy efficiently, manual volumetry is needed to study irregularly‐shaped subcortical structures.

Cerebrospinal fluid free sialic acid and aspartate transaminase levels in meningitis.

Sialic acid (SA) is a nine carbon sugar derived from mannosamine and pyruvate. High levels of sialic acid and aspartate transaminase (AST) levels in cerebrospinal fluid have been described in pyogenic meningitis (PM) compared to tubercular meningitis (TBM). To evaluate the levels of CSF free SA in PM and TBM and to assess the correlation between CSF free SA and CSF glucose or total protein levels. A total of 122 subjects were studied and divided into children and adults. Further, these have been subdivided into controls, PM and TBM. CSF free SA was estimated by thiobarbituric acid assay of Warren and AST by Reitmann and Frankel method. CSF free SA and AST levels in children and adults were significantly high in PM (p<0.001) as compared to TBM and controls. A very high CSF free SA and AST were found to be characteristic of PM, making them useful parameters to differentiate PM from TBM.

Cytomegalovirus Ventriculoencephalitis in a Peripheral Blood Stem Cell Transplant Recipient

Cytomegalovirus encephalitis occurs rarely in transplant recipients. We describe a patient with cytomegalovirus ventriculoencephalitis who had a very high CSF viral load but a low peripheral blood viral load. No resistance mutations were present in cerebrospinal fluid viral DNA, whereas DNA from blood showed a resistance mutation in the UL54 gene but not in the UL97 gene. Viral replication was intense in the brain ependyma and periventricular areas without evidence of peripheral cytomegalovirus disease. The data provide evidence for compartmentalization of cytomegalovirus infection. Levels of ganciclovir and foscarnet in the cerebrospinal fluid may be inadequate for treatment, even for some drug-susceptible strains, and, together with periventricular replication, may explain the disparity between cerebrospinal fluid viral load and peripheral blood viral load.

A Case of Chronic Inflammatory Demyelinating Polyneuropathy in a Girl with Type 1 DM

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disorder characterized by the symmetrical weakness in both proximal and distal muscles for at least 2 months, hyporeflexia or areflexia, nerve conduction abnormalities, and high CSF protein level. Diabetes mellitus, monoclonal gammopathy, hepatitis C infection, HIV infection, SLE, Sjogren syndrome and lymphoma have been associated with CIDP. The incidence of CIDP in diabetes is not known exactly, but occur more common among diabetic than nondiabetic patients. There is sometimes a difficulty in distinguishing between diabetic polyneuropathy and CIDP, but differential diagnosis is important because CIDP is treatable with immune-modulating therapy. We report a case of CIDP in 22-year-old girl with type 1 DM who presented with generalized motor weakness and walking disturbance which were treated with iv immunoglobulin

Pharmacokinetic Considerations in the Treatment of CNS Tumours

Despite aggressive therapy, the majority of primary and metastatic brain tumour patients have a poor prognosis with brief survival periods. This is because of the different pharmacokinetic parameters of systemically administered chemotherapeutic agents between the brain and the rest of the body. Specifically, before systemically administered drugs can distribute into the CNS, they must cross two membrane barriers, the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB). To some extent, these structures function to exclude xenobiotics, such as anticancer drugs, from the brain. An understanding of these unique barriers is essential to predict when and how systemically administered drugs will be transported to the brain. Specifically, factors such as physiological variables (e.g. blood flow), physicochemical properties of the drug (e.g. molecular weight), as well as influx and efflux transporter expression at the BBB and BCB (e.g. adenosine triphosphate-binding cassette transporters) determine what compounds reach the CNS. A large body of preclinical and clinical research exists regarding brain penetration of anticancer agents. In most cases, a surrogate endpoint (i.e. CSF to plasma area under the concentration-time curve [AUC] ratio) is used to describe how effectively agents can be transported into the CNS. Some agents, such as the topoisomerase I inhibitor, topotecan, have high CSF to plasma AUC ratios, making them valid therapeutic options for primary and metastatic brain tumours. In contrast, other agents like the oral tyrosine kinase inhibitor, imatinib, have a low CSF to plasma AUC ratio. Knowledge of these data can have important clinical implications. For example, it is now known that chronic myelogenous leukaemia patients treated with imatinib might need additional CNS prophylaxis. Since most anticancer agents have limited brain penetration, new pharmacological approaches are needed to enhance delivery into the brain. BBB disruption, regional administration of chemotherapy and transporter modulation are all currently being evaluated in an effort to improve therapeutic outcomes. Additionally, since many chemotherapeutic agents are metabolised by the cytochrome P450 3A enzyme system, minimising drug interactions by avoiding concomitant drug therapies that are also metabolised through this system may potentially enhance outcomes. Specifically, the use of non-enzyme-inducing antiepileptic drugs and curtailing nonessential corticosteroid use may have an impact.

Prehospital diagnostic and therapeutic management of otogenic Streptococcus pneumoniae meningitis

Prehospital diagnostics and therapeutic management, as well as clinical and laboratory data from 57 consecutive cases with otogenic pneumococcal meningitis (OPM) in Denmark during a 2-y period (1999-2000) were studied by review of discharge and medical records including a questionnaire sent to the general practitioners responsible for the individual patient. 12 cases were <2 y of age, whereas the remaining 45 cases were >21 y of age. Fever (in 98%) and altered consciousness (in 98%), respectively, were significantly more frequent prehospital symptoms (median duration of symptoms: 2 d (1-4)) than earache (in 71%, p < 0.0001), tympanic perforation (in 38%, p < 0.0001), and back rigidity (in 25%, p < 0.0001) in OPM. Some 82% visited a physician before admission, and an otogenic focus was diagnosed in 57%, a myringotomy was performed in 12%, and antibiotic therapy was initiated in 29% of these cases. Prehospital antibiotic therapy was more likely to be initiated in patients where the physician found an otogenic focus compared to patients where an otogenic was not found (46% vs 6%, respectively, p = 0.01). However, <10% of cases with OPM were treated for otitis media with adequate dosing of antibiotics for more than 1 d based on pharmacodynamic estimates. The clinical course was more severe in adults than in children (e.g. need for assisted ventilation (61% vs 0%, respectively, p < 0.01), development of sequelae (75% vs 8%, respectively, p < 0.01) together with higher CSF WBC and CSF protein levels (3738 vs 1361 cells/microl and 3.8 vs 1.6 g/l, respectively, p < 0.01), whereas corticosteroids were more frequently given to children than to adults (55% vs 3%, p < 0.001). Prehospital antibiotic therapy was not significantly associated with a more favourable outcome of OPM (50% vs 60%, respectively, p = 0.73). In conclusion, our results suggest that an otogenic focus is as frequent in adults as in children with pneumococcal meningitis and that an otogenic examination should be performed on patients presenting with fever and altered consciousness. Moreover, OPM seems predominantly to occur in patients receiving no or inadequate antibiotic therapy for otitis media.

Atypical transverse myelitis due to cytomegalovirus in an immunocompetent patient

Cytomegalovirus (CMV)-associated transverse myelitis is rare in immunocompetent patients. We report a 73-year-old man with no evidence of immune compromise, who developed acute transverse myelitis. Cerebrospinal fluid pleocytosis indicated central nervous system inflammation, and spinal MRI showed weak signal hypointensity in T1, hyperintensity in T2 and DP between C7 and T2, but no contrast enhancement. High CSF anti- CMV IgG index with normal CSF IgG index indicated intact blood-brain barrier, and supported the diagnosis of CMV-induced myelitis in an immunocompetent patient.

Vivid dreams, hallucinations, psychosis and REM sleep in Guillain–Barré syndrome

We conducted a prospective controlled study of the clinical and biological determinants of the mental status abnormalities in 139 patients with Guillain-Barré syndrome (GBS) and 55 patients without GBS placed in the intensive care unit (ICU controls). There were mental status changes in 31% of GBS patients and in 16% of controls (odds ratio = 2.3; P = 0.04). In GBS patients, they included vivid dreams (19%), illusions (30%, including an illusory body tilt), hallucinations (60%, mainly visual) and delusions (70%, mostly paranoid). They appeared a median 9 days after disease onset (range 1-40 days, during the progression or the plateau of the disease), and lasted a median 8 days. Seven (16%) patients experienced the symptoms before their admission to the ICU. Hallucinations were frequently hypnagogic, occurring as soon as the patients closed their eyes. Autonomic dysfunction, assisted ventilation and high CSF protein levels were significant risk factors for abnormal mental status in GBS patients. CSF hypocretin-1 (a hypothalamic neuropeptide deficient in narcolepsy) levels, measured in 20 patients, were lower in GBS patients with hallucinations (555 +/- 132 pg/ml) than in those without (664 +/- 71 pg/ml, P = 0.03). Since the mental status abnormalities had dream-like aspects, we examined their association with rapid eye movement sleep (REM sleep) using continuous sleep monitoring in 13 GBS patients with (n = 7) and without (n = 6) hallucinations and 6 tetraplegic ICU controls without hallucinations. Although sleep was short and fragmented in all groups, REM sleep latency was shorter in GBS patients with hallucinations (56 +/- 115 min) than in GBS patients without hallucinations (153 +/- 130 min) and in controls (207 +/- 179 min, P < 0.05). In addition, sleep structure was highly abnormal in hallucinators, with sleep onset in REM sleep periods (83%), abnormal eye movements during non-REM sleep (57%), high percentages of REM sleep without atonia (92 +/- 22%), REM sleep behaviour disorders and autonomic dysfunction (100%), reminiscent of a status dissociatus. The sleep abnormalities, that were almost absent in non-hallucinated GBS patients, were not exclusively related to ICU conditions, since they also appeared out of ICU, and were reversible, disappearing when the mental status abnormalities vanished while the patients were still in ICU. In conclusion, the mental status abnormalities experienced by GBS patients are different from the ICU delirium, are strongly associated with autonomic dysfunction, severe forms of the disease and possibly with a transitory hypocretin-1 transmission decrease. Sleep studies suggest that mental status abnormalities are wakeful dreams caused by a sleep and dream-associated disorder (status dissociatus).

Cerebrospinal fluid HIV viral load in different phases of HIV–associated brain disease

We compared CSF HIV viral load in 33 asymptomatic HIV seropositive patients, 11 patients with incipient minor motor deficits (MMD), 11 patients with sustained MMD, and 16 patients with HIV-associated dementia. Patients with incipient MMD showed significantly higher CSF viral load than asymptomatic patients. Demented patients also had higher CSF viral loads than asymptomatic patients. This phenomenon is independent of antiretroviral therapy. Thus, correlation of viral load with time suggests a multiphasic course of HIV-associated CNS disease.

Temporarily controlled HIV-1 replication after intravenous immunoglobulin treatment of Guillain-Barré syndrome

HIV establishes a latent infection in resting CD4(+) T-lymphocytes. A possible strategy to eliminate cellular reservoirs in long-lived, HIV-1-infected quiescent CD4(+) T-lymphocytes might be to add T-cell-activating agents to potent antiretroviral therapy. In this report we describe a patient with Guillain-Barré syndrome treated with high dose intravenous immunoglobulin (IVIG) in addition to antiretroviral therapy. A transiently increased viral load and immunoactivation during the IVIG treatment suggest activation of latently infected cells and increased turnover rate of the latent viral reservoir. HIV replication was controlled with plasma viral load <20 copies/ml, for at least 3 months after antiretroviral treatment interruption. CSF neural markers reflecting degenerative processes in the brain during the symptomatic period and follow-up were also analysed. Very high CSF sulfatide concentrations were found indicating that the pathology involves severe demyelination.We hypothesize that IVIG in this case contributed to an activation of latently infected cells, which led to a transient increase in plasma HIV-1 RNA during the IVIG treatment and a long period of undetectable viral load after antiretroviral treatment interruption. Further, this is the first time, to our knowledge, that detailed CSF findings are described in HIV-1 associated GBS.

CSF soluble Fas correlates with the severity of HIV-associated dementia.

Soluble Fas (sFas) and soluble Fas ligand (sFasL) are associated with cellular dysfunction and death and are elevated in CSF from patients with HIV dementia (HIV-D). The authors investigated whether these markers correlated with dementia severity and course. sFas and sFasL were measured in 15 highly active antiretroviral therapy (HAART)-naïve HIV-D subjects, 30 HAART-naïve HIV+ controls, and 17 HIV-controls. HIV-D subjects had higher CSF sFas levels than controls. Subjects with moderate/severe dementia had higher CSF sFas levels than those with mild dementia. CSF sFas trended lower in those with progressive dementia.