Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate.

BACKGROUND: Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-ß (Aß42) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aß42, increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively. OBJECTIVE: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals. METHODS: CSF concentrations of Aß42, P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years). RESULTS: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aß38, and Aß40), and ventricular CSF volume, but apart from this finding, no significant correlations were observed. CONCLUSION: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection.

BACKGROUND: It has been suggested that cerebrospinal fluid (CSF) CXCL13 is a diagnostic marker of Lyme neuroborreliosis (LNB), as its levels have been shown to be significantly higher in LNB than in several other CNS infections. Levels have also been shown to decline after treatment with intravenous ceftriaxone, but levels after treatment with oral doxycycline have previously not been studied. Like Borrelia burgdorferi, HIV also has neurotropic properties. Elevated serum CXCL13 concentrations have been reported in HIV patients, but data on CSF levels are limited. METHODS: We longitudinally analysed CSF CXCL13 concentrations in 25 LNB patients before and after oral doxycycline treatment. Furthermore, we analysed CSF CXCL13 concentrations in 16 untreated LNB patients, 27 asymptomatic untreated HIV-1 infected patients and 39 controls with no signs of infectious or inflammatory disease. RESULTS: In the longitudinal LNB study, initially high CSF CXCL13 levels declined significantly after doxycycline treatment, which correlated to a decreased CSF mononuclear cell count. In the cross-sectional study, all the LNB patients had CSF CXCL13 levels elevated above the lowest standard point of the assay (7.8 pg/mL), with a median concentration of 500 pg/mL (range 34-11,678). Of the HIV patients, 52% had elevated CSF CXCL13 levels (median 10 pg/mL, range 0-498). There was a clear overlap in CSF CXCL13 concentrations between LNB patients and asymptomatic HIV patients. All but one of the 39 controls had CSF CXCL13 levels below 7.8 pg/mL. CONCLUSIONS: We confirm previous reports of highly elevated CSF CXCL13 levels in LNB patients and that these levels decline after oral doxycycline treatment. The same pattern is seen for CSF mononuclear cells. CSF CXCL13 levels are elevated in neurologically asymptomatic HIV patients and the levels overlap those of LNB patients. The diagnostic value of CSF CXCL13 in LNB remains to be established.

Shunt surgery in patients with hydrocephalus and white matter changes.

OBJECT: Patients with idiopathic normal pressure hydrocephalus (iNPH) often present with impaired gait and cognition together with ventricular enlargement and normal intracranial pressure. Many have vascular risk factors as well as periventricular and deep white matter changes on MR imaging. Abnormal CSF dynamics, that is, high resistance to outflow or improvement after CSF drainage, indicate good effects of shunt surgery. The authors examined whether the worst-case iNPH patients with extensive vascular white matter disease and normal CSF dynamics would benefit from shunt surgery. These patients also fulfilled the criteria for Binswanger disease. Therefore, a randomized controlled double-blind study was performed. METHODS: Fourteen consecutive patients fulfilling the above criteria were randomized to receive either open or closed shunts. At 3 months after surgery, the patients with initially ligated shunts had their shunts opened. Clinical evaluation consisting of 7 quantitative psychometric and 6 continuous gait tests was performed preoperatively and 3 and 6 months after surgery. RESULTS: Patients randomized to receive open shunts had improved motor (30% increase) and psychometric (23% increase) scores 3 months after shunt placement. There were no significant changes between the 3- and 6-month follow-up in these same patients. Conversely, those with initially ligated shunts were unchanged during the first 3-month period, although they improved in both motor (28%) and cognitive (18%) functions following removal of the ligature. CONCLUSIONS: Patients with enlarged ventricles, hydrocephalic symptoms, and extensive vascular white matter changes benefit from shunt surgery.

Absolute quantification of cerebral blood flow in neurologically normal volunteers: dynamic-susceptibility contrast MRI-perfusion compared with computed tomography (CT)-perfusion.

To improve the reproducibility of arterial input function (AIF) registration and absolute cerebral blood flow (CBF) quantification in dynamic-susceptibility MRI-perfusion (MRP) at 1.5T, we rescaled the AIF by use of a venous output function (VOF). We compared CBF estimates of 20 healthy, elderly volunteers, obtained by computed tomography (CT)-perfusion (CTP) and MRP on two consecutive days. MRP, calculated without the AIF correction, did not result in any significant correlation with CTP. The rescaled MRP showed fair to moderate correlation with CTP for the central gray matter (GM) and the whole brain. Our results indicate that the method used for correction of partial volume effects (PVEs) improves MRP experiments by reducing AIF-introduced variance at 1.5T.

Neuropsychological effects of shunt treatment in idiopathic normal pressure hydrocephalus.

OBJECTIVE: To prospectively evaluate the effects of shunting on the neuropsychological performance of patients with idiopathic normal pressure hydrocephalus (INPH), to compare their performance with that of healthy individuals, and to estimate the predictive utility of putatively important factors. METHODS: A consecutive series of 47 patients with INPH underwent neurological, radiological, and neuropsychological examinations before and 3 months after shunt surgery. The same neuropsychological tests, measuring simple and target reaction times, dexterity, memory and learning, working memory, and aspects of executive functioning, were also administered to 159 healthy individuals. RESULTS: Performance on all neuropsychological tests, except Simple Reaction Time and Digit Span, significantly improved after surgery, with more severe functional deficits showing greatest improvement. Age, education, duration, vascular comorbidity, sex, and onset symptom all failed to predict the neuropsychological effects of treatment. Despite improvement 3 months after shunt surgery, INPH patients were still outperformed by healthy individuals. CONCLUSION: Most of the wide range of neuropsychological functions that are affected by INPH are markedly improved by shunt treatment, but not completely restored.

The neuropsychology of patients with clinically diagnosed idiopathic normal pressure hydrocephalus.

OBJECTIVE: To compare the neuropsychological performance of patients with idiopathic normal pressure hydrocephalus (INPH) with that of healthy individuals and to examine its relation to neurological signs, vascular comorbidity, and background factors. METHODS: A consecutive series of 58 patients with INPH underwent neurological, neuroradiological, and neuropsychological examinations. The neuropsychological tests, measuring vigilance, fine movements of the hands, learning, working memory, and aspects of executive functioning, were also administered to 108 healthy individuals. RESULTS: Patients performed worse than healthy individuals on all included tests. Significant correlations between test results were more frequent and stronger among patients and the degree of neuropsychological impairment was related to the severity of other signs of INPH. Patients with vascular risk factors performed worse than those without. CONCLUSION: The neuropsychological deficits in INPH are widely distributed, interrelated, associated with neurological signs, and aggravated by vascular comorbidity.

Spinal CSF absorption in healthy individuals.

The present study examines the extent of spinal cerebrospinal fluid (CSF) absorption in healthy individuals in relation to physical activity, CSF production, intracranial pressure (ICP), and spinal CSF movement. Thirty-four healthy individuals aged 21-35 yr were examined by lumbar puncture and radionuclide cisternography with repeated imaging. ICP was registered before and after CSF drainage, and CSF production was calculated. Spinal CSF absorption was calculated as reduction in spinal radionuclide activity. The radionuclide activity in the spinal subarachnoidal space was gradually decreased by 20 +/- 13% (mean +/- SD) during 1 h. The reduction was higher in active than in resting individuals (27 +/- 12% vs. 13 +/- 9%). The mean ICP in 19 of the individuals was 13.6 +/- 3.1 cm H(2)O. B-waves were found in 79% of the individuals, with a mean frequency of 0.6 +/- 0.3 min(-1). The mean CSF production rate was 0.34 +/- 0.13 ml/min. There were no correlations between radionuclide reduction, spinal movement of the radionuclide, and CSF production rate. The spinal radionuclide reduction found in this study indicates a spinal CSF absorption of 0.11-0.23 ml/min, more pronounced in active than in resting individuals.

Elastance correlates with outcome after endoscopic third ventriculostomy in adults with hydrocephalus caused by primary aqueductal stenosis.

OBJECTIVE: To study prospectively the correlation between clinical outcome after endoscopic third ventriculostomy (ETV) and resistance to the outflow of cerebrospinal fluid (R(out)) and elastance in adults with hydrocephalus caused by primary aqueductal stenosis (AS). METHODS: R(out) and elastance were measured in the subarachnoid space and intraventricularly before ETV in 15 consecutive patients. Three months after the ETV, the clinical effect was evaluated by standardized indices, and R(out) and elastance were measured. If symptoms persisted and the ETV was patent, shunt surgery was offered. The effect of the shunt operation and R(out) were measured after 3 months. RESULTS: Four patients experienced excellent improvement, six improved slightly, and five had unchanged or deteriorated symptoms after ETV. R(out) before ETV did not correlate with outcome. R(out) decreased after ETV with correlation to the clinical effect; in the six patients who had shunt surgery, R(out) decreased further. High preoperative elastance correlated strongly with a good outcome and reduction of ventricle size. Elastance did not change after ETV. CONCLUSION: R(out) intraventricularly and in the subarachnoid space could not predict the outcome of the ETV, but the reduction in R(out) correlated positively with clinical improvement. Preoperative elastance correlated positively with clinical improvement, and elastance was unchanged after ETV. Clinical improvement correlated positively with reduction in ventricle size.