Dataset Information

Cerebrospinal fluid and blood flow in mild cognitive impairment and Alzheimer's disease: a differential diagnosis from idiopathic normal pressure hydrocephalus.

ABSTRACT:

Background

Phase-contrast magnetic resonance imaging (PC-MRI) enables quantification of cerebrospinal fluid (CSF) flow and total cerebral blood (tCBF) flow and may be of value for the etiological diagnosis of neurodegenerative diseases. This investigation aimed to study CSF flow and intracerebral vascular flow in patients with Alzheimer's disease (AD) and patients with amnesic mild cognitive impairment (a-MCI) and to compare the results with patients with idiopathic normal pressure hydrocephalus (NPH) and with healthy elderly volunteers (HEV).

Methods

Ten a-MCI and 9 mild AD patients were identified in a comprehensive neurological and neuropsychological assessment. They underwent brain MRI; PC-MRI pulse sequence was performed with the following parameters: two views per segment; flip angle: 25° for vascular flow and 20° for CSF flow; field-of-view (FOV): 14 × 14 mm²; matrix: 256 × 128; slice thickness: 5 mm; with one excitation for exams on the 3 T machine, and 2 excitations for the 1.5 T machine exams. Velocity (encoding) sensitization was set to 80 cm/s for the vessels at the cervical level, 10 or 20 cm/s for the aqueduct and 5 cm/s for the cervical subarachnoid space (SAS). Dynamic flow images were analyzed with in-house processing software. The patients' results were compared with those obtained for HEVs (n = 12), and for NPH patients (n = 13), using multivariate analysis.

Results

Arterial tCBF and the calculated pulsatility index were significantly greater in a-MCI patients than in HEVs. In contrast, vascular parameters were lower in NPH patients. Cervical CSF flow analysis yielded similar values for all four populations. Aqueductal CSF stroke volumes (in μl per cardiac cycle) were similar in HEVs (34 ± 17) and AD patients (39 ± 18). In contrast, the aqueductal CSF was hyperdynamic in a-MCI patients (73 ± 33) and even more so in NPH patients (167 ± 89).

Conclusion

Our preliminary data show that a-MCI patients present with high systolic arterial peak flows, which are associated with higher mean total cerebral arterial flows. Aqueductal CSF oscillations are within normal range in AD and higher than normal in NPH. This study provides an original dynamic vision of cerebral neurodegenerative diseases, consistent with the vascular theory for AD, and supporting primary flow disturbances different from those observed in NPH.

SUBMITTER: El Sankari S

PROVIDER: S-EPMC3045982 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.ObjectiveTo investigate the role of soluble APP (sAPP) and amyloid beta (A?) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy A? and hyperphosphorylated tau (HP?) findings.MethodsThe study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against A? and HP?. CSF levels of AD-related biomarkers (A?42, p-tau, total tau), non-AD-related A? isoforms (A?38, A?40), sAPP isoforms (sAPP?, sAPP?), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE.ResultsLumbar CSF levels of sAPP? were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPP? showed a similar trend (p?=?0.06). CSF sAPP isoform levels showed no association to A? or HP? in the brain biopsy. Quantified A? load in the brain biopsy showed a negative correlation with CSF levels of A?42 in ventricular (r?=?-0.295, p?=?0.003) and lumbar (r?=?-0.356, p?=?0.01) samples, while the levels of A?38 and A?40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure.ConclusionsThe role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.

Project description:BackgroundLongitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.ObjectiveTo examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.MethodsL-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.ResultsAll biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.ConclusionLongitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Project description:The cerebrospinal fluid (CSF) tap test (TT) has been regarded as an important test for the prediction of shunt effectiveness in patients with suspected idiopathic normal pressure hydrocephalus (iNPH). Although its specificity and sensitivity are reportedly high, there remains some disagreement over this point. Herein, the TT as a test for predicting shunt effectiveness was investigated in our multicenter prospective study named SINPHONI and strategies to increase its predictability were examined.One hundred suspected iNPH patients with the following entry criteria were enrolled in the study: (1) 60 to 85 years old, (2) one or more of the NPH triad signs, (3) ventriculomegaly (Evans index > 0.3), (4) high convexity tightness in coronal-section MRI, and (5) no antecedent disorders. Changes in NPH triad symptoms were assessed using the iNPH grading scale and other measures before and after removal of 30 ml lumbar CSF. A positive response to TT was pre-defined by specific improvements on the grading and other scales. A ventriculoperitoneal shunt was performed with a programmable valve. The sensitivity and specificity of the TT was calculated with a contingency table. A decision tree analysis was performed to increase the predictability of the TT.Among 100 patients, 80 were shunt responders. A statistically-significant variable between shunt responders and non-responders was CSF pressure. The changes in single variables in the iNPH grading scale after TT showed high specificity with low sensitivity. In contrast, change of the total score in the iNPH grading scale showed a relatively high sensitivity of 71.3% with specificity of 65%. A decision tree analysis revealed that using the iNPH grading scale total score and pre-shunt CSF pressure ? 15 cmH20, sensitivity increased to 82.5%, without a decrease in specificity.The sensitivity and specificity of the TT for predicting shunt responsiveness were optimum when improvement on any iNPH grading scale was combined with CSF pressure ? 15 cmH20. To increase the sensitivity of the TT, further effort is necessary.This study is registered with ClinicalTrials.gov, with the number NCT00221091.

Project description:Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0-4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans' index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten's medial temporal atrophy scores, Fazeka's scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3-4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration.

Project description:BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH.ObjectiveTo conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately.MethodsOriginal studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses.ResultsThe study included 13 studies; seven addressed lumbar CSF levels of amyloid-β 1-42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-β 1-42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (- 0.55 SMD, p = 0.04) and Total-Tau (- 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-β 1-42 (- 0.26 SMD, p = 0.55) or the other included biomarkers.ConclusionThis meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-β 1-42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.