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Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility by CSF tap test.

ABSTRACT: Idiopathic Normal Pressure Hydrocephalus (iNPH)-the leading cause of reversible dementia in aging-is characterized by ventriculomegaly and gait, cognitive and urinary impairments. Despite its high prevalence estimated at 6% among the elderlies, iNPH remains underdiagnosed and undertreated due to the lack of iNPH-specific diagnostic markers and limited understanding of pathophysiological mechanisms. INPH diagnosis is also complicated by the frequent occurrence of comorbidities, the most common one being Alzheimer's disease (AD). Here we investigate the resting-state functional magnetic resonance imaging dynamics of 26 iNPH patients before and after a CSF tap test, and of 48 normal older adults. Alzheimer's pathology was evaluated by CSF biomarkers. We show that the interactions between the default mode, and the executive-control, salience and attention networks are impaired in iNPH, explain gait and executive disturbances in patients, and are not driven by AD-pathology. In particular, AD molecular biomarkers are associated with functional changes distinct from iNPH functional alterations. Finally, we demonstrate a partial normalization of brain dynamics 24?hr after a CSF tap test, indicating functional plasticity mechanisms. We conclude that functional changes involving the default mode cross-network interactions reflect iNPH pathophysiological mechanisms and track treatment response, possibly contributing to iNPH differential diagnosis and better clinical management.

SUBMITTER: Griffa A

PROVIDER: S-EPMC7927299 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility by CSF tap test.

Griffa Alessandra A Bommarito Giulia G Assal Frédéric F Herrmann François R FR Van De Ville Dimitri D Allali Gilles G

Human brain mapping 20201209 5

Idiopathic Normal Pressure Hydrocephalus (iNPH)-the leading cause of reversible dementia in aging-is characterized by ventriculomegaly and gait, cognitive and urinary impairments. Despite its high prevalence estimated at 6% among the elderlies, iNPH remains underdiagnosed and undertreated due to the lack of iNPH-specific diagnostic markers and limited understanding of pathophysiological mechanisms. INPH diagnosis is also complicated by the frequent occurrence of comorbidities, the most common on ...[more]

PMID: 33296129

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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:The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.

Dataset Information

Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility by CSF tap test.

Publications

Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility by CSF tap test.

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