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Increased ?-secretase activity in idiopathic normal pressure hydrocephalus patients with ?-amyloid pathology.

ABSTRACT: The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated ?- and ?-secretase activities in relation to amyloid-? (A?) pathology in the brain tissue samples collected from iNPH and AD patients. ?- and ?-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable A? plaques, ?-secretase activity was significantly increased (? 1.6-fold) when compared to iNPH samples without A? plaques (p = 0.009). In the AD samples, statistically significant differences in the ?-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, ?-secretase activity was unaltered in iNPH samples with or without A? plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased ?-secretase but not ?-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like A? pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the A? pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of A?.

SUBMITTER: Laitera T

PROVIDER: S-EPMC3974803 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with β-amyloid pathology.

Laiterä Tiina T Sarajärvi Timo T Haapasalo Annakaisa A Puli Lakshman L Kauppinen Tarja T Mäkinen Petra P Rauramaa Tuomas T Tanila Heikki H Jääskeläinen Juha E JE Alafuzoff Irina I Soininen Hilkka H Leinonen Ville V Hiltunen Mikko M

PloS one 20140403 4

The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase ac ...[more]

PMID: 24699723

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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

Increased ?-secretase activity in idiopathic normal pressure hydrocephalus patients with ?-amyloid pathology.

Publications

Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with β-amyloid pathology.

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