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      Two-Point Dynamic Observation of Alzheimer’s Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus


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          Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation.


          To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients.


          We analyzed CSF concentrations of tau, amyloid-β (Aβ) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF).


          Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aβ 42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau ( p = 0.02) and LRG ( p = 0.04), respectively.


          Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness.

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          Most cited references12

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          Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

          The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.
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            Validation of Grading Scale for Evaluating Symptoms of Idiopathic Normal-Pressure Hydrocephalus

            Background/Aims: We developed an idiopathic normal-pressure hydrocephalus grading scale (iNPHGS) to classify a triad of disorders (cognitive impairment, gait disturbance and urinary disturbance) of iNPH with a wide range of severity. The purpose of this study was to assess the reliability and validity of this scale in 38 patients with iNPH. Results: The interrater reliability of this scale was high. The iNPHGS cognitive domain score significantly correlated with the cognitive test scores, including the Mini-Mental State Examination (MMSE), the gait domain score with the Up and Go Test and Gait Status Scale scores, and the urinary domain score with the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score. The MMSE, Gait Status Scale and ICIQ-SF scores significantly improved in patients whose iNPHGS scores improved after CSF tapping but not in those whose iNPHGS scores did not improve after CSF tapping. Fourteen of the 38 patients received shunt operations. In these 14 patients, changes in the iNPHGS cognitive and urinary domains after CSF tapping were significantly associated with the changes after the shunt operation.
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              Idiopathic normal-pressure hydrocephalus: pathophysiology and diagnosis by CSF biomarkers.

              This observational study aimed to explore the pathophysiology of idiopathic normal-pressure hydrocephalus (iNPH) and to evaluate the diagnostic and prognostic value of CSF biomarkers. Lumbar CSF of patients with iNPH and healthy elderly individuals (HI) and ventricular CSF (VCSF) from the patients with iNPH pre and 6 months postsurgery were analyzed by ELISA. We analyzed neurofilament light protein (NFL), myelin basic protein (MBP), a panel of β-amyloid isoforms (Aβ38, Aβ40, and Aβ42), soluble amyloid precursor protein (sAPP) isoforms sAPPα and sAPPβ, total and phosphorylated tau protein (t- and p-tau), and inflammatory markers interleukin 8, interleukin 10, and monocyte chemoattractant protein 1. NFL was elevated and amyloid precursor protein (APP)-derived proteins and tau proteins were lower in patients with iNPH than in HI. Postsurgery, there was an increase of NFL, APP-derived proteins, p-tau, and albumin in VCSF, whereas levels of MBP and t-tau had decreased. Improved patients showed a greater increase of APP-derived proteins in VCSF following shunting than did those who did not improve. We interpret our data as iNPH pathophysiology to be characterized by a reduced periventricular metabolism and axonal degeneration but no major cortical damage.

                Author and article information

                J Alzheimers Dis
                J. Alzheimers Dis
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                20 September 2019
                29 October 2019
                : 72
                : 1
                : 271-277
                [a ] Department of Neurology, Kyoto University Graduate School of Medicine , Kyoto, Japan
                [b ] Department of Human Health Sciences, Kyoto University Graduate School of Medicine , Kyoto, Japan
                [c ] Department of Neurology, Yurinkai Ishiki Hospital , Kagoshima, Japan
                [d ] Normal Pressure Hydrocephalus Center, Rakuwakai Otowa Hospital , Kyoto, Japan
                [e ] Normal Pressure Hydrocephalus Center, Jifukai Atsuchi Neurosurgical Hospital , Kagoshima, Japan
                Author notes
                [* ]Correspondence to: Kengo Uemura, Department of Neurology, Yurinkai Ishiki Hospital, 2-4-15 Shimoishiki, Kagoshima 890-0005, Japan. Tel.: +81 99 220 4645; E-mail: ueken@ 123456kuhp.kyoto-u.ac.jp and Masamichi Atsuchi, Normal Pressure Hydrocephalus Center, Jifukai Atsuchi Neurosurgical Hospital, 4-13 Higashisengokucho, Kagoshima 892-0842, Japan. Tel.: +81 99 226 1231; E-mail: atsuchi0824@ 123456yahoo.co.jp .
                © 2019 – IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Research Article

                alzheimer’s disease,amyloid-β,cerebrospinal fluid biomarker,idiopathic normal pressure hydrocephalus,leucine rich α-2-glycoprotein,tap test,tau


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