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      Shared CSF Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus and Subcortical Small Vessel Disease

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          Abstract

          Introduction

          In this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers.

          Methods

          We analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ isoforms −38, −40, and −42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP −1, −2, −3, −9, and −10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale.

          Results

          All amyloid fragments were reduced in iNPH and SSVD ( p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP ( p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD.

          Conclusion

          The results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.

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          Most cited references53

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          A new rating scale for age-related white matter changes applicable to MRI and CT.

          MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using kappa statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Interrater reliability was good for MRI (kappa=0.67) and moderate for CT (kappa=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.
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            Diagnosing idiopathic normal-pressure hydrocephalus.

            The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on "normal-pressure hydrocephalus" were cited in MEDLINE, including 29 articles that met the more stringent criteria of including "idiopathic normal-pressure hydrocephalus" in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to "Options." Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.
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              Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia.

              Regulation of the extracellular matrix by proteases and protease inhibitors is a fundamental biological process for normal growth, development and repair in the CNS. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) are the major extracellular-degrading enzymes. Two other enzyme families, a disintegrin and metalloproteinase (ADAM), and the serine proteases, plasminogen/plasminogen activator (P/PA) system, are also involved in extracellular matrix degradation. Normally, the highly integrated action of these enzyme families remodels all of the components of the matrix and performs essential functions at the cell surface involved in signaling, cell survival, and cell death. During the inflammatory response induced in infection, autoimmune reactions and hypoxia/ischemia, abnormal expression and activation of these proteases lead to breakdown of the extracellular matrix, resulting in the opening of the blood-brain barrier (BBB), preventing normal cell signaling, and eventually leading to cell death. There are several key MMPs and ADAMs that have been implicated in neuroinflammation: gelatinases A and B (MMP-2 and -9), stromelysin-1 (MMP-3), membrane-type MMP (MT1-MMP or MMP-14), and tumor necrosis factor-alpha converting enzyme (TACE). In addition, TIMP-3, which is bound to the cell surface, promotes cell death and impedes angiogenesis. Inhibitors of metalloproteinases are available, but balancing the beneficial and detrimental effects of these agents remains a challenge.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                03 March 2022
                2022
                : 13
                : 839307
                Affiliations
                [1] 1Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
                [2] 2Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Mölndal, Sweden
                [3] 3Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal, Sweden
                [4] 4Clinical Neurochemistry Laboratory, Department of Clinical Chemistry, Universitair Ziekenhuis Brussel and Center for Neurosciences, Vrije Universiteit Brussel , Brussels, Belgium
                [5] 5Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium
                [6] 6Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London, United Kingdom
                [7] 7UK Dementia Research Institute at UCL , London, United Kingdom
                [8] 8Hong Kong Center for Neurodegenerative Diseases, Hong Kong , Hong Kong SAR, China
                Author notes

                Edited by: Madoka Nakajima, Juntendo University, Japan

                Reviewed by: Diego Iacono, Uniformed Services University of the Health Sciences (USU), United States; Samir Abu-Rumeileh, University Hospital in Halle, Germany

                *Correspondence: Anna Jeppsson anna.jeppsson@ 123456gu.se

                This article was submitted to Dementia and Neurodegenerative Diseases, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2022.839307
                8927666
                35309577
                10f7bb81-ae2b-40d2-a605-3417a3f4bae4
                Copyright © 2022 Jeppsson, Bjerke, Hellström, Blennow, Zetterberg, Kettunen, Wikkelsø, Wallin and Tullberg.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 December 2021
                : 27 January 2022
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 53, Pages: 9, Words: 6638
                Categories
                Neurology
                Original Research

                Neurology
                biomarkers,cerebrospinal fluid,cerebral small vessel disease,hydrocephalus,normal pressure

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