Cerebrospinal Fluid Biomarker and Brain Biopsy Findings in Idiopathic Normal Pressure Hydrocephalus

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From: PLoS ONE(Vol. 9, Issue 3)
Publisher: Public Library of Science
Document Type: Article
Length: 5,354 words
Lexile Measure: 1550L

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Author(s): Okko T. Pyykkö 1,*, Miikka Lumela 1, Jaana Rummukainen 4, Ossi Nerg 2, Toni T. Seppälä 3, Sanna-Kaisa Herukka 2,3, Anne M. Koivisto 2,3, Irina Alafuzoff 5, Lakshman Puli 3, Sakari Savolainen 1, Hilkka Soininen 2,3, Juha E. Jääskeläinen 1, Mikko Hiltunen 3, Henrik Zetterberg 6, Ville Leinonen 1

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurodegenerative disorder of unknown etiology in the elderly presenting with gait disorder, cognitive impairment, and urinary incontinence, with enlarged ventricles of the brain but normal or slightly elevated cerebrospinal fluid (CSF) pressure [1], [2]. Currently there is no pathological hallmark for iNPH [3]. Studies suggesting some potential genetic background of iNPH have been published [4], [5]. The present treatment of choice in iNPH is CSF diversion with an implanted shunt that relieves or even reverses the symptoms. Various procedures to evaluate CSF dynamics in patients with possible iNPH are used to identify those who could benefit from CSF shunting. These include the CSF tap test, external lumbar drainage test, infusion tests, and intraventricular or intracranial pressure (ICP) monitoring [6]-[9]. The most frequent differential diagnoses of iNPH are atypical Alzheimer's disease (AD) and vascular dementia [8], .

AD is characterized by the hallmark lesions of amyloid-[beta] (A[beta]) plaques and neurofibrillary tangles composed of hyperphosphorylated tau (HP[tau]) in the brain of patients with amnestic cognitive decline [11]-[13]. The amyloid cascade hypothesis states that A[beta] starts to accumulate decades before the clinical manifestations of AD [14], [15]. In vivo , A[beta] can be detected directly with brain biopsy [8], [16], or indirectly by observing low levels of A[beta] in CSF [17]. Fibrillar A[beta] can also be evaluated by positron emission tomography (PET) utilizing e.g. the 11 C-labeled Pittsburgh compound B [18] or [18 F]flutemetamol [19].

Although common pathways for iNPH and AD have been proposed [20], the findings in genetic [21] and A[beta] studies [8] suggest differences in etiologies of the two diseases. A[beta] and HP[tau] in the CSF may help to differentiate iNPH and AD patient groups or detect comorbid AD in iNPH [17]. In addition, these biomarkers have shown a potency to predict response to shunt in iNPH [22], [23].

A[beta] originates from a cell membrane-spanning protein, amyloid precursor protein (APP), which has diverse roles in normal neuronal function [24]. Soluble APP alpha (sAPP[alpha]) and beta (sAPP[beta]) result from the cleavage of APP by [alpha]- and [beta]-secretases, respectively. Low CSF levels of sAPP isoforms have been reported in post-stroke patients and iNPH compared to AD and normal healthy controls [25]-[28]. In addition, sAPP[alpha] has shown a marked prognostic value for cognitive performance following shunt surgery [27], and subsequent increase of ventricular sAPP-levels has been noted in shunt-responders [28].

Abnormal levels of proinflammatory cytokines, such as interleukins (IL), interferon-gamma (IFN-[gamma]), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-[alpha]), in CSF have been noted in various diseases of the nervous system, including AD [29]. In iNPH, several proinflammatory cytokines have been studied, but none of them has proven to be useful in diagnostics...

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