Alzheimer’s Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus

Article type: Research Article

Authors: Huovinen, Joel^a | Helisalmi, Seppo^b | Paananen, Jussi^c | Laiterä, Tiina^a | Kojoukhova, Maria^a | Sutela, Anna^d | Vanninen, Ritva^d | Laitinen, Marjo^b | Rauramaa, Tuomas^e | Koivisto, Anne M.^b | Remes, Anne M.^f | Soininen, Hilkka^b | Kurki, Mitja^{a; g} | Haapasalo, Annakaisa^{b; h} | Jääskeläinen, Juha E.^a | Hiltunen, Mikko^{b; c} | Leinonen, Ville^{a; *}

Affiliations: [a] Institute of Clinical Medicine –Neurosurgery, University of Eastern Finland and Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland | [b] Institute of Clinical Medicine –Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [c] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [d] Institute of Clinical Medicine – Pathology, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [e] Institute of Clinical Medicine – Radiology, University of Eastern Finland and Department of Radiology, Kuopio University Hospital, Kuopio, Finland | [f] Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland | [g] Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA; Stanley Center for Psychiatric Research, Broad Institute for Harvard and MIT, USA | [h] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Ville Leinonen, MD, PhD, Department of Neurosurgery, Kuopio University Hospital, P.O. Box 100,FIN-70029 KYS, Finland. Tel.: +358 44 717 2303; Fax: +358 17 173 916; E-mail: [email protected].

Abstract: Background:Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer’s disease (AD) seems to be frequent in iNPH. Objective:We aim to evaluate the role of AD-related polymorphisms in iNPH. Methods:Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. Results:Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. Conclusions:Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Keywords: Alzheimer’s disease, genetics, idiopathic normal pressure hydrocephalus, pathology, radiology

DOI: 10.3233/JAD-170583

Journal: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1077-1085, 2017