Joel Huovinen1, Seppo Helisalmi2, Jussi Paananen3, Tiina Laiterä1, Maria Kojoukhova1, Anna Sutela4, Ritva Vanninen4, Marjo Laitinen2, Tuomas Rauramaa5, Anne M Koivisto2, Anne M Remes6, Hilkka Soininen2, Mitja Kurki1,7, Annakaisa Haapasalo2,8, Juha E Jääskeläinen1, Mikko Hiltunen2,3, Ville Leinonen1. 1. Institute of Clinical Medicine -Neurosurgery, University of Eastern Finland and Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland. 2. Institute of Clinical Medicine -Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland. 3. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. 4. Institute of Clinical Medicine - Pathology, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, Kuopio, Finland. 5. Institute of Clinical Medicine - Radiology, University of Eastern Finland and Department of Radiology, Kuopio University Hospital, Kuopio, Finland. 6. Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland. 7. 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. 8. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
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.
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.
Entities:
Keywords:
Alzheimer’s disease; genetics; idiopathic normal pressure hydrocephalus; pathology; radiology
Authors: Nuno Santos Leal; Giacomo Dentoni; Bernadette Schreiner; Olli-Pekka Kämäräinen; Nelli Partanen; Sanna-Kaisa Herukka; Anne M Koivisto; Mikko Hiltunen; Tuomas Rauramaa; Ville Leinonen; Maria Ankarcrona Journal: Acta Neuropathol Commun Date: 2018-10-01 Impact factor: 7.801