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

Huovinen, Joel; Helisalmi, Seppo; Paananen, Jussi; Laiterä, Tiina; Kojoukhova, Maria; Sutela, Anna; Vanninen, Ritva; Laitinen, Matti; Rauramaa, Tuomas; Koivisto, Anne M.; Remes, Anne M.; Kurki, Mitja; Haapasalo, Annakaisa; Jääskeläinen, Juha E.; Hiltunen, Mikko; Leinonen, Ville

doi:10.3233/jad-170583

Cited by 11 publications

(7 citation statements)

References 41 publications

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“…The exact molecular mechanisms underlying this pathology are still unknown. Currently, the only available treatment for iNPH, is the implementation of a surgical CSF shunt which alleviates the symptoms in certain patients [ 15 ]. Interestingly, iNPH patients often present comorbidity with Alzheimer’s disease (AD) [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Leal

Dentoni

Schreiner

et al. 2018

acta neuropathol commun

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Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD.In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0605-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Leal

Dentoni

Schreiner

et al. 2018

acta neuropathol commun

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“…[16] 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. [16]…”

Section: Pathologymentioning

confidence: 89%

“…Another study had shown that allelic variation of NME8 gene was found to be statistically significant to be associated with iNPH patients compared to nondemented controls ( P = 0.014). [16] Furthermore, the allelic variation of NME8 gene was not related to the neuropathological changes in the brain biopsies of iNPH patients. These findings concluded that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD.…”

Section: Pathologymentioning

confidence: 99%

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Current updates on idiopathic normal pressure hydrocephalus

Liew

Takagi²,

Kato

et al. 2019

Asian J Neurosurg

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Idiopathic normal pressure hydrocephalus (iNPH) is one of the neurodegenerative diseases which can be treated surgically with favorable outcome. The gait disturbance, cognitive, and urinary symptoms are known as the clinical triad of iNPH. In this review, we have addressed the comorbidities, differential diagnoses, clinical presentations, and pathology of iNPH. We have also summarized the imaging studies and clinical procedures used for the diagnosis of iNPH. The treatment modality, outcomes, and prognosis were also discussed.

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“…The variant rs12263011 is embedded in a region with epigenetic promoter marks and thus it may modulate the expression of these genes approximately 0.5 Mb apart, through CI. FRMD4A (FERM domain-containing protein 4A) is a scaffolding protein that regulates epithelial polarity and has been previously identified as a genetic risk factor for LOAD and cognitive decline [40,41]. Even though this gene is an interesting candidate for an EEG endophenotype, the mechanism through which rs12263011 or any of the linked intronic SNPs ( Figure S6) may contribute to the phenotype is not clear.…”

Section: Locusmentioning

confidence: 99%

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band

et al. 2020

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Brain waves, measured by electroencephalography (EEG), are a powerful tool in the investigation of neurophysiological traits and a noninvasive and cost-effective alternative in the diagnostic of some neurological diseases. In order to identify novel Quantitative Trait Loci (QTLs) for brain wave relative power (RP), we collected resting state EEG data in five frequency bands (δ, θ, α, β1, and β2) and genome-wide data in a cohort of 105 patients with late onset Alzheimer’s disease (LOAD), 41 individuals with mild cognitive impairment and 45 controls from Iberia, correcting for disease status. One novel association was found with an interesting candidate for a role in brain wave biology, CLEC16A (C-type lectin domain family 16), with a variant at this locus passing the adjusted genome-wide significance threshold after Bonferroni correction. This finding reinforces the importance of immune regulation in brain function. Additionally, at a significance cutoff value of 5 × 10−6, 18 independent association signals were detected. These signals comprise brain expression Quantitative Loci (eQTLs) in caudate basal ganglia, spinal cord, anterior cingulate cortex and hypothalamus, as well as chromatin interactions in adult and fetal cortex, neural progenitor cells and hippocampus. Moreover, in the set of genes showing signals of association with brain wave RP in our dataset, there is an overrepresentation of loci previously associated with neurological traits and pathologies, evidencing the pleiotropy of the genetic variation modulating brain function.

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

Cited by 11 publications

References 41 publications

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Current updates on idiopathic normal pressure hydrocephalus

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band

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