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Article ; Online: iNPH-the mystery resolving.

Leinonen, Ville / Kuulasmaa, Teemu / Hiltunen, Mikko

2021 Volume 13, Issue 3, Page(s) e13720

Abstract: Idiopathic normal pressure hydrocephalus (iNPH) is characterized clinically by degradation of gait, cognition, and urinary continence. INPH is progressive (Andrén et al, 2014), still probably underdiagnosed (Williams et al, 2019) but potentially ... ...

Abstract	Idiopathic normal pressure hydrocephalus (iNPH) is characterized clinically by degradation of gait, cognition, and urinary continence. INPH is progressive (Andrén et al, 2014), still probably underdiagnosed (Williams et al, 2019) but potentially treatable by CSF diversion (Kazui et al, 2015). Familial aggregation is a strong indicator of genetic regulation in the disease process iNPH (Fig 1). Enlargement of brain ventricles is associated with failed cerebrospinal (CSF) homeostasis by so far mostly unknown mechanisms. A mutation of the cilia gene CFAP43 in iNPH family, confirmed by a knocked-out mouse model (Morimoto et al, 2019), allelic variation of NME8 (Huovinen et al, 2017), a segmental copy number loss in SFMBT1 in selected iNPH patients (Sato et al, 2016), and current results by Yang et al (2021) indicate that cilia dysfunction is one of the key mechanisms behind iNPH.
MeSH term(s)	Animals ; Humans ; Hydrocephalus, Normal Pressure/genetics ; Mice ; Repressor Proteins
Chemical Substances	Repressor Proteins ; SFMBT1 protein, human
Language	English
Publishing date	2021-02-08
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202013720
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Article ; Online: Gene Expression Profile as a Predictor of Seizure Liability.

Lipponen, Anssi / Kajevu, Natallie / Natunen, Teemu / Ciszek, Robert / Puhakka, Noora / Hiltunen, Mikko / Pitkänen, Asla

International journal of molecular sciences

2023 Volume 24, Issue 4

Abstract: Analysis platforms to predict drug-induced seizure liability at an early phase of drug development would improve safety and reduce attrition and the high cost of drug development. We hypothesized that a drug-induced in vitro transcriptomics signature ... ...

Abstract	Analysis platforms to predict drug-induced seizure liability at an early phase of drug development would improve safety and reduce attrition and the high cost of drug development. We hypothesized that a drug-induced in vitro transcriptomics signature predicts its ictogenicity. We exposed rat cortical neuronal cultures to non-toxic concentrations of 34 compounds for 24 h; 11 were known to be ictogenic (tool compounds), 13 were associated with a high number of seizure-related adverse event reports in the clinical FDA Adverse Event Reporting System (FAERS) database and systematic literature search (FAERS-positive compounds), and 10 were known to be non-ictogenic (FAERS-negative compounds). The drug-induced gene expression profile was assessed from RNA-sequencing data. Transcriptomics profiles induced by the tool, FAERS-positive and FAERS-negative compounds, were compared using bioinformatics and machine learning. Of the 13 FAERS-positive compounds, 11 induced significant differential gene expression; 10 of the 11 showed an overall high similarity to the profile of at least one tool compound, correctly predicting the ictogenicity. Alikeness-% based on the number of the same differentially expressed genes correctly categorized 85%, the Gene Set Enrichment Analysis score correctly categorized 73%, and the machine-learning approach correctly categorized 91% of the FAERS-positive compounds with reported seizure liability currently in clinical use. Our data suggest that the drug-induced gene expression profile could be used as a predictive biomarker for seizure liability.
MeSH term(s)	United States ; Animals ; Rats ; Adverse Drug Reaction Reporting Systems ; Drug-Related Side Effects and Adverse Reactions ; Transcriptome ; United States Food and Drug Administration ; Seizures
Language	English
Publishing date	2023-02-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24044116
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Article ; Online: A report from the 8th Kuopio Alzheimer Symposium.

Haapasalo, Annakaisa / Hiltunen, Mikko

Neurodegenerative disease management

2018 Volume 8, Issue 5, Page(s) 289–299

Abstract: The international Kuopio Alzheimer Symposium was organized by the University of Eastern Finland in Kuopio, Finland on June 6-8, 2018 for the 8th time. Approximately 300 researchers in the fields of neuroscience and neurology from 12 different countries ... ...

Abstract	The international Kuopio Alzheimer Symposium was organized by the University of Eastern Finland in Kuopio, Finland on June 6-8, 2018 for the 8th time. Approximately 300 researchers in the fields of neuroscience and neurology from 12 different countries around the world gathered to Kuopio to hear and discuss about the latest insights into the mechanisms and comorbidities and novel approaches for diagnosis, prediction, prevention and therapies of Alzheimer's disease and other neurodegenerative diseases. The 2-day international program on June 7-8 included a keynote session, five oral scientific sessions and a poster session. The international symposium was preceded by a 'Memory Day' on June 6, held in Finnish and targeted to Finnish healthcare professionals, including doctors, psychologists and nurses, who work daily with patients suffering from neurodegenerative diseases.
MeSH term(s)	Alzheimer Disease/complications ; Alzheimer Disease/diagnosis ; Alzheimer Disease/physiopathology ; Alzheimer Disease/therapy ; Animals ; Finland ; Humans
Language	English
Publishing date	2018-08-16
Publishing country	England
Document type	Congress
ISSN	1758-2032
ISSN (online)	1758-2032
DOI	10.2217/nmt-2018-0029
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Article: Cognitive and biomarker responses in healthy older adults to a 18-hole golf round and different walking types: a randomised cross-over study.

Kettinen, Julia / Tikkanen, Heikki / Hiltunen, Mikko / Murray, Andrew / Horn, Nils / Taylor, William R / Venojärvi, Mika

BMJ open sport & exercise medicine

2023 Volume 9, Issue 4, Page(s) e001629

Abstract: Introduction: The global burden of age-related cognitive decline is increasing, with the number of people aged 60 and over expected to double by 2050. This study compares the acute effects of age-appropriate cognitively demanding aerobic exercises ... ...

Abstract	Introduction: The global burden of age-related cognitive decline is increasing, with the number of people aged 60 and over expected to double by 2050. This study compares the acute effects of age-appropriate cognitively demanding aerobic exercises involving walking, on cognitive functions and exerkine responses such as brain-derived neurotrophic factor (BDNF) and cathepsin B (CTSB) in older, healthy adults. Methods/design: Healthy older golfers (n=25, 16 male and 9 female, 69±4 years) were enrolled in a 5-day randomised cross-over study and completed three different exercise trials (18-hole golf round, 6 km Nordic walking, 6 km walking) in a real-life environment, in random order and at a self-selected pace. Differences in cognition (the Trail-Making Test (TMT) AB) and exerkines (BDNF and CTSB) were analysed within groups using the Wilcoxon signed-rank test and between groups using the Kruskal-Wallis test. Results: All exercise types resulted in a significant decrease in the TMT A-test (p<0.05; golf: -4.43±1.5 s, Nordic walking: -4.63±1.6 s, walking: -6.75±2.26 s), where Nordic walking and walking demonstrated a decrease in the TMT B-test (p<0.05; Nordic walking: -9.62±7.2 s, walking: -7.55±3.2 s). In addition, all exercise types produced significant decreases in the TMT AB test scores (p<0.05), and Nordic walking (p=0.035) showed decreases in the TMTB-TMTA-test. There were no immediate postexercise changes in the levels of BDNF or CTSB. Conclusion: Acute bouts of golf, Nordic walking and walking improved cognitive functions irrespective of exerkines in healthy older adults. In addition, Nordic walking and walking in general enhanced executive functions. No significant effects were seen on the levels of BDNF and CTSB. Trial registration number: ISRCTN10007294.
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2817580-3
ISSN	2055-7647
ISSN	2055-7647
DOI	10.1136/bmjsem-2023-001629
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Article ; Online: Treatment of Status Epilepticus after Traumatic Brain Injury Using an Antiseizure Drug Combined with a Tissue Recovery Enhancer Revealed by Systems Biology.

Kajevu, Natallie / Lipponen, Anssi / Andrade, Pedro / Bañuelos, Ivette / Puhakka, Noora / Hämäläinen, Elina / Natunen, Teemu / Hiltunen, Mikko / Pitkänen, Asla

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: We tested a hypothesis that in silico-discovered compounds targeting traumatic brain injury (TBI)-induced transcriptomics dysregulations will mitigate TBI-induced molecular pathology and augment the effect of co-administered antiseizure treatment, ... ...

Abstract	We tested a hypothesis that in silico-discovered compounds targeting traumatic brain injury (TBI)-induced transcriptomics dysregulations will mitigate TBI-induced molecular pathology and augment the effect of co-administered antiseizure treatment, thereby alleviating functional impairment. In silico bioinformatic analysis revealed five compounds substantially affecting TBI-induced transcriptomics regulation, including calpain inhibitor, chlorpromazine, geldanamycin, tranylcypromine, and trichostatin A (TSA). In vitro exposure of neuronal-BV2-microglial co-cultures to compounds revealed that TSA had the best overall neuroprotective, antioxidative, and anti-inflammatory effects. In vivo assessment in a rat TBI model revealed that TSA as a monotherapy (1 mg/kg/d) or in combination with the antiseizure drug levetiracetam (LEV 150 mg/kg/d) mildly mitigated the increase in plasma levels of the neurofilament subunit pNF-H and cortical lesion area. The percentage of rats with seizures during 0-72 h post-injury was reduced in the following order: TBI-vehicle 80%, TBI-TSA (1 mg/kg) 86%, TBI-LEV (54 mg/kg) 50%, TBI-LEV (150 mg/kg) 40% (
Language	English
Publishing date	2023-09-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241814049
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Article ; Online: Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.

Saadmaan, Gazi / Dalmasso, Maria Carolina / Ramirez, Alfredo / Hiltunen, Mikko / Kemppainen, Nina / Lehtisalo, Jenni / Mangialasche, Francesca / Ngandu, Tiia / Rinne, Juha / Soininen, Hilkka / Stephen, Ruth / Kivipelto, Miia / Solomon, Alina

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Introduction: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial.: Methods: 1260 at-risk older individuals without dementia were randomized to ... ...

Abstract	Introduction: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial. Methods: 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N = 126 participants underwent magnetic resonance imaging (MRI), and N = 47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N = 107 and N = 38 had repeated 2-year scans. Results: The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (β = -0.27, p = 0.001), greater amyloid deposition (β = 0.48, p = 0.001), 2-year decline in hippocampus (β = -0.27, p = 0.01), total gray matter volume (β = -0.25, p = 0.01), and cortical thickness (β = -0.28, p = 0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (β = -0.60, p = 0.03). Discussion: AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE). Highlights: First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13843
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Zs.A 6316: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 540: Show issues

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Article ; Online: NDUFA1 p.Gly32Arg variant in early-onset dementia.

Huttula, Samuli / Väyrynen, Henri / Helisalmi, Seppo / Kytövuori, Laura / Luukkainen, Laura / Hiltunen, Mikko / Remes, Anne M / Krüger, Johanna

Neurobiology of aging

2022 Volume 114, Page(s) 113–116

Abstract: Early-onset dementia (EOD) is highly heritable. However, in many EOD cases the genetic etiology remains unknown. Mitochondrial dysfunction is associated with neurodegeneration and the complex I (CI) deficiency is the most common enzyme deficiency in ... ...

Abstract	Early-onset dementia (EOD) is highly heritable. However, in many EOD cases the genetic etiology remains unknown. Mitochondrial dysfunction is associated with neurodegeneration and the complex I (CI) deficiency is the most common enzyme deficiency in diseases related to oxidative phosphorylation. The X-chromosomal NDUFA1 gene is essential for the activity of CI. Mutations in NDUFA1 are associated with mitochondrial diseases especially with Leigh syndrome. CI deficiency is also associated with neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of this study was to evaluate the role of NDUFA1 variants in EOD patients. Next-generation sequencing panel was used to screen NDUFA1 variants in a cohort of 37 EOD patients with a family history of dementia or an atypical or rapidly progressive course of disease. We identified a hemizygous p.Gly32Arg variant in two brothers with AD. Subsequent screening of the variant in a larger cohort of EOD patients (n = 279) revealed three additional variant carriers (one male and two heterozygote females), suggesting that NDUFA1 variant p.Gly32Arg may play a role in neurodegenerative dementia.
MeSH term(s)	Alzheimer Disease/genetics ; Electron Transport Complex I/deficiency ; Female ; Humans ; Male ; Mitochondrial Diseases
Chemical Substances	Electron Transport Complex I (EC 7.1.1.2) ; NDUFA1 protein, human (EC 7.1.1.2)
Language	English
Publishing date	2022-01-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2021.09.026
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Zs.MG 10: Show issues

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Article ; Online: Supervised pathway analysis of blood gene expression profiles in Alzheimer's disease.

Moradi, Elaheh / Marttinen, Mikael / Häkkinen, Tomi / Hiltunen, Mikko / Nykter, Matti

Neurobiology of aging

2019 Volume 84, Page(s) 98–108

Abstract: Early identification and treatment of Alzheimer's disease (AD) is hampered by the lack of easily accessible biomarkers. Currently available fluid biomarkers of AD provide indications of the disease stage; however, these are measured in the cerebrospinal ... ...

Abstract	Early identification and treatment of Alzheimer's disease (AD) is hampered by the lack of easily accessible biomarkers. Currently available fluid biomarkers of AD provide indications of the disease stage; however, these are measured in the cerebrospinal fluid, requiring invasive procedures, which are not applicable at the population level. Thus, gene expression profiling of blood provides a viable alternative as a way to screen individuals at risk of AD. Previous studies have shown that despite the limited permeability of the blood-brain barriers, expression profiles of blood genes can be used for the diagnosis and prognosis of several brain disorders. Here, we propose a new approach to pathway analysis of blood gene expression profiles to classify healthy (control [CTL]), mildly cognitively impaired (mild cognitive impairment [MCI]; preclinical stage of AD), and AD subjects. In the pathway analysis, gene expression data are mapped to pathway scores according to a predefined gene set instead of considering each gene separately. The robustness of the analysis enables detection of weak differences between groups owing to the inherent dimension reduction. Our proposed method for pathway analysis takes advantage of linear discriminant analysis for identifying a linear combination of features best separating groups of subjects within each gene set. The gene expression data were retrieved from Gene Expression Omnibus (batch 1: GSE63060; batch 2: GSE63061). Predefined gene sets for pathway analysis were obtained from the Broad Institute Collection of Curated Pathways. The method achieved a 10-fold cross-validated area under receiver operating characteristic curve of 0.84 for classification of AD versus CTL and 0.80 for classification of mild cognitive impairment versus CTL. These results reveal the good potential of blood-based biomarkers for assisting early diagnosis and disease monitoring of AD.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Biomarkers/blood ; Gene Expression ; Humans
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2019.07.004
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Article ; Online: DPYSL5 is highly expressed in treatment-induced neuroendocrine prostate cancer and promotes lineage plasticity via EZH2/PRC2.

Kaarijärvi, Roosa / Kaljunen, Heidi / Nappi, Lucia / Fazli, Ladan / Kung, Sonia H Y / Hartikainen, Jaana M / Paakinaho, Ville / Capra, Janne / Rilla, Kirsi / Malinen, Marjo / Mäkinen, Petri I / Ylä-Herttuala, Seppo / Zoubeidi, Amina / Wang, Yuzhuo / Gleave, Martin E / Hiltunen, Mikko / Ketola, Kirsi

Communications biology

2024 Volume 7, Issue 1, Page(s) 108

Abstract: Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein ... ...

Abstract	Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Androgen Antagonists ; Prostate/pathology ; Hydrolases ; Microtubule-Associated Proteins ; Enhancer of Zeste Homolog 2 Protein/genetics
Chemical Substances	Androgen Antagonists ; DPYSL5 protein, human (EC 3.-) ; Hydrolases (EC 3.-) ; Microtubule-Associated Proteins ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43)
Language	English
Publishing date	2024-01-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05741-x
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Article ; Online: Organotypic Hippocampal Slice Cultures from Adult Tauopathy Mice and Theragnostic Evaluation of Nanomaterial Phospho-TAU Antibody-Conjugates.

Kemppainen, Susanna / Huber, Nadine / Willman, Roosa-Maria / Zamora, Ana / Mäkinen, Petra / Martiskainen, Henna / Takalo, Mari / Haapasalo, Annakaisa / Sobrino, Tomás / González Gómez, Manuel Antonio / Piñeiro, Yolanda / Rivas, José / Himmelreich, Uwe / Hiltunen, Mikko

Cells

2023 Volume 12, Issue 10

Abstract: Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain ...

Abstract	Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice cultures from postnatal tissue are an established research tool, but adult tissue-originating systems are missing, yet necessary, as young tissue-originating systems cannot fully model adult or senescent brains. To establish an adult-originating slice culture system for tauopathy studies, we made hippocampal slice cultures from transgenic 5-month-old hTau.P301S mice. In addition to the comprehensive characterization, we set out to test a novel antibody for hyperphosphorylated TAU (pTAU, B6), with and without a nanomaterial conjugate. Adult hippocampal slices retained intact hippocampal layers, astrocytes, and functional microglia during culturing. The P301S-slice neurons expressed pTAU throughout the granular cell layer and secreted pTAU to the culture medium, whereas the wildtype slices did not. Additionally, cytotoxicity and inflammation-related determinants were increased in the P301S slices. Using fluorescence microscopy, we showed target engagement of the B6 antibody to pTAU-expressing neurons and a subtle but consistent decrease in intracellular pTAU with the B6 treatment. Collectively, this tauopathy slice culture model enables measuring the extracellular and intracellular effects of different mechanistic or therapeutic manipulations on TAU pathology in adult tissue without the hindrance of the blood-brain barrier.
MeSH term(s)	Mice ; Animals ; Tauopathies/metabolism ; Mice, Transgenic ; Neurons/metabolism ; Brain/metabolism ; Hippocampus/metabolism
Language	English
Publishing date	2023-05-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12101422
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