المؤلفون: Heikkinen, Sami, Huber, Nadine, Katisko, Kasper, Kokkola, Tarja, Hartikainen, Paivi, Kruger, Johanna, Leinonen, Ville, Korhonen, Ville E., Herukka, Sanna-Kaisa, Remes, Anne M., Borroni, Barbara, Alberici, Antonella, Libri, Ilenia, Solje, Eino, Haapasalo, Annakaisa

المساهمون: Department of Neurosciences, Faculty of Medicine, Clinicum

مصطلحات موضوعية: Biomarker, C9orf72, Grn, Mapt, Tdp-43, cathepsin S, Diagnostics, Frontotemporal dementia, Proteinopathy, Tau, 3112 Neurosciences

الوصف: Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Heikkinen , S , Huber , N , Katisko , K , Kokkola , T , Hartikainen , P , Kruger , J , Leinonen , V , Korhonen , V E , Herukka , S-K , Remes , A M , Borroni , B , Alberici , A , Libri , I , Solje , E & Haapasalo , A 2023 , ' Serum Cathepsin S Levels Do Not Show Alterations in Different Clinical, Neuropathological, or Genetic Subtypes of Frontotemporal Dementia Patients nor in Comparison to Healthy Control Individuals ' , Journal of Alzheimer's Disease , vol. 93 , no. 2 , pp. 395-401 . https://doi.org/10.3233/JAD-221060Test; e49253ab-c09f-4fc6-b09e-d2df0016ab48; http://hdl.handle.net/10138/571125Test; 000989648900001

الإتاحة: http://hdl.handle.net/10138/571125Test

المؤلفون: Lehtola, Juha-Matti, Kärkkäinen, Virve, Andberg, Sami, Hannonen, Sanna, Rusanen, Minna, Saari, Toni, Korhonen, Ville, Hokkanen, Laura, Hallikainen, Merja, Hänninen, Tuomo, Kaarniranta, Kai, Bednarik, Roman, Leinonen, Ville, Koivisto, Anne M.

المساهمون: Department of Psychology and Logopedics, University of Helsinki, Department of Neurosciences, Clinicum, Helsinki University Hospital Area, Neurologian yksikkö

مصطلحات موضوعية: 3112 Neurosciences, 3124 Neurology and psychiatry, 515 Psychology, Alzheimer's disease (AD), biomarker, eye tracking (ET), idiopathic normal pressure hydrocephalus (iNPH), King-Devick (KD), saccadic eye movements

الوصف: Background: Functional defects in eye movements and reduced reading speed in neurodegenerative diseases represent a potential new biomarker to support clinical diagnosis. We investigated whether computer-based eye-tracking (ET) analysis of the King-Devick (KD) test differentiates persons with idiopathic normal pressure hydrocephalus (iNPH) from cognitively unimpaired [control (CO)] and persons with Alzheimer's disease (AD). Methods: We recruited 68 participants (37 CO, 10 iNPH, and 21 AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating interview. The KD reading test was performed using computer-based ET. We analyzed the total time used for the reading test, number of errors, durations of fixation and saccade, and saccade amplitudes. Results: The iNPH group significantly differed from the CO group in the KD test mean total time (CO 69.3 s, iNPH 87.3 s; P≤0.009) and eye-tracking recording of the mean saccade amplitude (CO 3.6 degree, iNPH 3.2 degree; P≤0.001). The AD group significantly differed from the CO group in each tested parameter. No significant differences were detected between the iNPH and AD groups. Conclusion: For the first time, we demonstrated altered reading ability and saccade amplitudes in patients with iNPH. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: The authors thank all study participants, statistician Tuomas Selander and study nurses Ulla Vanhanen, Kati Mönttinen, Kristiina Holopainen, Tarja Lappalainen, and Marita Parviainen. The authors are grateful to the Juho and Lempi Pitkänen foundation, the Maire Taponen Foundation, Maud Kuistila Foundation, Finnish Cultural Foundation, Finnish Brain Foundation and Finnish Government Research Funding for financial support.; Lehtola , J-M , Kärkkäinen , V , Andberg , S , Hannonen , S , Rusanen , M , Saari , T , Korhonen , V , Hokkanen , L , Hallikainen , M , Hänninen , T , Kaarniranta , K , Bednarik , R , Leinonen , V & Koivisto , A M 2022 , ' Computer-based Eye-tracking Analysis of King-Devick Test Differentiates Persons with Idiopathic Normal Pressure Hydrocephalus from Cognitively Unimpaired ' , Alzheimer Disease and Associated Disorders , vol. 36 , no. 4 , pp. 340-346 . https://doi.org/10.1097/WAD.0000000000000527Test; ORCID: /0000-0001-8342-9248/work/129615356; ORCID: /0000-0001-7721-3336/work/130606708; 85143088755; c4b61cbd-6a88-4c59-a3c0-3cd47a10da40; http://hdl.handle.net/10138/354870Test; 000923752200010

الإتاحة: http://hdl.handle.net/10138/354870Test

المؤلفون: Heikkinen, Sami, Huber, Nadine, Katisko, Kasper, Kokkola, Tarja, Hartikainen, Päivi, Krüger, Johanna, Leinonen, Ville, Korhonen, Ville E, Herukka, Sanna-Kaisa, Remes, Anne M, Borroni, Barbara, Alberici, Antonella, Libri, Ilenia, Solje, Eino, Haapasalo, Annakaisa

المساهمون: Kliininen lääketiede, A.I. Virtanen -instituutti

مصطلحات موضوعية: biomarker, cathepsin S, C9orf72, diagnostics, frontotemporal dementia, GRN, MAPT, proteinopathy, tau, TDP-43

الوصف: Frontotemporal dementia (FTD) can manifest as diverse clinical phenotypes and is frequently caused by mutations in different genes, complicating differential diagnosis. This underlines the urgent need for valid biomarkers. Altered lysosomal and immune functions proposedly contribute to FTD pathogenesis. Cathepsins, including cathepsin S, are enzymes preferentially expressed in brain in microglia, which influence lysosomal and immune function. Here, we examined whether alterations in serum cathepsin S levels associate with specific clinical, genetic, or neuropathological FTD subgroups, but no such alterations were observed. However, further research on other lysosomal proteins may reveal new biologically relevant biomarkers in FTD. ; final draft ; peerReviewed

وصف الملف: 395-401

العلاقة: Journal of Alzheimer's disease; https://doi.org/10.3233/JAD-221060Test; 93; https://erepo.uef.fi/handle/123456789/30066Test

الإتاحة: https://doi.org/10.3233/JAD-221060Test
https://erepo.uef.fi/handle/123456789/30066Test

المؤلفون: Hannonen, Sanna, Andberg, Sami, Kärkkäinen, Virve, Rusanen, Minna, Lehtola, Juha-Matti, Saari, Toni, Korhonen, Ville, Hokkanen, Laura, Hallikainen, Merja, Hänninen, Tuomo, Leinonen, Ville, Kaarniranta, Kai, Bednarik, Roman, Koivisto, Anne M.

المساهمون: Department of Psychology and Logopedics, University of Helsinki, Department of Neurosciences, HUS Neurocenter, Neurologian yksikkö, Geriatrian yksikkö

مصطلحات موضوعية: Alzheimer's disease, biomarker, CERAD, eye tracking, King-Devick, mild cognitive impairment, saccadic eye movements, CERAD NEUROPSYCHOLOGICAL BATTERY, KING-DEVICK TEST, ASSOCIATION WORKGROUPS, DIAGNOSTIC GUIDELINES, NATIONAL INSTITUTE, RECOMMENDATIONS, DEMENTIA, ALLELE, 3112 Neurosciences, 3124 Neurology and psychiatry, 515 Psychology, Neuropsychology

الوصف: Background: Wide-ranging functional defects in eye movements have been reported in Alzheimer's disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking. Objective: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD. Methods: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE= 28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE= 27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed. Results: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p < 0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p < 0.05). The KD error scores in the AD group differed significantly (p < 0.01) from the other groups. Conclusion: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: We are deeply grateful to all of the study participants. We also thank BEGAD research project study nurses Ulla Vanhanen, Kati Monttinen, and Kristiina Holopainen for recruiting the study participants. We thank biostatistician Tuomas Selander for help with the statistical analysis. This work was supported by Juho and Lempi Pitkanen Foundation.; Hannonen , S , Andberg , S , Kärkkäinen , V , Rusanen , M , Lehtola , J-M , Saari , T , Korhonen , V , Hokkanen , L , Hallikainen , M , Hänninen , T , Leinonen , V , Kaarniranta , K , Bednarik , R & Koivisto , A M 2022 , ' Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer's Disease ' , Journal of Alzheimer's Disease , vol. 88 , no. 2 , pp. 609-618 . https://doi.org/10.3233/JAD-215551Test; ORCID: /0000-0001-8342-9248/work/117173311; cf23b6b3-9995-43a9-a640-5ab028bd110c; http://hdl.handle.net/10138/346799Test; 000828034300020

الإتاحة: http://hdl.handle.net/10138/346799Test

المؤلفون: Katisko, Kasper, Huber, Nadine, Kokkola, Tarja, Hartikainen, Päivi, Krüger, Johanna, Heikkinen, Anna-Leena, Paananen, Veera, Leinonen, Ville, Korhonen, Ville E., Helisalmi, Seppo, Herukka, Sanna-Kaisa, Cantoni, Valentina, Gadola, Yasmine, Archetti, Silvana, Remes, Anne M., Haapasalo, Annakaisa, Borroni, Barbara, Solje, Eino

المساهمون: Suomen Lääketieteen Säätiö, Suomalais-Norjalainen Lääketieteen Säätiö, OLVI-Säätiö, Maire Taposen Säätiö, Suomen Kulttuurirahasto, Maud Kuistilan Muistosäätiö, Suomen Aivosäätiö, ALS tutkimuksen tuki ry, Sigrid Juséliuksen Säätiö, Academy of Finland, Kuopion Yliopistollinen Sairaala, Päivikki ja Sakari Sohlbergin Säätiö, Yrjö Jahnssonin Säätiö, Orionin Tutkimussäätiö, Instrumentariumin Tiedesäätiö

المصدر: Alzheimer's Research & Therapy ; volume 14, issue 1 ; ISSN 1758-9193

مصطلحات موضوعية: Cognitive Neuroscience, Neurology (clinical), Neurology

الوصف: Background Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 ...

الإتاحة: https://doi.org/10.1186/s13195-022-01091-8Test

المؤلفون: Lehtola, Juha-Matti, Kärkkäinen, Virve, Andberg, Sami, Hannonen, Sanna, Rusanen, Minna, Saari, Toni, Korhonen, Ville, Hokkanen, Laura, Hallikainen, Merja, Hänninen, Tuomo, Kaarniranta, Kai, Bednarik, Roman, Leinonen, Ville, Koivisto, Anne M.

المصدر: Alzheimer Disease & Associated Disorders ; volume 36, issue 4, page 340-346 ; ISSN 0893-0341

الوصف: Background: Functional defects in eye movements and reduced reading speed in neurodegenerative diseases represent a potential new biomarker to support clinical diagnosis. We investigated whether computer-based eye-tracking (ET) analysis of the King-Devick (KD) test differentiates persons with idiopathic normal pressure hydrocephalus (iNPH) from cognitively unimpaired [control (CO)] and persons with Alzheimer’s disease (AD). Methods: We recruited 68 participants (37 CO, 10 iNPH, and 21 AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating interview. The KD reading test was performed using computer-based ET. We analyzed the total time used for the reading test, number of errors, durations of fixation and saccade, and saccade amplitudes. Results: The iNPH group significantly differed from the CO group in the KD test mean total time (CO 69.3 s, iNPH 87.3 s; P ≤0.009) and eye-tracking recording of the mean saccade amplitude (CO 3.6 degree, iNPH 3.2 degree; P ≤0.001). The AD group significantly differed from the CO group in each tested parameter. No significant differences were detected between the iNPH and AD groups. Conclusion: For the first time, we demonstrated altered reading ability and saccade amplitudes in patients with iNPH.

الإتاحة: https://doi.org/10.1097/wad.0000000000000527Test

المؤلفون: Korhonen, Ville

مصطلحات موضوعية: fi=Rakennusmestarit|sv=Byggmästare|en=Construction Managers, vahingot ja vauriot, Rakennusalan työnjohdon tutkinto-ohjelma

الوصف: Tämän opinnäytetyön aiheena oli Kiinteistövahingon saneerausprosessin kehittäminen. Kiinteistöille sattuvia erilaisia vakuutuksista korvattavia vahinkoja sattuu kiinteistöille tuhansia vuosittain. Määrällisesti ja taloudellisesti suurimmat vahingot syntyvät palo- ja vesivahingoista. Opinnäytetyössä tutkittiin, olisiko mahdollista sujuvoittaa saneerausprosessin kulkua.

العلاقة: http://www.theseus.fi/handle/10024/851588Test; URN:NBN:fi:amk-202404166612

الإتاحة: http://www.theseus.fi/handle/10024/851588Test

المؤلفون: Lukkarinen, Heikki, Tesseur, Ina, Pemberton, Darrel, Van der Ark, Peter, Timmers, Maarten, Slemmon, Randy, Janssens, Luc, Streffer, Johannes, Van Nueten, Luc, Bottelbergs, Astrid, Rauramaa, Tuomas, Koivisto, Anne M., Herukka, Sanna-Kaisa, Korhonen, Ville E., Junkkari, Antti, Hiltunen, Mikko, Engelborghs, Sebastiaan, Blennow, Kaj, Zetterberg, Henrik, Kolb, Hartmuth C., Leinonen, Ville

المساهمون: Department of Neurosciences, University of Helsinki, Geriatrian yksikkö, Helsinki University Hospital Area

مصطلحات موضوعية: A beta(42), biomarkers, idiopathic normal pressure hydrocephalus, neurofilament light, neurogranin, P-tau, T-tau, CORTICAL BRAIN BIOPSY, ALZHEIMERS-DISEASE, CSF BIOMARKERS, PROTEIN NEUROGRANIN, PHOSPHORYLATED TAU, SYNAPTIC PROTEIN, AMYLOID-BETA, DIAGNOSIS, INCREASE, Neurosciences, Neurology and psychiatry

الوصف: Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-beta (A beta) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed A beta plaques in frontal cortical brain biopsy and 13 iNPH patients without A beta pathology. CSF Amyloid-beta(42) (A beta(42)), total tau (T-tau), phosphorylated tau (P-tau(181)), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but A beta(42) increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. A beta(42) instead showed divergent longitudinal decrease between A beta-positive and -negative patients in L-CSF, and thereafter increase in A beta-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (A beta(42) R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (A beta(42) 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only A beta(42) showed higher concentration in non-carriers of allele epsilon 4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy A beta pathology, while NFL normalized toward its pre-shunt levels. A beta(42) as biomarker seems ...

وصف الملف: application/pdf

العلاقة: We would like to acknowledge Marita Parviainen, RN, for assistance and cognitive testing. The study was funded by Janssen R-D, a division of Janssen Pharmaceutica NV, Kuopio University Hospital VTR (#5252614) fund and Sigrid Juselius Foundation. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alz-heimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzhei-mer Foundation (#AF-742881), Hj?rnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). We would like to acknowledge Marita Parviainen, RN, for assistance and cognitive testing. The study was funded by Janssen R&D, a division of Janssen Pharmaceutica NV, Kuopio University Hospital VTR (#5252614) fund and Sigrid Juselius Foundation. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236).; Lukkarinen , H , Tesseur , I , Pemberton , D , Van der Ark , P , Timmers , M , Slemmon , R , Janssens , L , Streffer , J , Van Nueten , L , Bottelbergs , A , Rauramaa , T , Koivisto , A M , Herukka , S-K , Korhonen , V E , Junkkari , A , Hiltunen , M , Engelborghs , S , Blennow , K , Zetterberg , H , Kolb , H C & Leinonen , V 2021 , ' Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus ' , Journal of Alzheimer's Disease , vol. 80 , no. 4 , pp. 1629-1642 . https://doi.org/10.3233/JAD-201361Test; http://hdl.handle.net/10138/331743Test; b44c09e8-f378-4b9d-b8d0-f55a3cdd882b; 000642444400027

الإتاحة: http://hdl.handle.net/10138/331743Test

المؤلفون: Leskelä, Stina, Hoffmann, Dorit, Rostalski, Hannah, Huber, Nadine, Wittrahm, Rebekka, Hartikainen, Päivi, Korhonen, Ville, Leinonen, Ville, Hiltunen, Mikko, Solje, Eino, Remes, Anne M., Haapasalo, Annakaisa

المساهمون: Academy of Finland, Yrjö Jahnssonin Säätiö, Päivikki ja Sakari Sohlbergin Säätiö, Sigrid Juséliuksen Säätiö, Orionin Tutkimussäätiö, H2020 Marie Skłodowska-Curie Actions, Instrumentariumin Tiedesäätiö, Suomen Aivosäätiö, Emil Aaltosen Säätiö, ALS-tutkimuksen tuki ry, Strategic Neuroscience Funding of the University of Eastern Finland

المصدر: Molecular Neurobiology ; volume 58, issue 11, page 5438-5458 ; ISSN 0893-7648 1559-1182

مصطلحات موضوعية: Neuroscience (miscellaneous), Cellular and Molecular Neuroscience, Neurology

الوصف: Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive cognitive dysfunction and frontal and temporal atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD, but pathogenic mechanisms underlying FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of FTLD patient–derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors. Fibroblasts from C9-HRE carriers were found to produce RNA foci, but no dipeptide repeat proteins, and they showed unchanged levels of C9orf72 mRNA transcripts. The main protein degradation pathways, the ubiquitin–proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to ATP production, were significantly reduced in the FTLD patient–derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that FTLD patient–derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing FTLD patient–derived fibroblasts as a platform for biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration.

الإتاحة: https://doi.org/10.1007/s12035-021-02475-xTest

المؤلفون: Räsänen, Joel, Huovinen, Joel, Korhonen, Ville E., Junkkari, Antti, Kastinen, Sami, Komulainen, Simo, Oinas, Minna, Avellan, Cecilia, Frantzen, Janek, Rinne, Jaakko, Ronkainen, Antti, Kauppinen, Mikko, Lönnrot, Kimmo, Perola, Markus, Koivisto, Anne M., Remes, Anne M., Soininen, Hilkka, Hiltunen, Mikko, Helisalmi, Seppo, Kurki, Mitja I., Jääskeläinen, Juha E., Leinonen, Ville

المصدر: Fluids and Barriers of the CNS 17(1) 57

مصطلحات موضوعية: Normal pressure hydrocephalus, Familial, Comorbidities, Diabetes, Depression, Genetics, SFMBT1

الوصف: Background: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families.Methods: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann–Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses.Results: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1–12.9, p = 0.030).Conclusions: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.

العلاقة: https://zenodo.org/record/4040018Test; https://doi.org/10.1186/s12987-020-00217-0Test; oai:zenodo.org:4040018

الإتاحة: https://doi.org/10.1186/s12987-020-00217-0Test
https://zenodo.org/record/4040018Test