Your search for: 'author:("Helisalmi, Seppo")' has returned 24 results. (0.032s) Save search

Authors: Alafuzoff, Irina | Overmyer, Margit | Helisalmi, Seppo | Soininen, Hilkka

Article Type: Research Article

Abstract: Epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAID) may have some therapeutic effect in Alzheimer's disease (AD) and experimental studies have shown that microglia activation by Aβ-peptide (Aβ) can be influenced by NSAIDs. We analysed 42 clinically and histopathologically verified demented patients fulfilling the histopathological CERAD criteria for definite AD, representing the terminal stage of brain degeneration. Our results indicate that regular NSAID use has a significant influence on the load of Aβ-peptide. Furthermore, our results indicate that regular NSAID use is associated with significantly lower counts of astrocytes and a trend of lower counts of activated microglia in …the brain tissue. The influence of NSAID use was noted in all ApoE genotypes however the trend of lower counts of glial cells with regular NSAID use was more marked in patients carrying the ApoE ε4/4 alleles. Based on our results one would anticipate that regular NSAID dosing could have a beneficial effect on the progression of the disease. However, the fact that we failed to observe significant differences for activated microglia might indicate an age or stage dependent difference in the glial response i.e. in their activation rate. More studies into age and stage related factors influencing the glial response are required if one is to devise novel pharmacological treatment strategies for AD. Show more

DOI: 10.3233/JAD-2000-2105

Citation: Journal of Alzheimer's Disease, vol. 2, no. 1, pp. 37-46, 2000

Authors: Seppälä, Toni T. | Koivisto, Anne M. | Hartikainen, Päivi | Helisalmi, Seppo | Soininen, Hilkka | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF …amyloid-β (Aβ)42 , tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ42 , highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ42 level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease. Show more

Keywords: Alzheimer's disease, amyloid, biomarker, cerebrospinal fluid, CSF, longitudinal, mild cognitive impairment, tau

DOI: 10.3233/JAD-2011-101911

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 583-594, 2011

Authors: Luukkainen, Laura | Helisalmi, Seppo | Kytövuori, Laura | Ahmasalo, Riitta | Solje, Eino | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39–65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the …C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1 , and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features. Show more

Keywords: Alzheimer’s disease, early onset, frontotemporal dementia, frontotemporal lobar degeneration, genetics, human, microtubule-associated protein tau, missense, mutation, presenilin-1

DOI: 10.3233/JAD-181256

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 775-782, 2019

Authors: Luukkainen, Laura | Huttula, Samuli | Väyrynen, Henri | Helisalmi, Seppo | Kytövuori, Laura | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods: Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1 , ATP13A2, UCHL1, HTRA2, GBA , and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 years) dementia patients presenting with …atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n  = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, frontotemporal dementia, frontotemporal lobar degeneration, gene, mutation, neurodegenerative disease, Parkinson’s disease, single nucleotide polymorphism

DOI: 10.3233/JAD-200069

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 955-965, 2020

Authors: Sarajärvi, Timo | Helisalmi, Seppo | Antikainen, Leila | Mäkinen, Petra | Koivisto, Anne Maria | Herukka, Sanna-Kaisa | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is a genetically complex disorder encompassing several individual susceptibility genes with low risk effects. To assess the risk gene effects in a cohort consisting of ∼1300 Finnish AD patients and controls, 21 candidate gene polymorphisms were selected for genotyping on the basis of the meta-analyses retrieved from the AlzGene database. A significant genotype and allele association with AD was observed with rs1800629 in the tumor necrosis factor α (TNF). Risk analysis revealed a protective effect for the minor allele carriers of rs1800629. This suggests that genetic alteration in TNF gene may play a role in AD.

Keywords: Alzheimer's disease, inflammation, polymorphism, risk gene, TNF

DOI: 10.3233/JAD-2010-100597

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 763-767, 2010

Authors: Korpioja, Anita | Krüger, Johanna | Koivuluoma, Susanna | Pylkäs, Katri | Moilanen, Virpi | Helisalmi, Seppo | Hiltunen, Mikko | Remes, Anne M.

Article Type: Research Article

Abstract: Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1 variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290* ) and eight missense variants in SORL1 . This is the first study …reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD. Show more

Keywords: Dementia, early onset Alzheimer’s disease, gene, human, mutation, neurodegenerative disease, single nucleotide polymorphism, SORL1

DOI: 10.3233/JAD-210207

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 761-770, 2021

Authors: Suhonen, Noora-Maria | Haanpää, Ramona M. | Korhonen, Ville | Jokelainen, Jari | Pitkäniemi, Anni | Heikkinen, Anna-Leena | Krüger, Johanna | Hartikainen, Päivi | Helisalmi, Seppo | Hiltunen, Mikko | Hänninen, Tuomo | Remes, Anne M.

Article Type: Research Article

Abstract: While the C9ORF72 expansion is a major cause of behavioral variant frontotemporal dementia (bvFTD), little is known of the resultant cognitive profile. Our aim was to characterize the neuropsychological profile of the C9ORF72 associated bvFTD. We contrasted structured neuropsychological assessments of the C9ORF72 expansion carrier bvFTD patients (n  = 26) with non-carrier bvFTD patients (n  = 47) and those with Alzheimer’s disease (AD) (n  = 47). As compared to the non-carrier bvFTD patients, the C9ORF72 expansion carriers performed at a higher level in an immediate verbal memory test while showing poorer phonemic verbal fluency. Additionally, the expansion carriers committed more errors in the …Stroop test and the Alternating S task relative to the non-carriers. Finally, while the AD patients outperformed both bvFTD patient groups in working memory, their performance was more impaired in episodic memory tasks relative to the bvFTD groups. We conclude that bvFTD patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD may aid in the early diagnosis of the disease as well as in targeting genetic testing. Show more

Keywords: Alzheimer’s disease, C9ORF72, frontotemporal dementia, frontotemporal lobar degeneration, genetics, neuropsychological tests, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-161142

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 479-489, 2017

Authors: Kämäläinen, Anna | Viswanathan, Jayashree | Natunen, Teemu | Helisalmi, Seppo | Kauppinen, Tarja | Pikkarainen, Maria | Pursiheimo, Juha-Pekka | Alafuzoff, Irina | Kivipelto, Miia | Haapasalo, Annakaisa | Soininen, Hilkka | Herukka, Sanna-Kaisa | Hiltunen, Mikko

Article Type: Short Communication

Abstract: Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

Keywords: Alzheimer's disease, granulin, GRN, microRNA, plasma, rs5848, temporal cortex

DOI: 10.3233/JAD-2012-120946

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 23-27, 2013

Authors: Natunen, Teemu | Helisalmi, Seppo | Vepsäläinen, Saila | Sarajärvi, Timo | Antikainen, Leila | Mäkinen, Petra | Herukka, Sanna-Kaisa | Koivisto, Anne Maria | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Research Article

Abstract: Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer's disease (AD) patients has been postulated to reflect defects in Aβ degradation or clearance. Here, we selected 12 genes (MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9) involved in Aβ catabolism on the basis of PubMed-based literature search and elucidated their genetic role in AD among Finnish case-control cohort consisting of total ∼1,300 AD patients and control subjects. Thirty one single nucleotide polymorphisms (SNPs) were selected for genotyping. In a smaller subset of AD patients, cerebrospinal fluid (CSF) levels of Aβ42 (n = 124), total-tau …(n = 59), and phospho-tau (n = 54) analyses were performed with respect to SNPs. Moreover, age of onset analyses with respect to the studied SNPs were conducted among the AD patient cohort (n = 642). Association analysis of the liver X receptor α (NR1H3) gene SNPs showed a protective effect for C allele carriers of rs7120118 (OR = 0.70, 95% CI 0.53–0.93), while the total-tau and phospho-tau levels in CSF were decreased in AD patients carrying the C allele. Also, a decrease in the age of onset was observed in AD patients carrying the A allele of rs723744 and the C allele of rs3794884 in transthyretin (TTR) gene. However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort. Show more

Keywords: Alzheimer's disease, Aβ clearance, Aβ degradation, NR1H3, risk gene, TTR

DOI: 10.3233/JAD-2011-111109

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 553-559, 2012

Authors: Sarajärvi, Timo | Marttinen, Mikael | Natunen, Teemu | Kauppinen, Tarja | Mäkinen, Petra | Helisalmi, Seppo | Laitinen, Marjo | Rauramaa, Tuomas | Leinonen, Ville | Petäjä-Repo, Ulla | Soininen, Hilkka | Haapasalo, Annakaisa | Hiltunen, Mikko

Article Type: Research Article

Abstract: The agonist-induced activation of human δ -opioid receptor (δ OR) has been shown to increase β- (BACE1) and γ -secretase activities leading to increased production of amyloid-β (Aβ) peptide. We have recently shown that phenylalanine to cysteine substitution at amino acid 27 in δ OR (δ OR-Phe27Cys) increases amyloid-β protein precursor processing through altered endocytic trafficking. Also, a genetic meta-analysis of the δ OR-Phe27Cys variation (rs1042114) in two independent Alzheimer’s disease (AD) patient cohorts indicated that the heterozygosity of δ OR-Phe27Cys increases the risk of AD. Here, we investigated α -, β-, and γ -secretase activities in human brain with …respect to δ OR-Phe27Cys variation in the temporal cortex of 71 subjects with varying degree of AD-related neurofibrillary pathology (Braak stages I-VI). As a result, a significant increase in β- (p  = 0.03) and γ - (p  = 0.01), but not α -secretase, activities was observed in late stage AD samples (Braak stages V-VI), which were heterozygous for δ OR-Phe27Cys as compared to the δ OR-Phe27 and δ OR-Cys27 homozygotes. The augmented β-secretase activity was not associated with increased mRNA expression or protein levels of BACE1 in the late stage AD patients, who were heterozygous for the δ OR-Phe27Cys variation. These findings suggest that δ OR-Phe27Cys variation modulates β- and γ -secretase activity in the late stages of AD likely via post-translational mechanisms other than alterations in the mRNA or protein levels of BACE1, or, in the expression of γ -secretase complex components. Show more

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, β-secretase, γ-secretase, δ-opioid receptor

DOI: 10.3233/JAD-150221

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 507-516, 2015