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| 4. |
- Tanskanen, T., et al.
(författare)
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Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci
- 2018
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Ingår i: International Journal of Cancer. - Stockholm : Wiley. - 0020-7136 .- 1097-0215. ; 142:3, s. 540-546
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p=2.08 x 10(-4); OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50 x 10(-9); OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate<0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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| 6. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 7. |
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| 8. |
- Palin, K, et al.
(författare)
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Contribution of allelic imbalance to colorectal cancer
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3664-
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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| 9. |
- Cajuso, T, et al.
(författare)
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Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4022-
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Tidskriftsartikel (refereegranskat)abstract
- Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
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- Tanja, S, et al.
(författare)
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Air temperature triggers the recovery of evergreen boreal forest photosynthesis in spring
- 2003
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013. ; 9:10, s. 1410-1426
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Tidskriftsartikel (refereegranskat)abstract
- The timing of the commencement of photosynthesis (P-*) in spring is an important determinant of growing-season length and thus of the productivity of boreal forests. Although controlled experiments have shed light on environmental mechanisms triggering release from photoinhibition after winter, quantitative research for trees growing naturally in the field is scarce. In this study, we investigated the environmental cues initiating the spring recovery of boreal coniferous forest ecosystems under field conditions. We used meteorological data and above-canopy eddy covariance measurements of the net ecosystem CO2 exchange (NEE) from five field stations located in northern and southern Finland, northern and southern Sweden, and central Siberia. The within- and intersite variability for P-* was large, 30-60 days. Of the different climate variables examined, air temperature emerged as the best predictor for P-* in spring. We also found that 'soil thaw', defined as the time when near-surface soil temperature rapidly increases above 0degreesC, is not a useful criterion for P-*. In one case, photosynthesis commenced 1.5 months before soil temperatures increased significantly above 0degreesC. At most sites, we were able to determine a threshold for air-temperature-related variables, the exceeding of which was required for P-*. A 5-day running-average temperature (T-5) produced the best predictions, but a developmental-stage model (S) utilizing a modified temperature sum concept also worked well. But for both T-5 and S, the threshold values varied from site to site, perhaps reflecting genetic differences among the stands or climate-induced differences in the physiological state of trees in late winter/early spring. Only at the warmest site, in southern Sweden, could we obtain no threshold values for T-5 or S that could predict P-* reliably. This suggests that although air temperature appears to be a good predictor for P-* at high latitudes, there may be no unifying ecophysiological relationship applicable across the entire boreal zone.
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| 19. |
- Tuovinen, EA, et al.
(författare)
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Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency
- 2020
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Ingår i: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 1573-2592 .- 0271-9142. ; 40:3, s. 503-514
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Tidskriftsartikel (refereegranskat)abstract
- Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient’s clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.
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| 24. |
- Feodoroff, Benjamin, et al.
(författare)
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Clonal Distribution and Virulence of Campylobacter jejuni Isolates in Blood
- 2013
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 19:10, s. 1653-1655
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Tidskriftsartikel (refereegranskat)abstract
- Campylobacter jejuni bacteria are highly diverse enteropathogens. Seventy-three C. jejuni isolates from blood collected in Finland were analyzed by multilocus sequence typing and serum resistance. Approximately half of the isolates belonged to the otherwise uncommon sequence type 677 clonal complex. Isolates of this clonal complex were more resistant than other isolates to human serum.
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| 31. |
- Hoek, Gerard, et al.
(författare)
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A review of exposure assessment methods for epidemiological studies of health effects related to industrially contaminated sites
- 2018
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Ingår i: Epidemiologia & Prevenzione. - : Inferenze. - 1120-9763 .- 2385-1937. ; 42:5-6, s. 21-36
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: this paper is based upon work from COST Action ICSHNet. Health risks related to living close to industrially contaminated sites (ICSs) are a public concern. Toxicology-based risk assessment of single contaminants is the main approach to assess health risks, but epidemiological studies which investigate the relationships between exposure and health directly in the affected population have contributed important evidence. Limitations in exposure assessment have substantially contributed to uncertainty about associations found in epidemiological studies. OBJECTIVES: to examine exposure assessment methods that have been used in epidemiological studies on ICSs and to provide recommendations for improved exposure assessment in epidemiological studies by comparing exposure assessment methods in epidemiological studies and risk assessments. METHODS: after defining the multi-media framework of exposure related to ICSs, we discussed selected multi-media models applied in Europe. We provided an overview of exposure assessment in 54 epidemiological studies from a systematic review of hazardous waste sites; a systematic review of 41 epidemiological studies on incinerators and 52 additional studies on ICSs and health identified for this review. RESULTS: we identified 10 multi-media models used in Europe primarily for risk assessment. Recent models incorporated estimation of internal biomarker levels. Predictions of the models differ particularly for the routes 'indoor air inhalation' and 'vegetable consumption'. Virtually all of the 54 hazardous waste studies used proximity indicators of exposure, based on municipality or zip code of residence (28 studies) or distance to a contaminated site (25 studies). One study used human biomonitoring. In virtually all epidemiological studies, actual land use was ignored. In the 52 additional studies on contaminated sites, proximity indicators were applied in 39 studies, air pollution dispersion modelling in 6 studies, and human biomonitoring in 9 studies. Exposure assessment in epidemiological studies on incinerators included indicators (presence of source in municipality and distance to the incinerator) and air dispersion modelling. Environmental multi-media modelling methods were not applied in any of the three groups of studies. CONCLUSIONS: recommendations for refined exposure assessment in epidemiological studies included the use of more sophisticated exposure metrics instead of simple proximity indicators where feasible, as distance from a source results in misclassification of exposure as it ignores key determinants of environmental fate and transport, source characteristics, land use, and human consumption behaviour. More validation studies using personal exposure or human biomonitoring are needed to assess misclassification of exposure. Exposure assessment should take more advantage of the detailed multi-media exposure assessment procedures developed for risk assessment. The use of indicators can be substantially improved by linking definition of zones of exposure to existing knowledge of extent of dispersion. Studies should incorporate more often land use and individual behaviour.
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| 37. |
- Morawska, L., et al.
(författare)
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Indoor aerosols: from personal exposure to risk assessment
- 2013
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Ingår i: Indoor Air. - : Hindawi Limited. - 0905-6947. ; 23:6, s. 462-487
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Forskningsöversikt (refereegranskat)abstract
- Motivated by growing considerations of the scale, severity, and risks associated with human exposure to indoor particulate matter, this work reviewed existing literature to: (i) identify state-of-the-art experimental techniques used for personal exposure assessment; (ii) compare exposure levels reported for domestic/school settings in different countries (excluding exposure to environmental tobacco smoke and particulate matter from biomass cooking in developing countries); (iii) assess the contribution of outdoor background vs indoor sources to personal exposure; and (iv) examine scientific understanding of the risks posed by personal exposure to indoor aerosols. Limited studies assessing integrated daily residential exposure to just one particle size fraction, ultrafine particles, show that the contribution of indoor sources ranged from 19% to 76%. This indicates a strong dependence on resident activities, source events and site specificity, and highlights the importance of indoor sources for total personal exposure. Further, it was assessed that 10-30% of the total burden of disease from particulate matter exposure was due to indoor-generated particles, signifying that indoor environments are likely to be a dominant environmental factor affecting human health. However, due to challenges associated with conducting epidemiological assessments, the role of indoor-generated particles has not been fully acknowledged, and improved exposure/risk assessment methods are still needed, together with a serious focus on exposure control.
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| 38. |
- Neuvonen, E, et al.
(författare)
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Associations of Depressive Symptoms and Cognition in the FINGER Trial: A Secondary Analysis of a Randomised Clinical Trial
- 2022
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Depression and cognition are associated, but the role of depressive symptoms in lifestyle interventions to prevent dementia needs further study. We investigated the intervention effect on depressive symptoms and their associations with cognition in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER; NCT01041989), a two-year multidomain lifestyle trial. One thousand two-hundred and sixty individuals (60–77 years) at risk for dementia were randomised into a multidomain intervention (diet, exercise, cognitive training, and vascular/metabolic risk monitoring) or control group (regular health advice). Depressive symptoms (Zung scale) and cognition (modified Neuropsychological Test Battery) were evaluated at baseline, 12, and 24 months. One thousand one-hundred and twenty-five participants had baseline Zung data. Mean Zung score decreased 0.73 (SD 5.6) points in the intervention and 0.36 (5.6) points in the control group, with nonsignificant between-group difference (group × time coefficient −0.006, 95% CI −0.019 to 0.007). Overall, higher baseline Zung score was associated with less improvement in global cognition (−0.140, p = 0.005) and memory (−0.231, p = 0.005). Participants with clinically significant baseline depressive symptoms (Zung ≥ 40 points) had less intervention benefit to executive functioning (group × time × Zung −0.096, 95% CI −0.163 to −0.028). Change in Zung score was not associated with change in cognition. Clinically significant depressive symptoms warrant more attention when designing dementia-prevention interventions.
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| 39. |
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| 41. |
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| 42. |
- Pennanen, C, et al.
(författare)
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The effect of apolipoprotein polymorphism on brain in mild cognitive impairment: a voxel-based morphometric study
- 2006
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 22:1, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effect of apolipoprotein E (ApoE) on the whole brain in 51 individuals with mild cognitive impairment using voxel-based morphometry. Between cases heterozygous for the ApoE Ε4 (n = 15) and those who were ApoE Ε4 noncarriers (n = 28), only the right parahippocampal gyrus, with the entorhinal cortex included, reached the level of statistical significance. In cases homozygous for the Ε4 allele (n = 8) versus noncarriers, the greatest atrophy was located in the right amygdala followed by the right parahippocampal gyrus, the left amygdala and the left medial dorsal thalamic nucleus.
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| 45. |
- Rumrich, IK, et al.
(författare)
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Smoking during pregnancy in Finland - Trends in the MATEX cohort
- 2019
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Ingår i: Scandinavian journal of public health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 47:8, s. 890-898
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In Finland, smoking rates in the general population are decreasing due to increased awareness of the adverse effects and tightened tobacco legislation. However, previous studies have shown that smoking in pregnant Finnish women remained as high as in the general Finnish female population at around 15% in 2010. Our aim was to describe temporal and spatial trends in smoking behaviour, and determinants of changes in smoking behaviour between first and second pregnancy. Methods: Self-reported smoking from the Finnish Medical Birth Register covered the years 1991–2015 ( N=1,435,009). The association of maternal age and socioeconomic status with smoking rate was analysed. Spatial trends were assessed at municipality level. Results: The overall smoking rate during early pregnancy remained fairly stable at around 15% from 1991 to 2015, but increased in teenage and young women below 25 years of age. The mean smoking rate (36%) was higher in these age groups than in older pregnant women (11%). Through the study period the smoking rate remained higher in blue collar workers compared with higher socioeconomic groups. Between the first and second child, on average only 4% of women started to smoke and 41% quitted. Smoking rates developed less favourably in Eastern Finland. Conclusions: The observed increase in smoking rate during pregnancy in teenage and young women is concerning. Pregnancy is a trigger point for smoking cessation in a big fraction of pregnant women. More studies are needed to explain the opposite trends of smoking rates in Northern and Western Finland compared with Eastern Finland.
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| 46. |
- Sipila, Sarianna, et al.
(författare)
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Effects of physical and cognitive training on gait speed and cognition in older adults : A randomized controlled trial
- 2021
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley-Blackwell. - 0905-7188 .- 1600-0838. ; 31:7, s. 1518-1533
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Tidskriftsartikel (refereegranskat)abstract
- Gait speed is a measure of health and functioning. Physical and cognitive determinants of gait are amenable to interventions, but best practices remain unclear. We investigated the effects of a 12-month physical and cognitive training (PTCT) on gait speed, dual-task cost in gait speed, and executive functions (EFs) compared with physical training (PT) (ISRCTN52388040). Community-dwelling older adults, who did not meet physical activity recommendations, were recruited (n = 314). PT included supervised walking/balance (once weekly) and resistance/balance training (once weekly), home exercises (2-3 times weekly), and moderate aerobic activity 150 min/week in bouts of >10 min. PTCT included the PT and computer training (CT) on EFs 15-20 min, 3-4 times weekly. The primary outcome was gait speed. Secondary outcomes were 6-min walking distance, dual-task cost in gait speed, and EF (Stroop and Trail Making B-A). The trial was completed by 93% of the participants (age 74.5 [SD3.8] years; 60% women). Mean adherence to supervised sessions was 59%-72% in PT and 62%-77% in PTCT. Home exercises and CT were performed on average 1.9 times/week. Weekly minutes spent in aerobic activities were 188 (median 169) in PT and 207 (median 180) in PTCT. No significant interactions were observed for gait speed (PTCT-PT, 0.02; 95%CI -0.03, 0.08), walking distance (-3.8; -16.9, 9.3) or dual-task cost (-0.22; -1.74, 1.30). Stroop improvement was greater after PTCT than PT (-6.9; -13.0, -0.8). Complementing physical training with EFs training is not essential for promotion of gait speed. For EF's, complementing physical training with targeted cognitive training provides additional benefit.
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| 47. |
- Skarp-de Haan, Caroline P. A., et al.
(författare)
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Comparative genomics of unintrogressed Campylobacter coli clades 2 and 3
- 2014
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Ingår i: BMC Genomics. - : BioMed Central. - 1471-2164. ; 15:129
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Tidskriftsartikel (refereegranskat)abstract
- Background: Campylobacter jejuni and C. coli share a multitude of risk factors associated with human gastrointestinal disease, yet their phylogeny differs significantly. C. jejuni is scattered into several lineages, with no apparent linkage, whereas C. coli clusters into three distinct phylogenetic groups (clades) of which clade 1 has shown extensive genome-wide introgression with C. jejuni, yet the other two clades (2 and 3) have less than 2% of C. jejuni ancestry. We characterized a C. coli strain (76339) with four novel multilocus sequence type alleles (ST-5088) and having the capability to express gamma-glutamyltranspeptidase (GGT); an accessory feature in C. jejuni. Our aim was to further characterize unintrogressed C. coli clades 2 and 3, using comparative genomics and with additional genome sequences available, to investigate the impact of horizontal gene transfer in shaping the accessory and core gene pools in unintrogressed C. coli. Results: Here, we present the first fully closed C. coli clade 3 genome (76339). The phylogenomic analysis of strain 76339, revealed that it belonged to clade 3 of unintrogressed C. coli. A more extensive respiratory metabolism among unintrogressed C. coli strains was found compared to introgressed C. coli (clade 1). We also identified other genes, such as serine proteases and an active sialyltransferase in the lipooligosaccharide locus, not present in C. coli clade 1 and we further propose a unique scenario for the evolution of Campylobacter ggt. Conclusions: We propose new insights into the evolution of the accessory genome of C. coli clade 3 and C. jejuni. Also, in silico analysis of the gene content revealed that C. coli clades 2 and 3 have genes associated with infection, suggesting they are a potent human pathogen, and may currently be underreported in human infections due to niche separation.
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| 48. |
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| 49. |
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| 50. |
- Tervo, S, et al.
(författare)
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Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects
- 2004
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 17:3, s. 196-203
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background: </i>Mild cognitive impairment (MCI) has attracted considerable interest as a potential predictor of Alzheimer’s disease (AD). Both the apolipoprotein E (ApoE) Ε4 allele and vascular factors have been associated with a higher risk for AD, recently they have also been linked to the risk of MCI. <i>Objectives: </i>To estimate the incidence of MCI among cognitively healthy elderly subjects during a 3-year follow-up, and to evaluate the impact of demographic and vascular factors as well as the ApoE Ε4 allele on the conversion to MCI. <i>Methods: </i>At baseline, the cognitive abilities of 806 out of 1,150 eligible subjects (aged 60–76 years) from a population-based sample were examined. Cognitively intact subjects (n = 747) were followed for an average of 3 years. <i>Results: </i>66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01–1.16), ApoE Ε4 allele carriers (OR 2.04, 95% CI 1.15–3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05–3.29) were more likely to convert to MCI than those individuals of lower age and without an ApoE Ε4 allele or medicated hypertension. Persons with high education (OR 0.79, 95% CI 0.70–0.89) were less likely to convert to MCI than persons with low or no education. In subjects with both the ApoE Ε4 allele and medicated hypertension, the crude OR for conversion was 3.92 (95% CI 1.81–8.49). In subjects with cardiovascular disease, the crude OR for conversion was 2.13 (95% CI 1.26–3.60). Gender, elevated blood pressure, diabetes or cerebrovascular disease had no significant effect on the conversion to MCI. <i>Conclusion:</i> Higher age, the presence of at least one ApoE Ε4 allele and medicated hypertension are independent risk factors, but high education is a protective factor for MCI. The results suggest that vascular factors may have an important role in the pathogenesis of MCI.
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