| 1. |
- Ferencz, Beata
(författare)
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Genetic and lifestyle influences on memory, brain structure, and dementia
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis investigated genetic, inflammatory, and lifestyle influences on cognition, brain structure, and dementia. The influence of TOMM40 polymorphisms (Study I), a PICALM, BIN1 and CLU genetic risk score (GRS; Studies II, III), and inflammatory cytokines (Study IV) was assessed, as well as potential interactions with physical activity (Studies II-IV). All studies were based on the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), including a subsample that had participated in magnetic resonance imaging (MRI). In Study I, the influence of TOMM40 polymorphisms (rs11556505 and rs2075650) on episodic memory and hippocampal volume was investigated. There was no independent influence of TOMM40 polymorphisms on episodic memory and hippocampal volume. However, carriers of an APOE ε4 allele who also harbored TOMM40 risk alleles relied more heavily on hippocampal volume for episodic memory performance. Study II confirmed our hypothesis that high genetic risk (GRS >4) based on Alzheimer’s disease (AD) candidate genes (PICALM rs3851179, rs541458, BIN1 rs744373, and CLU rs11136000) was associated with worse episodic memory performance in non-demented older adults. Interestingly, there was an interaction between physical activity and GRS. The combination of physical inactivity and high genetic risk was most detrimental to memory performance, whereas a high GRS could be compensated for by physical activity. In Study III, we investigated if the same GRS was associated with incident dementia, primarily AD. Despite the associations with memory performance in Study II, there was no effect of GRS on incident dementia during a follow-up period of 6 years. Nonetheless, we did replicate previous work showing that physical inactivity is associated with increased risk of dementia. Study IV investigated the influence of inflammatory cytokines and physical activity on graymatter volume and global cognitive decline. Although there was no relation between inflammatory cytokines and brain volume, high levels of IL-12p40 in individuals who were physically inactive were associated with smaller lateral prefrontal cortex and hippocampal volumes, as well as with global cognitive decline over 6 years. This suggests that levels of inflammation may be especially detrimental for brain and cognitive integrity in individuals who are physically inactive. In summary, the studies in this thesis suggest that physical inactivity is associated with reduced episodic memory performance, compromised structural brain volume, and dementia risk. Moreover, physical inactivity in combination with a high GRS or systemic inflammation was especially detrimental to episodic memory as well as to frontal and hippocampal volumes, respectively.
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| 2. |
- Ferencz, Beata, et al.
(författare)
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Genetics and Underlying Pathology of Dementia
- 2015
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Ingår i: Neuropsychology Review. - : Springer Science and Business Media LLC. - 1040-7308 .- 1573-6660. ; 25:1, s. 113-124
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Forskningsöversikt (refereegranskat)abstract
- As the population steadily ages, dementia, in all its forms, remains a great societal challenge. Yet, our knowledge of their etiology remains rather limited. To this end, genetic studies can give us insight into the underlying mechanisms that lead to the development of dementia, potentially facilitating treatments in the future. In this review we cover the most recent genetic risk factors associated with the onset of the four most common dementia types today, including Alzheimer's disease (AD), Vascular Dementia (VaD), Frontotemporal Lobar Degeneration (FTLD) and Lewy Body Dementia (LBD). Moreover, we discuss the overlap in major underlying pathologies of dementia derived from their genetic associations. While all four dementia types appear to involve genes associated with tau-pathology and neuroinflammation only LBD, AD and VaD appear to involve amyloid genes while LBD and FTLD share alpha synuclein genes. Together these findings suggest that some of the dementias may exist along a spectrum and demonstrates the necessity to conduct large-scale studies pinpointing the etiology of the dementias and potential gene and environment interactions that may influence their development.
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| 3. |
- Ferencz, Beata, et al.
(författare)
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Promising Genetic Biomarkers of Preclinical Alzheimer's Disease : The Influence of APOE and TOMM40 on Brain Integrity
- 2012
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Ingår i: International Journal of Alzheimer's Disease. - : Hindawi Limited. - 2090-8024 .- 2090-0252. ; 2012
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Forskningsöversikt (refereegranskat)abstract
- Finding biomarkers constitutes a crucial step for early detection of Alzheimer's disease (AD). Brain imaging techniques have revealed structural alterations in the brain that may be phenotypic in preclinical AD. The most prominent polymorphism that has been associated with AD and related neural changes is the Apolipoprotein E (APOE) ε4. The translocase of outer mitochondrial membrane 40 (TOMM40), which is in linkage disequilibrium with APOE, has received increasing attention as a promising gene in AD. TOMM40 also impacts brain areas vulnerable in AD, by downstream apoptotic processes that forego extracellular amyloid beta aggregation. The present paper aims to extend on the mitochondrial influence in AD pathogenesis and we propose a TOMM40-induced disconnection of the medial temporal lobe. Finally, we discuss the possibility of mitochondrial dysfunction being the earliest pathophysiological event in AD, which indeed is supported by recent findings.
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| 4. |
- Ferencz, Beata, et al.
(författare)
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The Benefits of Staying Active in Old Age : Physical Activity Counteracts the Negative Influence of PICALM, BIN1, and CLU Risk Alleles on Episodic Memory Functioning
- 2014
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Ingår i: Psychology and Aging. - : American Psychological Association (APA). - 0882-7974 .- 1939-1498. ; 29:2, s. 440-449
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Tidskriftsartikel (refereegranskat)abstract
- PICALM, BIN1, CLU, and APOE are top candidate genes for Alzheimer's disease, and they influence episodic memory performance in old age. Physical activity, however, has been shown to protect against age-related decline and counteract genetic influences on cognition. The aims of this study were to assess whether (a) a genetic risk constellation of PICALM, BIN1, and CLU polymorphisms influences cognitive performance in old age; and (b) if physical activity moderates this effect. Data from the SNAC-K population-based study were used, including 2,480 individuals (age range = 60 to 100 years) free of dementia at baseline and at 3- to 6-year follow-ups. Tasks assessing episodic memory, perceptual speed, knowledge, and verbal fluency were administered. Physical activity was measured using self-reports. Individuals who had engaged in frequent health-or fitness-enhancing activities within the past year were compared with those who were inactive. Genetic risk scores were computed based on an integration of risk alleles for PICALM (rs3851179 G allele, rs541458 T allele), BIN1 (rs744373 G allele), and CLU (rs11136000 T allele). High genetic risk was associated with reduced episodic memory performance, controlling for age, education, vascular risk factors, chronic diseases, activities of daily living, and APOE gene status. Critically, physical activity attenuated the effects of genetic risk on episodic memory. Our findings suggest that participants with high genetic risk who maintain a physically active lifestyle show selective benefits in episodic memory performance.
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| 5. |
- Ferencz, Beata, et al.
(författare)
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The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age
- 2013
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 6087 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 x 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r(2) = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE epsilon 4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R-2 = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R-2 = 0.08) risk alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE epsilon 4 carriers with additional TOMM40 risk alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60.
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| 6. |
- Laukka, Erika J., et al.
(författare)
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Genetic Effects on Old-Age Cognitive Functioning : A Population-Based Study
- 2013
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Ingår i: Psychology and Aging. - : American Psychological Association (APA). - 0882-7974 .- 1939-1498. ; 28:1, s. 262-274
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Tidskriftsartikel (refereegranskat)abstract
- Associations between genotypes and cognitive outcomes may provide clues as to which mechanisms cause individual differences in old-age cognitive performance. We investigated the effects of five polymorphisms on cognitive functioning in a population-based sample of 2,694 persons without dementia (60-102 years). A structural equation model (SEM) was fit to the cognitive data, yielding five specific latent factors (perceptual speed, episodic memory, semantic memory, category fluency, and letter fluency), as well as a global cognitive factor. These factors showed the expected associations with chronological age. Genotyping was performed for five single-nucleotide polymorphisms that have been associated with cognitive performance: APOE (rs429358), COMT (rs4680), BDNF (rs6265), KIBRA (rs17070145), and CLSTN2 (rs6439886). After controlling for age, gender, and education, as well as correcting for multiple comparisons, we observed negative effects of being an APOE ε4 carrier on episodic memory and perceptual speed. Furthermore, being a CLSTN2 TT carrier was associated with poorer semantic memory. For the global factor, the same pattern of results was observed. In addition, being a BDNF any A carrier was associated with better cognitive performance. Also, older age was associated with stronger genetic effects of APOE on global cognition. However, this interaction effect was partly driven by the presence of preclinical dementia cases in our sample. Similarly, excluding future dementia cases attenuated the effects of APOE on episodic memory and global cognition, suggesting that part of the effects of APOE on old-age cognitive performance may be driven by dementia-related processes.
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| 7. |
- Megyesfalvi, Zsolt, et al.
(författare)
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Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer : an international multicenter study
- 2022
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 257:5, s. 674-686
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Tidskriftsartikel (refereegranskat)abstract
- The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators.
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| 8. |
- Papenberg, Göran, et al.
(författare)
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Dopamine Receptor Genes Modulate Associative Memory in Old Age
- 2017
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Ingår i: Journal of cognitive neuroscience. - : MIT Press - Journals. - 0898-929X .- 1530-8898. ; 29:2, s. 245-253
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Tidskriftsartikel (refereegranskat)abstract
- Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE epsilon 4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.
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| 9. |
- Papenberg, Göran, et al.
(författare)
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Physical activity and inflammation : effects on gray-matter volume and cognitive decline in aging
- 2016
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 37:10, s. 3462-3473
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has been positively associated with gray-matter integrity. In contrast, pro-inflammatory cytokines seem to have negative effects on the aging brain and have been related to dementia. It was investigated whether an inactive lifestyle and high levels of inflammation resulted in smaller gray-matter volumes and predicted cognitive decline across 6 years in a population-based study of older adults (n=414). Self-reported physical activity (fitness-enhancing, health-enhancing, inadequate) was linked to gray-matter volume, such that individuals with inadequate physical activity had the least gray matter. There were no overall associations between different pro-and anti-inflammatory markers (IL-1, IL-6, IL-10, IL-12p40, IL-12p70, G-CSF, and TNF-) and gray-matter integrity. However, persons with inadequate activity and high levels of the pro-inflammatory marker IL-12p40 had smaller volumes of lateral prefrontal cortex and hippocampus and declined more on the Mini-Mental State Examination test over 6 years compared with physically inactive individuals with low levels of IL-12p40 and to more physically active persons, irrespective of their levels of IL-12p40. These patterns of data suggested that inflammation was particularly detrimental in inactive older adults and may exacerbate the negative effects of physical inactivity on brain and cognition in old age. Hum Brain Mapp 37:3462-3473, 2016.
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| 10. |
- Radeczky, Peter, et al.
(författare)
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Bone-Specific Metastasis Pattern of Advanced-Stage Lung Adenocarcinoma According to the Localization of the Primary Tumor
- 2021
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Ingår i: Pathology and Oncology Research. - : Frontiers Media SA. - 1219-4956 .- 1532-2807. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with advanced-stage lung adenocarcinoma (LADC) often develop distant metastases in the skeletal system. Yet, the bone-specific metastasis pattern is still controversial. We, therefore, aimed to examine how the primary tumor location affects bone specificity and survival in LADC patients diagnosed with skeletal metastases. Methods: In total, 209 bone-metastatic Caucasian LADC patients from two thoracic centers were included in this study. Focusing on the specific location of primary tumors and bone metastatic sites, clinicopathological variables were included in a common database and analyzed retrospectively. Skeletal metastases were diagnosed according to the contemporary diagnostic guidelines and confirmed by bone scintigraphy. Besides region- and side-specific localization, primary tumors were also classified as central or peripheral tumors based on their bronchoscopic visibility. Results: The most common sites for metastasis were the spine (n = 103) and the ribs (n = 60), followed by the pelvis (n = 36) and the femur (n = 22). Importantly, femoral (p = 0.022) and rib (p = 0.012) metastases were more frequently associated with peripheral tumors, whereas centrally located LADCs were associated with humeral metastases (p = 0.018). Moreover, we deduced that left-sided tumors give rise to skull metastases more often than right-sided primary tumors (p = 0.018). Of note, however, the localization of the primary tumor did not significantly influence the type of affected bones. Multivariate Cox regression analysis adjusted for clinical parameters demonstrated that central localization of the primary tumor was an independent negative prognostic factor for overall survival (OS). Additionally, as expected, both chemotherapy and bisphosphonate therapy conferred a significant benefit for OS. Conclusion: The present study demonstrates unique bone-specific metastasis patterns concerning primary tumor location. Peripherally located LADCs are associated with rib and femoral metastases and improved survival outcomes. Our findings might contribute to the development of individualized follow‐up strategies in bone-metastatic LADC patients and warrant further clinical investigations on a larger sample size.
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