| 51961. |
- Gkanatsiou, Eleni, et al.
(författare)
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A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer's disease.
- 2019
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Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 701, s. 125-131
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid angiopathy (CAA) is a type of vascular disease present in more than 50% of demented elderly and more than 80% of Alzheimer's disease (AD) patients. Both CAA and AD are characterized by extracellular Aβ deposits with the distinction that CAA has vascular deposits while AD has amyloid plaques. In this study, we used immunoprecipitation (IP) in combination with mass spectrometry (MS) to test the hypothesis that the Aβ peptide pattern differs between subjects having Aβ plaque pathology only and subjects with Aβ plaque pathology together with CAA pathology. Occipital lobes from 12 AD brains, ranging from no CAA to severe CAA, were extracted using 70% formic acid followed by IP-MS analysis. The Aβ peptide pattern differed greatly between subjects with no CAA compared to subjects with CAA. In cases with CAA, the most abundant Aβ peptides ended at amino acid 40 including Aβ1-40 (P = .048) and Aβ 2-40 (P = .0253) which were significantly increased compared to cases with no CAA. This was in contrast to subjects with no CAA where the most abundant Aβ peptides ended at amino acid 42 of which Aβ1-42 (P = .0101) and Aβ2-42 (P = .0051) as well as the pyroglutamate (pGlu)-modified peptides pGlu Aβ3-42 (P = .0177), and pGlu Aβ11-42 (P = .0088) were significantly increased compared to CAA subjects. The results are in line with earlier immunohistochemistry data and show that the molecular composition of the Aβ deposits found in blood vessels are different to the parenchymal deposits, suggesting they arise from distinct pathogenic pathways. This information may be useful in the development of pathology-specific biomarkers.
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| 51962. |
- Gkanatsiou, Eleni, et al.
(författare)
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Amyloid pathology and synaptic loss in pathological aging
- 2021
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 159:2, s. 258-272
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid beta (A beta) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and A beta peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion A beta peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of A beta 40 was higher in AD while for A beta 42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of A beta 40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of A beta.
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| 51963. |
- Gkanatsiou, Eleni, et al.
(författare)
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Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains.
- 2021
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Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 754
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Tidskriftsartikel (refereegranskat)abstract
- The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
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| 51964. |
- Gkanatsiou, Eleni
(författare)
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Revealing the complex nature of amyloid beta and its relation to dementia
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer disease (AD) is the most common type of dementia and characterized by the accumulation of amyloid plaques in the extracellular space of the brain parenchyma. Amyloid plaques consist of amyloid beta peptides (Aβ). Amyloid pathology can also be involved in other types of dementia, either as a driving force or as a coexisting pathology. In this thesis was the Aβ peptide content in relation to different amyloid deposits, types of dementia and regions investigated with the goal to improve our understanding of amyloid pathology in dementia. To analyse Aβ peptides, a hybrid immunoprecipitation - mass spectrometry method was used. The studies presented here reveal a different Aβ peptide pattern in individuals with amyloid pathology, but cognitively unaffected, compared with AD patients, who suffer from cognitive decline. Moreover, vascular Aβ contribution, due to cerebral amyloid angiopathy, differs from amyloid plaque Aβ contribution. For other groups with plaque pathology, such as Down syndrome, dementia with Lewy bodies, and Parkinson’s disease dementia, there are minor differences in the Aβ peptide pattern compared with AD. In this work, the Aβ content of the protofibril/oligomeric forms, a major anti-amyloid therapeutical target, is also revealed. This thesis can be the beginning of a deeper understanding of the complex nature of amyloid pathology and its contribution to dementia.
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| 51965. |
- Gkaniatsa, Eleftheria, et al.
(författare)
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Adrenal Vein Sampling in the Young - Necessary or Not?
- 2023
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Ingår i: Experimental and Clinical Endocrinology & Diabetes. - 0947-7349. ; 131:07/08, s. 435-437
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Forskningsöversikt (refereegranskat)abstract
- Current clinical guidelines from the US Endocrine Society state that adrenal venous sampling (AVS) may not be necessary in patients younger than 35 years with marked aldosteronism and a solitary adrenal adenoma on imaging. At the time when the guidelines were published, only one study supported the statement, a study that included 6 patients younger than 35 years, all of whom had unilateral adenoma on imaging and unilateral primary aldosteronism (PA), according to AVS. Since then, to our knowledge, four additional studies have been published that provide data on concordance between conventional imaging and AVS among patients younger than 35 years. In these studies, 7 of 66 patients with unilateral disease on imaging had bilateral disease, according to AVS. We find it, therefore, reasonable to conclude that imaging studies alone inaccurately predict laterality in a significant number of young patients with PA and that available data challenge the current clinical guidelines.
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| 51966. |
- Gkaniatsa, Eleftheria, et al.
(författare)
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Adrenal venous sampling in young patients with primary aldosteronism. Extravagance or irreplaceable?
- 2021
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 106:5
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Tidskriftsartikel (refereegranskat)abstract
- Current clinical guidelines suggest that adrenal venous sampling (AVS) may not be mandatory in young patients with primary aldosteronism (PA) and a solitary adrenal adenoma on imaging.The aim of this study was to further elucidate whether conventional imaging alone is sufficient to distinguish unilateral from bilateral PA among patients aged 40 years or younger.This was a retrospective study where data from 45 patients with PA, aged between 26 and 40 years, who underwent successful AVS between 2005 and 2019, were analyzed. Results concerning laterality on imaging studies and AVS were recorded. Outcome in surgically treated patients was assessed according to the Primary Aldosteronism Surgical Outcomes (PASO) criteria.In four of 25 patients with unilateral aldosterone production according to AVS, CT inaccurately suggested bilateral disease. Following unilateral adrenalectomy, all four patients showed complete clinical success. Five of 20 patients with bilateral aldosterone production according to AVS had a solitary adrenal nodule (8-19 mm) on imaging. Two of these five patients were treated with unilateral adrenalectomy, neither having complete biochemical and/or clinical success postoperatively. Two of 16 patients younger than 35 years had discordant results, one with unilateral, and one with bilateral aldosterone production, according to AVS.Imaging studies inaccurately predicted laterality in a significant number of young patients with PA. In contrast to current clinical guidelines, our results support AVS for subtype evaluation in young adults with PA, including patients 35 years or younger.
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| 51967. |
- Gkaniatsa, Eleftheria, et al.
(författare)
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Increasing Incidence of Primary Aldosteronism in Western Sweden During 3 Decades -Yet An Underdiagnosed Disorder
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:9, s. E3603-E3610
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Tidskriftsartikel (refereegranskat)abstract
- Context: Primary aldosteronism (PA) is the most common cause of secondary hypertension.Yet, the incidence of PA in the general population has not been studied. Objective: To estimate the incidence of PA in the general population. Design and methods: Patients who had received a diagnostic code for PA between 1987 and 2016 were identified in the Swedish National Patient Registry. Assessment of clinical and biochemical data was used to validate the diagnosis. The annual incidence of PA was calculated by using the number of inhabitants in the Vastra Gotaland County as a reference. Results: Of 570 identified patients, 473 (83%) had confirmed PA. Eligible for the incidence analysis were 416 patients, 248 (60%) men and 168 (40%) women, diagnosed with PA between 1987 and 2016. The mean (+/- standard deviation) age at diagnosis was 56 +/- 12 years. The median (interquartile range) annual incidence was 2 (1-2) cases per million between 1987 and 1996, 6 (4-9) cases per million between 1997 and 2006 and 17 (12-24) cases per million between 2007 and 2016. At the end of the study (December 31, 2016), 386 patients with confirmed PA were alive and living in the Vastra Gotaland County, giving a prevalence of 231 cases per million (0.022%). Conclusions: Despite increasing incidence, the proportion of patients identified with PA is lower than expected. Given the serious consequences of untreated PA, the noticeably low prevalence at the end of the study stresses the need to increase the awareness of PA among health care providers.
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| 51968. |
- Gkaniatsa, Eleftheria, et al.
(författare)
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Mortality in Patients With Primary Aldosteronism: A Swedish Nationwide Study.
- 2023
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Ingår i: Hypertension (Dallas, Tex. : 1979). - 1524-4563. ; 80:12, s. 2601-2610
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Tidskriftsartikel (refereegranskat)abstract
- Primary aldosteronism (PA) is associated with increased mortality. The extent to which this phenomenon is affected by sex, age, comorbidities at diagnosis, and different treatment modalities is largely unknown. The objective was to determine all-cause and cause-specific mortality in a population-based cohort of patients with PA and the impact of age at diagnosis, sex, comorbidities, and treatment modalities.We used national registers to identify patients diagnosed with PA between 1997 and 2019 (n=2419) and controls (n=24 187) from the general population, matched for sex, age, and county of residence. We obtained mortality data from the Cause-of-Death Register. We used Cox regression models, adjusted for socioeconomic factors and diabetes, to estimate adjusted hazard ratios (HRs [95% CI]).Overall, 346 (14.3%) patients with PA and 2736 (11.3%) controls died during a median follow-up time of 8.1 years. PA was associated with increased risk from all-cause mortality (HR, 1.23 [95% CI, 1.10-1.38]), death from cardiovascular disease (HR, 1.57 [95% CI, 1.30-1.89]), and stroke (HR, 1.85 [95% CI, 1.16-2.93]). Patients with cardiovascular disease at diagnosis (HR, 1.53 [1.26-1.85]), age >56 years (HR, 1.28 [95% CI, 1.13-1.45]), patients treated with a low dose of a mineralocorticoid receptor antagonist (HR, 1.30 [95% CI, 1.02-1.66]), and untreated patients (HR, 2.51 [95% CI, 1.72-3.67]) had excess mortality.Mortality, mainly due to cardiovascular disease, is increased in patients with PA compared with controls from the general population, particularly in patients aged >56 years, patients with preexisting cardiovascular comorbidities, and patients receiving low dose of a mineralocorticoid receptor antagonist.
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| 51969. |
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| 51970. |
- Gkourogianni, Alexandra, et al.
(författare)
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Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
- 2020
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell Publishing Inc.. - 0803-5253 .- 1651-2227. ; 109:10, s. 2067-2074
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
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