| 1. |
- Silventoinen, Karri, et al.
(författare)
-
Genetic and environmental variation in educational attainment : an individual-based analysis of 28 twin cohorts
- 2020
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural–geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41–0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30–0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900–1949 (a2 = 0.44; 0.41–0.46) than in the later cohorts born in 1950–1989 (a2 = 0.38; 0.36–0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29–0.33 and c2 = 0.34; 0.32–0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
|
|
| 2. |
- Hampel, Harald, et al.
(författare)
-
Advances in the therapy of Alzheimer's disease : targeting amyloid beta and tau and perspectives for the future
- 2015
-
Ingår i: Expert Review of Neurotherapeutics. - : Informa UK Limited. - 1473-7175 .- 1744-8360. ; 15:1, s. 83-105
-
Forskningsöversikt (refereegranskat)abstract
- Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
|
|
| 3. |
- Hampel, Harald, et al.
(författare)
-
Perspective on Future Role of Biological Markers in Clinical Therapy Trials of Alzheimer's Disease: A Long-Range Point of View Beyond 2020.
- 2014
-
Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 88:4, s. 426-449
-
Tidskriftsartikel (refereegranskat)abstract
- Recent advances in understanding the molecular mechanisms underlying various paths towards the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.
|
|
| 4. |
- Lista, Simone, et al.
(författare)
-
Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study.
- 2017
-
Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908.
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n=35), FTD (n=9), MCI (n=41), cognitively HC (n=23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-β peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases.
|
|
| 5. |
- Lista, Simone, et al.
(författare)
-
Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives
- 2024
-
Ingår i: MOLECULAR PSYCHIATRY. - 1359-4184 .- 1476-5578.
-
Forskningsöversikt (refereegranskat)abstract
- Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (A beta), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of A beta instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of A beta associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, alpha-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and beta-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.
|
|
| 6. |
- Napolitano, Francesco, et al.
(författare)
-
Role of Aberrant Striatal Dopamine D-1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine
- 2010
-
Ingår i: The Journal of Neuroscience. - 1529-2401. ; 30:33, s. 11043-11056
-
Tidskriftsartikel (refereegranskat)abstract
- Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP32) at Thr75 residue, but preserved D-2 receptor (D2R) function. However, although we demonstrated that striatal D-1 receptor (D1R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D1R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.
|
|
| 7. |
- Silventoinen, Karri, et al.
(författare)
-
Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts
- 2022
-
Ingår i: Scientific Reports. - : Nature Portfolio. - 2045-2322. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.
|
|
| 8. |
- Telloni, Daniele, et al.
(författare)
-
Exploring the Solar Wind from Its Source on the Corona into the Inner Heliosphere during the First Solar Orbiter-Parker Solar Probe Quadrature
- 2021
-
Ingår i: Astrophysical Journal Letters. - : Institute of Physics Publishing (IOPP). - 2041-8205 .- 2041-8213. ; 920:1
-
Tidskriftsartikel (refereegranskat)abstract
- This Letter addresses the first Solar Orbiter (SO)-Parker Solar Probe (PSP) quadrature, occurring on 2021 January 18 to investigate the evolution of solar wind from the extended corona to the inner heliosphere. Assuming ballistic propagation, the same plasma volume observed remotely in the corona at altitudes between 3.5 and 6.3 solar radii above the solar limb with the Metis coronagraph on SO can be tracked to PSP, orbiting at 0.1 au, thus allowing the local properties of the solar wind to be linked to the coronal source region from where it originated. Thanks to the close approach of PSP to the Sun and the simultaneous Metis observation of the solar corona, the flow-aligned magnetic field and the bulk kinetic energy flux density can be empirically inferred along the coronal current sheet with an unprecedented accuracy, allowing in particular estimation of the Alfven radius at 8.7 solar radii during the time of this event. This is thus the very first study of the same solar wind plasma as it expands from the sub-Alfvenic solar corona to just above the Alfven surface.
|
|
| 9. |
- Telloni, Daniele, et al.
(författare)
-
Linking Small-scale Solar Wind Properties with Large-scale Coronal Source Regions through Joint Parker Solar Probe-Metis/Solar Orbiter Observations
- 2022
-
Ingår i: Astrophysical Journal. - : IOP Publishing Ltd. - 0004-637X .- 1538-4357. ; 935:2
-
Tidskriftsartikel (refereegranskat)abstract
- The solar wind measured in situ by Parker Solar Probe in the very inner heliosphere is studied in combination with the remote-sensing observation of the coronal source region provided by the METIS coronagraph aboard Solar Orbiter. The coronal outflows observed near the ecliptic by Metis on 2021 January 17 at 16:30 UT, between 3.5 and 6.3 R (circle dot) above the eastern solar limb, can be associated with the streams sampled by PSP at 0.11 and 0.26 au from the Sun, in two time intervals almost 5 days apart. The two plasma flows come from two distinct source regions, characterized by different magnetic field polarity and intensity at the coronal base. It follows that both the global and local properties of the two streams are different. Specifically, the solar wind emanating from the stronger magnetic field region has a lower bulk flux density, as expected, and is in a state of well-developed Alfvenic turbulence, with low intermittency. This is interpreted in terms of slab turbulence in the context of nearly incompressible magnetohydrodynamics. Conversely, the highly intermittent and poorly developed turbulent behavior of the solar wind from the weaker magnetic field region is presumably due to large magnetic deflections most likely attributed to the presence of switchbacks of interchange reconnection origin.
|
|
