Type-2 diabetes (T2D) and glucose metabolic imbalances have been linked to neurodegenerative diseases, including Parkinson's disease (PD). To detect potential effects of different glucose levels on ...gene expression, by RNA-seq we analyzed the transcriptome of dermal fibroblasts from idiopathic PD (iPD) patients, LRRK2-associated PD (L2PD) patients, and healthy controls (total n = 21 cell lines), which were cultured at two different glucose concentrations (25 and 5 mM glucose). In PD patients we identified differentially expressed genes (DEGs) that were related to biological processes mainly involving the plasmatic cell membrane, the extracellular matrix, and also neuronal functions. Such pathway deregulation was largely similar in iPD or L2PD fibroblasts. Overall, the gene expression changes detected in this study were associated with PD independently of glucose concentration.
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism ...(Parkinson's disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
This paper presents a new southern North Atlantic plate model from Late Cretaceous to present, with the aim of constraining the kinematics of the Iberian plate during the last 83.5 Myr. This model is ...presented along with a detailed isochron map generated through the analysis of 3 aeromagnetic tracks and ~400 ship tracks from the National Centers for Environmental Information database. We present a new technique to obtain well‐constrained estimates of the Iberia‐North America plate motions from magnetic anomalies, overcoming the scarcity of large‐offset fracture zones and transform faults. We build an integrated kinematic model for NW Africa, Morocco, Iberia, Europe, and North America, which shows that the deformation is partitioned between Pyrenees and Betic‐Rif orogenic domain during the Late Cretaceous‐Oligocene time interval. In the Eastern Betics domain, the calculated amount of NW Africa‐Iberia convergence is ~80 km between 83.5 and 34 Ma, followed by ~150 km since the Oligocene. The motion of Iberia relative to Europe in the Central Pyrenees is characterized by overall NE directed transpressional motion during the Campanian and the Paleocene, followed by NW directed transpressional movement until the Lutetian and overall NNW directed convergence from Bartonian to Chattian. This motion occurs along the axis of the Bay of Biscay from the Santonian–Campanian boundary to the middle Priabonian, subsequently jumping to King's Trough at Anomaly 17 (36.62 Ma).
Key Points
New southern North Atlantic (Iberia‐North America) isochron map from Late Cretaceous to present
Iberia was an independent plate from 83.5 to ~20.1 Ma, and the convergence between NW Africa and Iberia was active since 83.5 Ma
Iberia‐Europe convergence (Central Pyrenees) was NE directed from 83.5 to ~56 Ma, NW directed until ~46 Ma, and NNW directed till ~20.1 Ma
Abstract Alzheimer's disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD ...(FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2 , and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes DEG respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.
High-oligomeric and low-total-α-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson’s disease (PD), but with inconsistent or limited data, particularly on their clinical and ...structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-α-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD 21 non-demented (PDND) + 20 demented (PDD), intended to reflect the premotor–motor–dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF
τ
and CSF Aβ. CSF oligomeric-α-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor–motor–dementia PD continuum (iRBD + PDND + PDD). CSF total-α-synuclein positively correlated with age, CSF Aβ, and, particularly, CSF
τ
, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF
τ
. Low CSF total-α-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF
τ
. Conversely, the associations of high (instead of low) CSF total-α-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF
τ
. These findings suggest that CSF oligomeric- and total-α-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor–motor–dementia PD continuum. CSF total-α-synuclein correlations with CSF
τ
and Aβ support the hypothesis of an interaction among these proteins in PD, with CSF
τ
probably influencing the presence of high (instead of low) CSF total-α-synuclein and its correlates mostly in the setting of PD-related dementia.
We present new crust and lithosphere thickness maps of the African mainland based on integrated modeling of elevation and geoid data and thermal analysis. The approach assumes local isostasy, thermal ...steady state, and linear density increase with depth in the crust and temperature‐dependent density in the lithospheric mantle. Results are constrained by a new comprehensive compilation of seismic Moho depth data consisting of 551 data points and by published tomography models relative to LAB depth. The crustal thickness map shows a N‐S bimodal distribution with higher thickness values in the cratonic domains of southern Africa (38–44 km) relative to those beneath northern Africa (33–39 km). The most striking result is the crustal thinning (28–30 km thickness) imaged along the Mesozoic West and Central African Rift Systems. Our crustal model shows noticeable differences compared to previous models. After excluding the Afar plume region, where the modeling assumptions are not fulfilled, our model better fits the available seismic data (76.3% fitting; root mean square error = 4.3 km). The LAB depth map shows large spatial variability (90 to 230 km), with deeper LAB related to cratonic domains and shallower LAB related to Mesozoic and Cenozoic rifting domains, in agreement with tomography models. Though crustal and lithosphere thickness maps show similar regional patterns, major differences are found in the Atlas Mountains, the West African Rift System, and the intracratonic basins. The effects of lateral variations in crustal density as well as the nonisostatic contribution to elevation in the Afar plume region, which we estimate to be ~1.8 km, are also discussed.
Key Points
We present 10 min resolution crust and lithosphere maps of Africa constrained by a compilation of seismic Moho data and tomography models
Our maps cover large areas of Africa where no data are available showing 76% fit with seismic data after excluding the Afar plume region
Misfit with seismic data in the Afar region is discussed in terms of residual topography related to sublithospheric processes
We investigate the lithospheric structure of the Iberian Peninsula and lateral crustal density variations using a three-step approach. First the crustal and mantle lithosphere thicknesses are ...calculated from joint geoid and elevation modeling combined with thermal analysis further constrained by seismic data. We then compute the 3D gravity effect of the resulting lithospheric structure to separate the measured Bouguer anomaly into its regional and local components. Finally we invert the residual gravity anomalies to highlight lateral average crustal density variations and discuss them in terms of crustal structures. Our results show that for the majority of the study area the crustal thickness does correlate with the regional topography pattern. The highest topography – above 1500m – shows thicknesses above 44km with local values up to 48km. Crustal thicknesses in the range of 36–40km are obtained in the uplifted Alpine areas while a thinner crust is observed in sedimentary basins and in the Iberian Massif (30 to 35km) with the exception of SW Iberia region where the crust thins from 30 to 28km. Thick lithosphere – above 140km – is found along the Pyrenees, the Cantabrian Mountains, the Iberian Chain and in the Betics while the thinnest lithosphere is found in SW Iberia (90km). 3D inversion of residual anomalies show that for the majority of the area the average density of the crust is in the range of 2810±10kgm−3. The denser crust is found in the NW and SW regions of the Iberian Massif (+30kgm−3 on average) and locally in the Pyrenees (above +70kgm−3), NW of the Iberian Chain (+15kgm−3 on average) and in the southern Internal Betics (+70kgm–3). The least dense crust is found in the central and western Betic Chain (−30kgm−3 on average) and in sedimentary basin depocenters.
•3D Lithospheric structure of the Iberian Peninsula and crustal density variations•The Variscan domain is characterized by a relatively flat Moho and a thin lithosphere.•The Alpine domain shows a more variable Moho relief and a thicker lithosphere.•Denser crust in the Iberian Massif and locally in the Pyrenees and Iberian Chain•Least dense crust in the Betics and in sedimentary basin depocenters
Abstract Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been ...separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types ( p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.
We use thermodynamically self-consistent and hybrid methods to analyze the correlation of important physical parameters (e.g. bulk density, elastic moduli) with bulk Mg# and modal composition in ...mantle peridotites at upper mantle conditions. Temperature (anharmonic and anelastic), pressure and compositional derivatives for all these parameters are evaluated. The results show that the widely used correlations between Vp/Vs and Mg# in peridotites are strictly valid only for garnet-bearing assemblages at temperatures <
900
°C. The correlation breaks down when: i) spinel is the stable Al-rich phase in the assemblage and ii) when anelastic attenuation of seismic velocities becomes important (
T
≳
900
°C). This implies that the range of applicability of published Vp/Vs–Mg# correlations for the upper mantle is limited to a depth interval between the spinel–garnet phase transition and the 900
°C isotherm. We use numerical simulations to show that this depth interval is virtually nonexistent in lithospheres thinner than ∼
140
km and can comprise up to ∼
50% of the lithospheric mantle in thick (>
220
km) lithospheric domains. In addition, we show that for most of the upper mantle the expected Δ(Vp/Vs) values associated with compositional variations are smaller than the resolution limit of current seismological methods. All these considerations suggest that the Vp/Vs ratio is not a reliable measure of compositional variations and that for large parts of the upper mantle compositional anomalies cannot be separated from thermal anomalies on the basis of seismological studies only. We further confirm that the only reliable indicator of compositional anomalies in a peridotitic mantle is the ratio of density to shear wave velocities (
ρ/Vs). Our results demonstrate that geophysical–petrological models (forward or inverse) that model these two fields (i.e. density and Vs) self-consistently within a robust thermodynamic framework are necessary for characterizing the small-scale thermal and compositional structure of the lithosphere and sublithospheric upper mantle.
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