Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective ...cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention.
The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets.
In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected.
The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration.
German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.
Background
Neuroimaging markers based on MRI often provide better prediction than traditional neuropsychological scores. With advancements of machine learning, data patterns may offer opportunities ...to personalize clinical practice that leads to better outcomes for patients at risk of dementia such as Alzheimer’s disease (AD) (Davatzikos et al., 2019). AD is a multifactorial process associated with ageing, brain atrophy, genes, proteins, vascular risk, and brain state activity (Frisoni et al., 2010). These processes do covary and interact in a complex fashion which needs to be accounted when aiming at predicting clinical outcomes for staging and stratification of disease‐modifying treatments.
Method
In our probabilistic predictive framework we focus on data from the DZNE DELCODE cohort (Jessen et al., 2018) consisting of T1‐weighted and FLAIR images to assess distributed patterns of Voxel‐based Morphometry (VBM) and White Matter Lesions for 929 subjects; subject‐specific demographics (age, sex, education) and available CSF biomarkers for 438 subjects. We developed a machine learning framework for brain‐based predictions of (A) memory performance (Wolfsgruber et al., 2020) and (B) CSF Amyloid 42/40 and p‐tau biomarker status using a Gaussian process multi‐kernel (GP‐MKL) learning approach (Rasmussen & Williams, 2006). The proposed GP‐MKL model combines multiple features (atrophy patterns, demographics age, sex, education, white matter lesions volume & apoe4) expected to characterize the transition from healthy ageing towards dementia in terms of cognitive symptoms and biomarker status (Figure 1). We evaluate predictive models and different feature combinations using 10‐fold cross‐validation.
Result
The framework enabled optimal individual prediction of memory performance (highest correlation true vs. predicted of r = 0.751 ± 0.082, R2 = 0.56, Fig. 2) using a combination of demographics, brain tissue segments (GM & CSF) & CSF biomarkers (Aß42/40 & p‐tau). When estimating the CSF biomarker positivity, the AUC‐ROC score achieved 0.735 for Aß42/40 (Fig. 4A) and 0.802 for p‐tau (Fig. 4B) using a combination of brain tissue segments (GM & CSF), demographics, and cognitive testing.
Conclusion
In conclusion, multiple domains and imaging facets contribute to reliable estimation of individual cognitive memory performance and biomarker positivity in dementia and enable promising predictive technologies for staging and treatment stratification.
Background
The NIA‐AA proposed ATN (Amyloid/Tau/Neurodegeneration) as a classification system for AD pathology. The Amyloid Cascade Hypothesis (ACH) implies a sequence across ATN groups that patients ...might undergo during transition from healthy towards AD: A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (Amyloid‐conversion first, Tau‐conversion second, N‐conversion last; therefore ‘ATN’) and alternative progressions (ANT, TAN, TNA, NAT, NTA) using Voxel‐based Morphometry (VBM) of brain anatomy in a large MRI sample.
Method
We used the DELCODE cohort of 437 subjects (49% female) which underwent lumbar puncture, MRI scanning and neuropsychological assessment. ATN classification was performed using (A+/‐) CSF‐Abeta42over40, (T+/‐) CSF‐phospho‐Tau, and (N+/‐) adjusted hippocampal volume. We compared voxel‐based model evidence for monotonic decline of gray matter volume across various sequences over ATN groups accounting for age, sex, education, TIV and WMH. The evidence of each progression was assessed using the Bayesian Information Criterion on voxel‐ and ROI‐level. First, face validity of the ACH transition trajectory A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ for VBM was compared against 23 biologically less plausible (permuted) sequences among AD‐continuum ATN groups. Then we evaluated the evidence for 6 brain volume progressions from A‐T‐N‐ towards A+T+N+ (ATN, ANT, TAN, TNA, NAT, NTA) including also non‐AD continuum ATN groups.
Result
The ACH‐based progression A‐T‐N‐→A+T‐N‐→A+T+N‐→A+T+N+ is in line with cognitive decline and clinical diagnosis (Figure 1&2). It also has highest evidence in 9% of the gray matter voxels (especially MTL; Figure 3&4). Many (especially cortical) regions were compatible with alternative non‐monotonic volume progressions (‘AP 1’: 16%, ‘AP 2’: 14%; see Figure 3) over ACH progression sequence, compatible with early amyloid‐related tissue expansion or sampling effects due to brain‐reserve (Figure 5). Volume decline in 65% of voxels was more compatible with ATN/ANT progression (A flips first) when compared to alternative sequences (TAN, TNA, NAT, NTA).
Conclusion
Early Amyloid status conversion (before Tau and Neurodegeneration) is compatible with brain volume loss observed during AD progression. The ATN classification and the ACH are compatible with monotonic progress of MTL atrophy.
BACKGROUNDThe efficacy of drug-eluting stents (DES) for the treatment of in-stent restenosis (ISR) after DES implantation is not well defined. This study compared the clinical outcome after the use ...of everolimus-eluting stents (EES) for the treatment of bare-metal stent (BMS) versus DES restenosis.
METHODNinety-four patients with 94 ISR were included in this study. Sixty-four patients had BMS-ISR and 30 patients had DES-ISR. Patients were treated by repeat PCI using an EES. The primary endpoint of the study was survival free of target lesion revascularization (TLR) at 12 months or DES-ISR versus BMS-ISR patients. The secondary endpoints were survival free of major adverse cardiac events (MACE) and definite stent thrombosis.
RESULTSThe baseline clinical and angiographic parameters were comparable between the two groups. Treatment of DES-ISR was associated with higher rates of recurrent TLR, myocardial infarction (MI), and MACE at the 12-month follow-up compared with the treatment of BMS-ISR (23.3 versus 1.6%, P=0.002 for TLR; 13.3 versus 0%, P=0.017 for MI; and 30 versus 4.6%, P=0.003 for MACE). There were no differences in mortality and definite stent thrombosis between both groups (P=0.5686 and 0.6927, respectively). Initial stent number (odds ratio=1.13, 95% confidence interval 1.02–1.25; P=0.024) and initial stent type being a DES (odds ratio=8.11, 95% confidence interval 5.99–10.45; P<0.001) were independent predictors of recurrent TLR after the treatment of ISR using an EES.
CONCLUSIONEES used for the treatment of DES-ISR is associated with higher rates of recurrent revascularization, MI, and MACE compared with EES for the treatment of BMS-ISR.
First-generation drug-eluting stents have been proved to be very effective for the treatment of bare metal stent in-stent restenosis (BMS ISR). The efficacy of second-generation drug-eluting stents ...in this setting remains less well defined. The present study compared the long-term clinical outcome after treatment of BMS ISR using the second-generation everolimus-eluting stent (EES) to that after treatment using the paclitaxel-eluting stent (PES). A total of 174 patients with BMS ISR underwent percutaneous coronary intervention using a PES (95 patients) or an EES (79 patients) from 2003 to 2010. The patients in the PES and EES groups were followed up for 42.2 ± 22.2 and 18.3 ± 8.2 months, respectively. The primary end point of the study was survival free of major adverse cardiac events at 1 year. The secondary end points were survival free of the need for revascularization of the target lesion and definite stent thrombosis. The baseline clinical and angiographic parameters were comparable between the 2 groups. The freedom from major adverse cardiac event rate at 1 year of follow-up was 4.5% and 13.6% (p = 0.0663) for the EES and PES groups, respectively. The target lesion revascularization (TLR) rates were greater in the PES group at 1 year of follow-up compared to the EES group (1% vs 11.5%, p = 0.0193). The rate of myocardial infarction, death, and definite stent thrombosis for the EES and PES groups at 1 year of follow-up was 0% versus 4.2% (p = 0.0984), 3% versus 2.1% (p = 0.6855), and 0% versus 2.1% (p = 0.2382), respectively. The use of a PES for treatment of ISR was the only independent predictor of recurrent TLR at 1 year of follow-up (odds ratios 1.11, 95% confidence interval 1.05 to 1.18; p = 0.0193). During the complete follow-up period, the rates of TLR, myocardial infarction, death, major adverse cardiac events, and definite stent thrombosis were not different between the 2 treatment groups. In conclusion, EES resulted in reduced rates of TLR at 1 year of follow-up compared to PES when used for treatment of BMS ISR. However, at long-term follow-up, the event rates between EES and PES were comparable after treatment of BMS ISR.
AIMSFirst-generation drug-eluting stents have been proven to be very effective for the treatment of bare-metal stent in-stent restenosis (BMS ISR). Efficacy of second-generation drug-eluting stents ...in this setting remains less well defined. This study compared 3-year clinical outcomes after treatment of BMS ISR using second-generation everolimus-eluting stents (EES) to first-generation paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES).
METHODSThis was a retrospective observational study. A total of 264 consecutive patients with BMS ISR underwent percutaneous coronary intervention using EES (75 patients), PES (95 patients), or SES (94 patients) from 2003 to 2009. The primary endpoint of the study was survival free of major adverse cardiac events (MACE) at 3 years. Secondary endpoints were survival free of need for revascularization of the target lesion and definite stent thrombosis. Clinical follow-up could be obtained in 99% of patients.
RESULTSBaseline clinical and angiographic parameters were comparable between the three groups. MACE at the 3-year follow-up were 27, 30, and 27%, for the EES, PES, and SES groups, respectively (P=0.874). The target lesion revascularization rates for EES, PES, and SES groups were 15, 20, and 23%, respectively (P=0.429). Rates of definite stent thrombosis at the 3-year follow-up were comparable between the three groups at 0, 2.1, and 1.0%, respectively (P=0.437). Rates of myocardial infarction and death were also similar between the three groups. Diabetes mellitus was the only independent predictor of MACE at the 3-year follow-up (odds ratio=1.14, 95% confidence interval 1.00–1.30; P=0.038), whereas renal insufficiency was the only independent predictor for death (odds ratio=1.10, 95% confidence interval 0.850–1.274; P=0.011).
CONCLUSIONSecond-generation EES is as effective and safe as the first-generation PES or SES in the treatment of BMS ISR. Diabetes mellitus is the only independent predictor for MACE at the long-term follow-up.
Background: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. ...Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. Methods: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets. Results: In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF A beta 42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected. Conclusions: The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF A beta 42 concentration.
The continental settings of Central Asia witnessed increased desertification during the Cenozoic as a result of mountain uplift and the Paratethys retreat. The interaction of these tectonic‐scale ...processes with orbitally forced climate change and their influence on Asia's atmospheric moisture distribution are poorly constrained. A Miocene succession of continental mudflat deposits, exposed in the Aktau Mountains (Ili Basin, south‐east Kazakhstan), has great potential as a terrestrial palaeoclimate archive. About 90 m of the 1700 m thick succession comprise alluvial mudflat deposits and appear as cyclic alternation of coarse sheet floods, mudflat fines and semi‐arid hydromorphic soils. In this study, bulk‐sediment mineralogy and geochemistry, magnetic susceptibility, sediment colour and palynology are used to reconstruct environmental conditions by determining changes and forcing mechanisms in the intensity of sediment discharge, weathering and pedogenesis. The results presented here indicate four major periods of arid soil formation and one palustrine interval characterized by higher evaporation rates under highly alkaline/saline conditions. A positive correlation between weathering indices and the Mg/Al ratio suggest that these horizons correspond to maximum rates of evapotranspiration and aridity. The formation of mudflat fines is, instead, interpreted as representing higher detrital sediment production by more intense alluvial fan activity during times of higher precipitation. Time series analysis of weathering indices, colour and magnetic susceptibility data yields cycle‐to‐frequency ratios with the potential to represent Milankovitch cyclicity with short and long eccentricity as dominant periodicities. Periods of pronounced aridity, paced by long eccentricity forcing, reflect changes in moisture availability. On longer tectonic timescales, the persistent appearance of gypsum indicates a shift towards more arid conditions. This trend in climate is considered to result from the closure of the eastern gateway of the Mediterranean to the Indian Ocean that restricted circulation and enhanced salinity within the Eastern Paratethys.
The effects of Cenozoic orbitally forced climatic change on Central Asia's atmospheric moisture distribution are not well constrained so far. Here, we study a Miocene succession of continental mudflat deposits in SE Kazakhstan to reconstruct environmental conditions affecting the intensity of sediment discharge, weathering and pedogenesis by an integrated approach of bulk‐sediment mineralogy and geochemistry, magnetic susceptibility, sediment colour and palynology. We identified periods of pronounced aridity to be paced by long eccentricity reflecting changes in moisture availability. On tectonic time scales, a climatic shift towards more aridity was probably caused by restriction within the Eastern Paratethys.
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