Diffusion tensor imaging (DTI) is used to study tissue composition and architecture
in vivo. To increase the signal to noise ratio (SNR) of DTI contrasts, studies typically use more than the minimum ...of 6 diffusion weighting (DW) directions or acquire repeated observations of the same set of DW directions. Simulation-based studies have sought to optimize DTI acquisitions and suggest that increasing the directional resolution of a DTI dataset (i.e., the number of distinct directions) is preferable to repeating observations, in an equal scan time comparison. However, it is not always clear how to translate these recommendations into practice when considering physiological noise and scanner stability. Furthermore, the effect of different DW schemes on
in vivo DTI findings is not fully understood. This study characterizes how the makeup of a DW scheme, in terms of the number of directions, impacts the precision and accuracy of
in vivo fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) findings. Orientation dependence of DTI reliability is demonstrated
in vivo and a principled theoretical framework is provided to support and interpret findings with simulation results. As long as sampling orientations are well balanced, differences in DTI contrasts due to different DW schemes are shown to be small relative to intra-session variability. These differences are accentuated at low SNR, while minimized at high SNR. This result suggests that typical clinical studies, which use similar protocols but different well-balanced DW schemes, are readily comparable within the experimental precision.
Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols ...for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan–rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22–61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1–5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols.
► Presents and evaluates a 60-min multi-parametric imaging protocol at 3T. ► Assesses brain function, structural, micro-architecture, and quantitative parameters. ► Tabulates intensity, variability, and reproducibility of MR contrasts. ► Provides a resource for study planning and algorithm optimization. ► Establishes a baseline for development multi-parametric imaging protocols.
Serum Lipid Levels and Cognitive Change in Late Life Reynolds, Chandra A.; Gatz, Margaret; Prince, Jonathan A. ...
Journal of the American Geriatrics Society,
March 2010, Letnik:
58, Številka:
3
Journal Article
Recenzirano
Odprti dostop
OBJECTIVES: To assess the effect of lipids and lipoproteins on longitudinal cognitive performance and cognitive health in late life and to consider moderating factors such as age and sex that may ...clarify conflicting prior evidence.
DESIGN: Prospective cohort study.
SETTING: A 16‐year longitudinal study of health and cognitive aging.
PARTICIPANTS: Eight hundred nineteen adults from the Swedish Adoption Twin Study of Aging aged 50 and older at first cognitive testing, including 21 twin pairs discordant for dementia.
MEASUREMENTS: Up to five occasions of cognitive measurements encompassing verbal, spatial, memory, and perceptual speed domains across a 16‐year span; baseline serum lipids and lipoproteins including high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein (apo)A1, apoB, total serum cholesterol, and triglycerides.
RESULTS: The effect of lipids on cognitive change was most evident before age 65. In women, higher HDL‐C and lower apoB and triglycerides predicted better maintenance of cognitive abilities, particularly verbal ability and perceptual speed, than age. Lipid values were less predictive of cognitive trajectories in men and, where observed, were in the contrary direction (i.e., higher total cholesterol and apoB values predicted better perceptual speed performance though faster rates of decline). In twin pairs discordant for dementia, higher total cholesterol and apoB levels were observed in the twin who subsequently developed dementia.
CONCLUSION: High lipid levels may constitute a more important risk factor for cognitive health before age 65 than after. Findings for women are consistent with clinical recommendations, whereas for men, the findings correspond with earlier age‐associated shifts in lipid profiles and the importance of lipid homeostasis to cognitive health.
A fundamental question in human genetics is the degree to which the polygenic character of complex traits derives from polymorphism in genes with similar or with dissimilar functions. The many ...genome-wide association studies now being performed offer an opportunity to investigate this, and although early attempts are emerging, new tools and modeling strategies still need to be developed and deployed. Towards this goal, we implemented a new algorithm to facilitate the transition from genetic marker lists (principally those generated by PLINK) to pathway analyses of representational gene sets in either threshold or threshold-free downstream applications (e.g. DAVID, GSEA-P, and Ingenuity Pathway Analysis). This was applied to several large genome-wide association studies covering diverse human traits that included type 2 diabetes, Crohn's disease, and plasma lipid levels. Validation of this approach was obtained for plasma HDL levels, where functional categories related to lipid metabolism emerged as the most significant in two independent studies. From analyses of these samples, we highlight and address numerous issues related to this strategy, including appropriate gene based correction statistics, the utility of imputed versus non-imputed marker sets, and the apparent enrichment of pathways due solely to the positional clustering of functionally related genes. The latter in particular emphasizes the importance of studies that directly tie genetic variation to functional characteristics of specific genes. The software freely provided that we have called ProxyGeneLD may resolve an important bottleneck in pathway-based analyses of genome-wide association data. This has allowed us to identify at least one replicable case of pathway enrichment but also to highlight functional gene clustering as a potentially serious problem that may lead to spurious pathway findings if not corrected.
Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by ...pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8
T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab.
Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.
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The combination of venetoclax and hypomethylating agent (HMA/venetoclax) has emerged as a treatment option for patients with de novo acute myeloid leukemia (AML) who are unfit to receive intensive ...chemotherapy. In this single-center retrospective study, we evaluated clinical outcomes following treatment with HMA/venetoclax in 35 patients with advanced myeloproliferative neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes or AML with extramedullary disease. The composite complete remission (CR) rate (including confirmed/presumed complete cytogenetic response, acute leukemia response-complete, CR and CR with incomplete hematologic recovery) was 42.9% with median overall survival (OS) of 9.7 months. Complex karyotype was associated with inferior median OS (3.7 versus 12.2 months; p = 0.0002) and composite CR rate (22% versus 50.0%; p = 0.2444). Although SRSF2 mutations were associated with higher composite CR rate (80.0% versus 28.0%; p = 0.0082), this was not associated with longer median OS (10.9 versus 8.0 months; p = 0.2269). Future studies should include these patient subgroups.
Apolipoprotein E ε4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion (I)/deletion (D) polymorphism (indel) of ...the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age, ethnic group, and carrier status of the apolipoprotein E ε4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction warrants further investigation.
Identifying biological pathways that vary across the age spectrum can provide insight into fundamental mechanisms that impact disease and frailty in the elderly. Few methodological approaches offer ...the means to explore this question on as broad a scale as gene expression profiling. Here, we have evaluated mRNA expression profiles as a function of age in two populations; one consisting of 191 individuals with ages-at-death ranging from 65-100 years and with post-mortem brain mRNA measurements of 13,216 genes and a second with 1240 individuals ages 15-94 and lymphocyte mRNA estimates for 18,519 genes.
Among negatively correlated transcripts, an enrichment of mitochondrial genes was evident in both populations, providing a replication of previous studies indicating this as a common signature of aging. Sample differences were prominent, the most significant being a decrease in expression of genes involved in translation in lymphocytes and an increase in genes involved in transcription in brain, suggesting that apart from energy metabolism other basic cell processes are affected by age but in a tissue-specific manner. In assessing genomic architecture, intron/exon sequence length ratios were larger among negatively regulated genes in both samples, suggesting that a decrease in the expression of non-compact genes may also be a general effect of aging. Variance in gene expression itself has been theorized to change with age due to accumulation of somatic mutations and/or increasingly heterogeneous environmental exposures, but we found no evidence for such a trend here.
Results affirm that deteriorating mitochondrial gene expression is a common theme in senescence, but also highlight novel pathways and features of gene architecture that may be important for understanding the molecular consequences of aging.
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