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| 5. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 6. |
- Starks, E. J., et al.
(författare)
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Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOE epsilon 4 Carriers
- 2015
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 46:2, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Background: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. Objective: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. Method: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: A beta(42), P-Tau(181), and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOE epsilon 4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF A beta 42. Results: No significant main effects of HOMA-IR on P-Tau181, T-Tau, or A beta 42 were observed; however, significant interactions were observed between HOMA-IR and APOE epsilon 4 on CSF markers related to tau. Among APOE epsilon 4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOE epsilon 4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on A beta 42 levels in CSF. Conclusion: IR among asymptomatic APOE epsilon 4 carriers was associated with higher P-Tau(181) and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.
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| 7. |
- Naylor, Mary D, et al.
(författare)
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Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.
- 2012
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 8:5, s. 445-52
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Tidskriftsartikel (refereegranskat)abstract
- To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.
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| 8. |
- Darst, B. F., et al.
(författare)
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Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-beta Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease
- 2017
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 55:2, s. 473-484
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-beta (A beta) deposition and neurodegeneration: A beta clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral A beta deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid A beta deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.
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| 10. |
- Yang, H., et al.
(författare)
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Preliminary Characterization of Submarine Basalt Magnetic Mineralogy Using Amplitude-Dependence of Magnetic Susceptibility
- 2024
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Ingår i: Geochemistry, Geophysics, Geosystems. - 1525-2027. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- The past ∼200 million years of Earth's geomagnetic field behavior have been recorded within oceanic basalts, many of which are only accessible via scientific ocean drilling. Obtaining the best possible paleomagnetic measurements from such valuable samples requires an a priori understanding of their magnetic mineralogies when choosing the most appropriate protocol for stepwise demagnetization experiments (either alternating field or thermal). Here, we present a quick, and non-destructive method that utilizes the amplitude-dependence of magnetic susceptibility to screen submarine basalts prior to choosing a demagnetization protocol, whenever conducting a pilot study or other detailed rock-magnetic characterization is not possible. We demonstrate this method using samples acquired during International Ocean Discovery Program Expedition 391. Our approach is rooted in the observation that amplitude-dependent magnetic susceptibility is observed in basalt samples whose dominant magnetic carrier is multidomain titanomagnetite (∼TM60–65, (Ti0.60–0.65Fe0.35–0.40)Fe2O4). Samples with low Ti contents within titanomagnetite or samples that have experienced a high degree of oxidative weathering do not display appreciable amplitude dependence. Due to their low Curie temperatures, basalts that possess amplitude-dependence should ideally be demagnetized either using alternating fields or via finely-spaced thermal demagnetization heating steps below 300°C. Our screening method can enhance the success rate of paleomagnetic studies of oceanic basalt samples.
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| 11. |
- Almeida, R. P., et al.
(författare)
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Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease
- 2015
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 72:6, s. 699-706
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. OBJECTIVE To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which A beta 42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/A beta 42 and p-tau/A beta 42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013. MAIN OUTCOMES AND MEASURES Cerebrospinal fluid levels of A beta 42, t-tau, p-tau, t-tau/A beta 42, and p-tau/A beta 42. RESULTS There were significant age x CR interactions for CSF t-tau (beta [SE] = -6.72 [2.84], P = .02), p-tau (beta [SE] = -0.71 [0.27], P = .01), t-tau/A beta 42 (beta [SE] = -0.02 [0.01], P = .02), and p-tau/A beta 42 (beta [SE] = -0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. CONCLUSIONS AND RELEVANCE In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.
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| 12. |
- Erickson, C. M., et al.
(författare)
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KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:16
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Tidskriftsartikel (refereegranskat)abstract
- Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated beta-amyloid (A beta) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on A beta burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on A beta was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater A beta burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on A beta load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0.001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher A beta burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated A beta aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.
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| 13. |
- Hoy, A. R., et al.
(författare)
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Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging
- 2017
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While beta-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years) from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE epsilon 4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI.
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| 15. |
- Berntsen, Peter, 1974, et al.
(författare)
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Biomechanical effects of environmental and engineered particles on human airway smooth muscle cells
- 2010
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 7:Suppl 3
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Tidskriftsartikel (refereegranskat)abstract
- The past decade has seen significant increases in combustion-generated ambient particles, which contain a nanosized fraction (less than 100 nm), and even greater increases have occurred in engineered nanoparticles (NPs) propelled by the booming nanotechnology industry. Although inhalation of these particulates has become a public health concern, human health effects and mechanisms of action for NPs are not well understood. Focusing on the human airway smooth muscle cell, here we show that the cellular mechanical function is altered by particulate exposure in a manner that is dependent upon particle material, size and dose. We used Alamar Blue assay to measure cell viability and optical magnetic twisting cytometry to measure cell stiffness and agonist-induced contractility. The eight particle species fell into four categories, based on their respective effect on cell viability and on mechanical function. Cell viability was impaired and cell contractility was decreased by (i) zinc oxide (40-100 nm and less than 44 mu m) and copper(II) oxide (less than 50 nm); cell contractility was decreased by (ii) fluorescent polystyrene spheres (40 nm), increased by (iii) welding fumes and unchanged by (iv) diesel exhaust particles, titanium dioxide (25 nm) and copper(II) oxide (less than 5 mu m), although in none of these cases was cell viability impaired. Treatment with hydrogen peroxide up to 500 mu M did not alter viability or cell mechanics, suggesting that the particle effects are unlikely to be mediated by particle-generated reactive oxygen species. Our results highlight the susceptibility of cellular mechanical function to particulate exposures and suggest that direct exposure of the airway smooth muscle cells to particulates may initiate or aggravate respiratory diseases.
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| 16. |
- Schultz, Stephanie A, et al.
(författare)
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Cardiorespiratory Fitness Attenuates the Influence of Amyloid on Cognition.
- 2015
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Ingår i: Journal of the International Neuropsychological Society : JINS. - 1469-7661. ; 21:10, s. 841-50
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD. (JINS, 2015, 21, 841-850).
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| 17. |
- Thoram, S., et al.
(författare)
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Nature and Origin of Magnetic Lineations Within Valdivia Bank : Ocean Plateau Formation by Complex Seafloor Spreading
- 2023
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Ingår i: Geophysical Research Letters. - 0094-8276. ; 50:13
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Tidskriftsartikel (refereegranskat)abstract
- Valdivia Bank (VB) is a Late Cretaceous oceanic plateau formed by volcanism from the Tristan-Gough hotspot at the Mid-Atlantic Ridge (MAR). To better understand its origin and evolution, magnetic data were used to generate a magnetic anomaly grid, which was inverted to determine crustal magnetization. The magnetization model reveals quasi-linear polarity zones crossing the plateau and following expected MAR paleo-locations, implying formation by seafloor spreading over ∼4 Myr during the formation of anomalies C34n-C33r. Paleomagnetism and biostratigraphy data from International Ocean Discovery Program Expedition 391 confirm the magnetic interpretation. Anomaly C33r is split into two negative bands, likely by a westward ridge jump. One of these negative anomalies coincides with deep rift valleys, indicating their age and mechanism of formation. These findings imply that VB originated by seafloor spreading-type volcanism during a plate reorganization, not from a vertical stack of lava flows as expected for a large volcano.
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| 18. |
- Wang, Rui, et al.
(författare)
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Impact of sex and APOE ε4 on age-related cerebral perfusion trajectories in cognitively asymptomatic middle-aged and older adults : A longitudinal study.
- 2021
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 41:11, s. 3016-3027
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral hypoperfusion is thought to contribute to cognitive decline in Alzheimer's disease, but the natural trajectory of cerebral perfusion in cognitively healthy adults has not been well-studied. This longitudinal study is consisted of 950 participants (40-89 years), who were cognitively unimpaired at their first visit. We investigated the age-related changes in cerebral perfusion, and their associations with APOE-genotype, biological sex, and cardiometabolic measurements. During the follow-up period (range 0.13-8.24 years), increasing age was significantly associated with decreasing cerebral perfusion, in total gray-matter (β=-1.43), hippocampus (-1.25), superior frontal gyrus (-1.70), middle frontal gyrus (-1.99), posterior cingulate (-2.46), and precuneus (-2.14), with all P-values < 0.01. Compared with male-ɛ4 carriers, female-ɛ4 carriers showed a faster decline in global and regional cerebral perfusion with increasing age, whereas the age-related decline in cerebral perfusion was similar between male- and female-ɛ4 non-carriers. Worse cardiometabolic profile (i.e., increased blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower cerebral perfusion at all the visits. When time-varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE-ɛ4 on age-related cerebral perfusion-trajectories became largely attenuated. Our findings demonstrate that APOE-genotype and sex interactively impact cerebral perfusion-trajectories in mid- to late-life. This effect may be partially explained by cardiometabolic alterations.
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| 19. |
- Bendlin, Barbara B, et al.
(författare)
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CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.
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| 23. |
- Mielke, Michelle M, et al.
(författare)
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Cerebrospinal fluid sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer's disease.
- 2014
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 35:11, s. 2486-94
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Tidskriftsartikel (refereegranskat)abstract
- Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Aβ) and tau pathology but invivo human studies are lacking. We determined cerebrospinal fluid levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Aβ1-42, AβX-38, AβX-40, and AβX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36-69years, with a parental history of Alzheimer's disease. The 18-carbon acyl chain length ceramide species was associated with AβX-38 (r= 0.312, p= 0.003), AβX-40 (r= 0.327, p= 0.002), and T-tau (r= 0.313, p= 0.003) but not with AβX-42 (r= 0.171, p= 0.106) or p-tau (r= 0.086, p= 0.418). All sphingomyelin species correlated (most p < 0.001) with all Aβ species and T-tau; many also correlated with p-tau. Results remained in regression models after controlling for age and APOE genotype. These results suggest invivo relationships between cerebrospinal fluid ceramides and sphingomyelins and Aβ and tau levels in cognitively normal individuals at increased risk for Alzheimer's disease, indicating these sphingolipids may be associated with early pathogenesis.
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| 24. |
- Motovylyak, Alice, et al.
(författare)
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Age-related differences in white matter microstructure measured by advanced diffusion MRI in healthy older adults at risk for Alzheimer’s disease
- 2022
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric—fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO—is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer’s disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.
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| 25. |
- Schultz, Stephanie A, et al.
(författare)
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Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD.
- 2017
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Ingår i: Neurology. - 1526-632X. ; 88:17, s. 1650-1658
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Tidskriftsartikel (refereegranskat)abstract
- To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers.Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF.A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF.In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.
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