| 1. |
- Allison, S. L., et al.
(författare)
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Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum
- 2019
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an “AD signature” composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). Methods: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. Results: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112–0.298) and A + T+ CU groups (Cliff's deltas = 0.212–0.731). Conclusions: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature. © 2019
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| 2. |
- Dumitrescu, L., et al.
(författare)
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Sex differences in the genetic predictors of Alzheimer's pathology
- 2019
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 142, s. 2581-2589
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Tidskriftsartikel (refereegranskat)abstract
- Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 x 10(-8)) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 x 10(-8)) but not females (P = 0.85, sex-interaction P = 2.9 x 10(-4)). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
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| 3. |
- 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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| 4. |
- Law, L. L., et al.
(författare)
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Cardiorespiratory Fitness Modifies Influence of Sleep Problems on Cerebrospinal Fluid Biomarkers in an At-Risk Cohort
- 2019
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 69:1, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer's disease (AD) pathophysiology, including reduced amyloid-beta (A beta) and tau pathology. However, few studies have examined CRF and sleep in the same analysis. Objective: To examine the relationship between sleep and core AD cerebrospinal fluid (CSF) biomarkers among at-risk healthy late-middle-aged adults and determine whether CRF modifies this association. Methods: Seventy-four adults (age = 64.38 +/- 5.48, 68.9% female) from the Wisconsin Registry for Alzheimer's Prevention participated. Sleep was evaluated using the Medical Outcomes Study Sleep Scale, specifically the Sleep Problems Index I (SPI), which incorporates domains of sleep disturbance, somnolence, sleep adequacy, and shortness of breath. Higher scores indicate greater sleep problems. To assess CRF, participants underwent a graded exercise test. CSF was collected via lumbar puncture, from which A beta(42), total-tau (t-tau), and phosphorylated-tau (p-tau) were immunoassayed. Regression analyses examined the association between SPI and CSF biomarkers, and the interaction between SPI and CRF on these same biomarkers, adjusting for relevant covariates. Results: Higher SPI scores were associated with greater p-tau (p = 0.027) and higher t-tau/A beta(42) (p = 0.021) and p-tau/A beta(42) (p = 0.009) ratios. Analyses revealed significant SPI*CRF interactions for t-tau (p = 0.016), p-tau (p = 0.008), and p-tau/A beta(42)(p = 0.041); with a trend for t-tau/A beta(42) (p = 0.061). Specifically, the relationship between poorer sleep and these biomarkers was significant among less fit individuals, but not among those who were more fit. Conclusion: In a late-middle-aged at-risk cohort, CRF attenuated the association between poor sleep and levels of select CSF biomarkers. This suggests fitness may play an important role in preventing AD by protecting against pathology, even in impaired sleep.
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| 5. |
- Merluzzi, A. P., et al.
(författare)
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Differential effects of neurodegeneration biomarkers on subclinical cognitive decline
- 2019
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Ingår i: Alzheimer's and Dementia: Translational Research and Clinical Interventions. - : Wiley. - 2352-8737. ; 5, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurodegeneration appears to be the biological mechanism most proximate to cognitive decline in Alzheimer's disease. We test whether t-tau and alternative biomarkers of neurodegeneration—neurogranin and neurofilament light protein (NFL)—add value in predicting subclinical cognitive decline. Methods: One hundred fifty cognitively unimpaired participants received a lumbar puncture for cerebrospinal fluid and at least two neuropsychological examinations (mean age at first visit = 59.3 ± 6.3 years; 67% female). Linear mixed effects models were used with cognitive composite scores as outcomes. Neurodegeneration interactions terms were the primary predictors of interest: age × NFL or age × neurogranin or age × t-tau. Models were compared using likelihood ratio tests. Results: Age × NFL accounted for a significant amount of variation in longitudinal change on preclinical Alzheimer's cognitive composite scores, memory composite scores, and learning scores, whereas age × neurogranin and age × t-tau did not. Discussion: These data suggest that NFL may be more sensitive to subclinical cognitive decline compared to other proposed biomarkers for neurodegeneration. © 2019
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