Dataset Information

Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.

ABSTRACT:

Background

Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer's disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and other limbic and paralimbic areas. We further hypothesized that AD PRSs would affect the microstructure of fiber tracts connecting the hippocampus with other brain areas.

Methods

We analyzed the association between AD PRSs and brain imaging parameters using T1-weighted structural (n = 272) and diffusion-weighted scans (n = 197).

Results

We found a significant association between AD PRSs and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p = .001). This effect remained when the APOE gene was excluded (p = .031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors and not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRSs (p = .009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults.

Conclusions

This finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD.

SUBMITTER: Foley SF

PROVIDER: S-EPMC5177726 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.

Foley Sonya F SF Tansey Katherine E KE Caseras Xavier X Lancaster Thomas T Bracht Tobias T Parker Greg G Hall Jeremy J Williams Julie J Linden David E J DE

Biological psychiatry 20160316 2

<h4>Background</h4>Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer's disease (AD). Because neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesized that higher polygenic risk scores (PRSs) for AD would be associated with reduced volume of the hippocampus and ...[more]

PMID: 27157680

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Project description:BACKGROUND:Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk. METHODS:We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation). RESULTS:MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses. CONCLUSIONS:Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.

Project description:Generalized joint hypermobility (GJH), in the absence of symptoms, is a common clinical finding. The joint instability present due to excessive musculoskeletal flexibility in hypermobile joints impairs the external force production during muscle contraction. However, whether GJH is associated with muscle weakness is unclear. This study evaluated differences in upper and lower limb muscle strengths among asymptomatic young adults with and without GJH.One hundred six young adults (53 hypermobile, i.e. 25 male (mean age 22 ± 1.8); 28 female (mean age 21 ± 1.8), and 53 non-hypermobile, i.e. 25 male (mean age 19 ± 1.06); 28 female (mean age 20 ± 1.4) were selected using a cut-off ≥ 4 on Beighton and Horan Joint Mobility Index. Isometric strength of elbow and knee extensors was measured using an isokinetic dynamometer. Independent sample t- tests were done to compare the muscle strengths of hypermobile and non-hypermobile participants. One-way ANCOVA was applied to control the effect of height and body mass on muscle strength.Male hypermobile participants had significantly less strength than non-hypermobile males in the right (71.7 Nm, SD = 23.1, vs 97.6 Nm, SD = 47.4, p = 0.006*) and left (74.8 Nm, SD = 24.3, vs 97.7 Nm, SD = 45.5, p = 0.007*) elbow extensors and right knee extensors (188.7 Nm, SD = 83.3, vs 228.3 Nm, SD = 106.7, p = 0.03*). In females, both elbow extensors (right: 51.9 Nm, SD = 16.2 vs 48.8 Nm, SD = 17.8, p = 0.4; left: 48.9 Nm, SD = 17.2, vs 44.7 Nm, SD = 15.1, p = 0.2) and knee extensors (right: 161.3 Nm, SD = 74.9 vs 145.5 Nm, SD = 75.8, p = 0.3; left: 155.2 Nm, SD = 73 vs 124.3 Nm, SD = 69.6, p = 0.07) strength were not statistically different between hypermobile and non-hypermobile participants.The findings indicate that male participants with GJH have less isometric muscle strength in both elbow extensors and right knee extensors compared to non-hypermobile male participants. Female hypermobile participants did not show any significant differences in muscle strength compared to non-hypermobile female participants.

Dataset Information

Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.

Background

Methods

Results

Conclusions

Publications

Multimodal Brain Imaging Reveals Structural Differences in Alzheimer's Disease Polygenic Risk Carriers: A Study in Healthy Young Adults.

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