scholarly journals Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression

2021 ◽  
Author(s):  
Shady Rahayel ◽  
Christina Tremblay ◽  
Andrew Vo ◽  
Ying-Qiu Zheng ◽  
Stéphane Lehéricy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Functioning ◽  
Rem Sleep ◽  
Brain Atrophy ◽  
Brain Connectivity ◽  
Structural Connectivity ◽  
Alpha Synuclein ◽  
Tissue Deformation ◽  
Agent Based ◽  
Gba Gene

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the atrophy simulated based on brain connectivity and gene expression recreated cortical thinning (r=0.51, p=0.0007) and tissue deformation (r=0.52, p=0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive functioning, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

scholarly journals Relating Global and Local Connectome Changes to Dementia and Targeted Gene Expression in Alzheimer's Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Samar S. M. Elsheikh ◽  
Emile R. Chimusa ◽  
Nicola J. Mulder ◽  
Alessandro Crimi ◽  
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Betweenness Centrality ◽  
Brain Connectivity ◽  
Structural Connectivity ◽  
Genetic Risk Factors ◽  
Functional Connections

Networks are present in many aspects of our lives, and networks in neuroscience have recently gained much attention leading to novel representations of brain connectivity. The integration of neuroimaging characteristics and genetics data allows a better understanding of the effects of the gene expression on brain structural and functional connections. The current work uses whole-brain tractography in a longitudinal setting, and by measuring the brain structural connectivity changes studies the neurodegeneration of Alzheimer's disease. This is accomplished by examining the effect of targeted genetic risk factors on the most common local and global brain connectivity measures. Furthermore, we examined the extent to which Clinical Dementia Rating relates to brain connections longitudinally, as well as to gene expression. For instance, here we show that the expression of PLAU gene increases the change over time in betweenness centrality related to the fusiform gyrus. We also show that the betweenness centrality metric impact dementia-related changes in distinct brain regions. Our findings provide insights into the complex longitudinal interplay between genetics and brain characteristics and highlight the role of Alzheimer's genetic risk factors in the estimation of regional brain connectivity alterations.

scholarly journals Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

2019 ◽  
Author(s):  
Miruna C. Barbu ◽  
Athina Spiliopoulou ◽  
Marco Colombo ◽  
Paul McKeigue ◽  
Toni-Kim Clarke ◽  
...  
Keyword(s):  
Gene Expression ◽  
White Matter ◽  
Quantitative Trait ◽  
Brain Connectivity ◽  
Structural Connectivity ◽  
Genotype Data ◽  
Eqtl Mapping ◽  
Uk Biobank ◽  
Genome Wide

AbstractBackgroundExpression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity.MethodsUsing large-scale eQTL mapping studies, we computed 6,457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA=14,518) and mean diffusivity (NMD=14,485), representing white matter structural integrity.ResultsWe found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (βabsolute FA=0.0339-0.0453; MD=0.0308-0.0381) and individual tracts (βabsolute FA=0.0320-0.0561; MD=0.0295-0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson’s disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C).DiscussionOur findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these findings suggest it may be possible, in future, to map potential trait- and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.

scholarly journals Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability

2021 ◽  
Author(s):  
Christina Tremblay ◽  
Shady Rahayel ◽  
Andrew Vo ◽  
Filip Morys ◽  
Golia Shafiei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Atrophy ◽  
De Novo ◽  
Brain Connectivity ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Alpha Synuclein ◽  
Cell Type ◽  
Expression Of Genes

Atrophy in multiple brain regions has been reported in the early stages of Parkinson's Disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell type distribution and gene expression combine to determine the pattern of disease progression remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here we used MRI data from the Parkinson Progression Markers Initiative to test this model by mapping the progression of brain atrophy over one, two and four years and relating it to brain structural and functional connectivity, cell type expression and gene ontology enrichment analyses. In this longitudinal study, we derived atrophy progression maps for the three time points using deformation-based morphometry applied to T1-weighted MRI from 74 de novo Parkinson's Disease patients (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). After regressing out the expected age and sex effects associated with normal aging, we found that atrophy significantly progressed over two and four years in the caudate, nucleus accumbens, hippocampus, and the temporal, parietal, occipital and posterior cingulate cortex. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's Disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's Disease.

scholarly journals The Relationship Between Daily Rapid-Eye Movement Sleep and Cognitive Functioning in Older Adults

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 159-159
Author(s):  
Tiana Broen ◽  
Tomiko Yoneda ◽  
Jonathan Rush ◽  
Jamie Knight ◽  
Nathan Lewis ◽  
...  
Keyword(s):  
Older Adults ◽  
Working Memory ◽  
Cognitive Functioning ◽  
Eye Movement ◽  
Rem Sleep ◽  
Cognitive Tests ◽  
Rapid Eye Movement ◽  
Targeted Interventions ◽  
The Impact ◽  
The Relationship

Abstract Previous cross-sectional research suggests that age-related decreases in Rapid-Eye Movement (REM) sleep may contribute to poorer cognitive functioning (CF); however, few studies have examined the relationship at the intraindividual level by measuring habitual sleep over multiple days. Applying a 14-day daily diary design, the current study examines the dynamic relationship between REM sleep and CF in 69 healthy older adults (M age=70.8 years, SD=3.37; 73.9% female; 66.6% completed at least an undergraduate degree). A Fitbit device provided actigraphy indices of REM sleep (minutes and percentage of total sleep time), while CF was measured four times daily on a smartphone via ambulatory cognitive tests that captured processing speed and working memory. This research addressed the following questions: At the within-person level, are fluctuations in quantity of REM sleep associated with fluctuations in next day cognitive measures across days? Do individuals who spend more time in REM sleep on average, perform better on cognitive tests than adults who spend less time in REM sleep? A series of multilevel models were fit to examine the extent to which each index of sleep accounted for daily fluctuations in performance on next day cognitive tests. Results indicated that during nights when individuals had more REM sleep minutes than was typical, they performed better on the working memory task the next morning (estimate = -.003, SE = .002, p = .02). These results highlight the impact of REM sleep on CF, and further research may allow for targeted interventions for earlier treatment of sleep-related cognitive impairment.

scholarly journals A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

2020 ◽  
Vol 14 ◽  
Author(s):  
Mette Soerensen ◽  
Dominika Marzena Hozakowska-Roszkowska ◽  
Marianne Nygaard ◽  
Martin J. Larsen ◽  
Veit Schwämmle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cognitive Functioning ◽  
Association Study ◽  
Gene Expression Data ◽  
Monozygotic Twins ◽  
Later Life ◽  
Expression Data ◽  
Genome Wide ◽  
A Genome

scholarly journals Uncovering Statistical Links Between Gene Expression and Structural Connectivity Patterns in the Mouse Brain

2021 ◽  
Author(s):  
Nestor Timonidis ◽  
Alberto Llera ◽  
Paul H. E. Tiesinga
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Structural Connectivity ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Synaptic Function ◽  
Reticular Nucleus ◽  
Sources Of Information ◽  
Independent Components ◽  
Brain Connectome

AbstractFinding links between genes and structural connectivity is of the utmost importance for unravelling the underlying mechanism of the brain connectome. In this study we identify links between the gene expression and the axonal projection density in the mouse brain, by applying a modified version of the Linked ICA method to volumetric data from the Allen Institute for Brain Science for identifying independent sources of information that link both modalities at the voxel level. We performed separate analyses on sets of projections from the visual cortex, the caudoputamen and the midbrain reticular nucleus, and we determined those brain areas, injections and genes that were most involved in independent components that link both gene expression and projection density data, while we validated their biological context through enrichment analysis. We identified representative and literature-validated cortico-midbrain and cortico-striatal projections, whose gene subsets were enriched with annotations for neuronal and synaptic function and related developmental and metabolic processes. The results were highly reproducible when including all available projections, as well as consistent with factorisations obtained using the Dictionary Learning and Sparse Coding technique. Hence, Linked ICA yielded reproducible independent components that were preserved under increasing data variance. Taken together, we have developed and validated a novel paradigm for linking gene expression and structural projection patterns in the mouse mesoconnectome, which can power future studies aiming to relate genes to brain function.

scholarly journals Diet-Induced Obesity Disrupts Trace Element Homeostasis and Gene Expression in the Olfactory Bulb

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3909
Author(s):  
Melissa S. Totten ◽  
Derek M. Pierce ◽  
Keith M. Erikson
Keyword(s):  
Gene Expression ◽  
Olfactory Bulb ◽  
Trace Element ◽  
Alpha Synuclein ◽  
Divalent Metal Transporter 1 ◽  
Diet Induced Obesity ◽  
Mrna Gene ◽  
The Impact ◽  
Mrna Gene Expression ◽  
Obese Male

The aim of this study was to determine the impact of diet-induced obesity (DIO) on trace element homeostasis and gene expression in the olfactory bulb and to identify potential interaction effects between diet, sex, and strain. Our study is based on evidence that obesity and olfactory bulb impairments are linked to neurodegenerative processes. Briefly, C57BL/6J (B6J) and DBA/2J (D2J) male and female mice were fed either a low-fat diet or a high-fat diet for 16 weeks. Brain tissue was then evaluated for iron, manganese, copper, and zinc concentrations and mRNA gene expression. There was a statistically significant diet-by-sex interaction for iron and a three-way interaction between diet, sex, and strain for zinc in the olfactory bulb. Obese male B6J mice had a striking 75% increase in iron and a 50% increase in manganese compared with the control. There was an increase in zinc due to DIO in B6J males and D2J females, but a decrease in zinc in B6J females and D2J males. Obese male D2J mice had significantly upregulated mRNA gene expression for divalent metal transporter 1, alpha-synuclein, amyloid precursor protein, dopamine receptor D2, and tyrosine hydroxylase. B6J females with DIO had significantly upregulated brain-derived neurotrophic factor expression. Our results demonstrate that DIO has the potential to disrupt trace element homeostasis and mRNA gene expression in the olfactory bulb, with effects that depend on sex and genetics. We found that DIO led to alterations in iron and manganese predominantly in male B6J mice, and gene expression dysregulation mainly in male D2J mice. These results have important implications for health outcomes related to obesity with possible connections to neurodegenerative disease.

The Effect of Dopamine on Gene Expression of Alpha-synuclein and Transcription Factors GATA-1, GATA-2, and ZSCAN21 in Parkinson’s Disease

2018 ◽  
Vol 12 (5) ◽  
pp. 410-418
Author(s):  
A. K. Emelyanov ◽  
A. O. Lavrinova ◽  
E. M. Litusova ◽  
N. A. Knyazev ◽  
D. G. Kulabukhova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Alpha Synuclein

scholarly journals Brain Atrophy of Secondary REM-Sleep Behavior Disorder in Neurodegenerative Disease

2016 ◽  
Vol 52 (3) ◽  
pp. 1101-1109 ◽  
Author(s):  
Hee-Jin Kim ◽  
Hyung Kyun Im ◽  
Juhan Kim ◽  
Jee-young Han ◽  
Mony de Leon ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Rem Sleep ◽  
Brain Atrophy ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Sleep Behavior

scholarly journals Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

2020 ◽  
Author(s):  
René L. Vidal ◽  
Denisse Sepulveda ◽  
Paulina Troncoso-Escudero ◽  
Paula Garcia-Huerta ◽  
Constanza Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Cell Function ◽  
Alpha Synuclein ◽  
Protective Effects ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

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