Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.

Download Full-text

Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease

BMC Neurology ◽

10.1186/s12883-019-1567-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Rogier A. Feis ◽

Mark J. R. J. Bouts ◽

Elise G. P. Dopper ◽

Nicola Filippini ◽

Verena Heise ◽

...

Keyword(s):

Alzheimer’S Disease ◽

White Matter ◽

Functional Connectivity ◽

Frontotemporal Dementia ◽

Grey Matter ◽

Region Of Interest ◽

Grey Matter Volume ◽

Matter Volume ◽

Mutation Carriers ◽

Healthy Carriers

Abstract 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.

Download Full-text

Morphological changes after cranial fractionated photon radiotherapy: localized loss of white matter and grey matter volume with increasing dose

Clinical and Translational Radiation Oncology ◽

10.1016/j.ctro.2021.08.010 ◽

2021 ◽

Author(s):

S.H.J. Nagtegaal ◽

S David ◽

E.E. van Grinsven ◽

M.J.E. van Zandvoort ◽

E. Seravalli ◽

...

Keyword(s):

White Matter ◽

Grey Matter ◽

Morphological Changes ◽

Grey Matter Volume ◽

Matter Volume ◽

Photon Radiotherapy

Download Full-text

Education modulates brain maintenance in presymptomatic frontotemporal dementia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320439 ◽

2019 ◽

Vol 90 (10) ◽

pp. 1124-1130 ◽

Cited By ~ 7

Author(s):

Stefano Gazzina ◽

Mario Grassi ◽

Enrico Premi ◽

Maura Cosseddu ◽

Antonella Alberici ◽

...

Keyword(s):

At Risk ◽

Frontotemporal Dementia ◽

Grey Matter ◽

Principal Component ◽

Grey Matter Volume ◽

Brain Reserve ◽

Matter Volume ◽

Brain Maintenance ◽

Over Time

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

Download Full-text

Causal effect of atrial fibrillation on brain white or grey matter volume: A Mendelian randomization study

10.1101/2020.12.17.20248314 ◽

2020 ◽

Author(s):

Sehoon Park ◽

Soojin Lee ◽

Yaerim Kim ◽

Semin Cho ◽

Kwangsoo Kim ◽

...

Keyword(s):

Atrial Fibrillation ◽

White Matter ◽

Grey Matter ◽

Mendelian Randomization ◽

Brain Volume ◽

Causal Effect ◽

Grey Matter Volume ◽

Volume Loss ◽

White Matter Volume ◽

Matter Volume

AbstractBackgroundAtrial fibrillation (AF) and brain volume loss are prevalent in older individuals. Further study investigating the causal effect of AF on brain volume is warranted.MethodsThis study was a Mendelian randomization (MR) analysis. The genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis and included 537,409 individuals of European ancestry. The outcome summary statistics for quantile-normalized white or grey matter volume measured by magnetic resonance imaging were provided by the previous GWAS of 8426 white British UK Biobank participants. The main MR method was the inverse variance weighted method, supported by sensitivity MR analysis including MR-Egger regression and the weighted median method. The causal estimates from AF to white or grey matter volume were further adjusted for effects of any stroke or ischemic stroke by multivariable MR analysis.ResultsA higher genetic predisposition for AF (one standard deviation increase) was significantly associated with lower white matter volume [beta −0.128 (−0.208, −0.048)] but not grey matter volume [beta −0.041 (−0.101, 0.018)], supported by all utilized sensitivity MR analyses. The multivariable MR analysis indicated that AF is causally linked to lower white matter volume independent of the stroke effect.ConclusionsAF is a causative factor for white matter volume loss. The effect of AF on grey matter volume was inapparent in this study. A future trial is necessary to confirm whether appropriate AF management can be helpful in preventing cerebral white matter volume loss or related brain disorders in AF patients.

Download Full-text

Age-specific adult rat brain MRI templates and tissue probability maps

10.31219/osf.io/htgqn ◽

2021 ◽

Cited By ~ 1

Author(s):

Eilidh MacNicol ◽

Paul Wright ◽

Eugene Kim ◽

Irene Brusini ◽

Oscar Esteban ◽

...

Keyword(s):

White Matter ◽

Rat Brain ◽

Grey Matter ◽

Brain Volume ◽

Grey Matter Volume ◽

Total Brain Volume ◽

Adult Rat ◽

Matter Volume ◽

Probability Maps ◽

Total Brain

Age-specific resources mitigate biases in human MRI processing arising from structural changes across the lifespan. There are fewer age-specific resources for preclinical imaging, and they only represent developmental periods rather than adulthood. Since rats recapitulate many facets of human aging, it was hypothesized that brain volume and each tissue’s relative contribution to total brain volume would change with age in the adult rat. However, the currently available tissue probability maps, which provide a priori information for tissue volume estimation, provide inaccurate grey matter probabilities in subcortical structures, particularly the thalamus. Consequently, age-specific templates and tissue probability maps were generated from a longitudinal study that scanned a cohort of rats at 3, 5, 11, and 17 months old. Mixed-effects models assessed the effect of age on brain, grey matter, white matter, and CSF volumes, and the relative tissue proportions. Grey and white matter volume increased with age, and the tissue proportions relative to total brain volume varied throughout adulthood. Furthermore, we present evidence of a systematic underestimation of thalamic grey matter volume with existing resources, which is mitigated with the use of age-specific tissue probability maps since the derived estimates better matched histological evidence. To reduce age-related biases in image pre-processing, a set of rat brain resources from across the adult lifespan is consequently released to expand the preclinical MRI community’s fundamental resources.

Download Full-text

Allostatic load as a predictor of grey matter volume and white matter integrity in old age: The Whitehall II MRI study

Scientific Reports ◽

10.1038/s41598-018-24398-9 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 9

Author(s):

Enikő Zsoldos ◽

Nicola Filippini ◽

Abda Mahmood ◽

Clare E. Mackay ◽

Archana Singh-Manoux ◽

...

Keyword(s):

White Matter ◽

Old Age ◽

Allostatic Load ◽

Grey Matter ◽

White Matter Integrity ◽

Grey Matter Volume ◽

Matter Volume ◽

Mri Study

Download Full-text

Late chronotype is linked to greater cortical thickness in the left fusiform and entorhinal gyri

10.21203/rs.3.rs-588446/v1 ◽

2021 ◽

Author(s):

Michal Rafal Zareba ◽

Magdalena Fafrowicz ◽

Tadeusz Marek ◽

Ewa Beldzik ◽

Halszka Oginska ◽

...

Keyword(s):

White Matter ◽

Cortical Thickness ◽

Grey Matter ◽

Brain Regions ◽

Affective Processing ◽

Grey Matter Volume ◽

Imaging Data ◽

White Matter Volume ◽

Matter Volume ◽

Anatomical Basis

Abstract Humans can be classified as early, intermediate and late chronotypes based on the preferred sleep and wakefulness patterns. The anatomical basis of these distinctions remains largely unexplored. Using magnetic resonance imaging data from 113 healthy young adults (71 females), we aimed to replicate cortical thickness and grey matter volume chronotype differences reported earlier in the literature using a greater sample size, as well as to explore the volumetric white matter variation linked to contrasting circadian phenotypes. Instead of comparing the chronotypes, we correlated the individual chronotype scores with their morphometric brain measures. The results revealed one cluster in the left fusiform and entorhinal gyri showing increased cortical thickness with increasing preference for eveningness, potentially providing an anatomical substrate for chronotype-sensitive affective processing. No significant results were found for grey and white matter volume. We failed to replicate cortical thickness and volumetric grey matter distinctions in the brain regions reported in the literature. Furthermore, we found no association between white matter volume and chronotype. Thus, while this study confirms that circadian preference is associated with specific structural substrates, it adds to the growing concerns that reliable and replicable neuroimaging research requires datasets much larger than those commonly used.

Download Full-text