Longitudinal multimodal MRI as prognostic and diagnostic biomarker in presymptomatic familial frontotemporal dementia

Jiskoot, Lize C.; Panman, Jessica L.; Meeter, Lieke H.H.; Dopper, Elise G.P.; Kaat, Laura Donker; Franzen, Sanne; Ende, Emma L. van der; Minkelen, Rick van; Rombouts, Serge A.R.B.; Papma, Janne M.; Swieten, John C. van

doi:10.1093/brain/awy288

Cited by 80 publications

(122 citation statements)

References 81 publications

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“…One of the key findings in our study is the accelerated changes in mI/Cr and NAA/mI that occurred in approximately 2 years prior to symptom onset, suggesting a change in the trajectory of 1 H MRS metabolite ratios prior to symptom onset. Our findings are consistent with the trajectories reported in a recent longitudinal study of converters with MAPT and GRN mutations, demonstrating that loss of white matter integrity and grey matter volume were present 2 years before symptom onset . In addition, previous cross‐sectional studies in asymptomatic MAPT mutation carriers report presence of 1 H MRS metabolite ratio abnormalities, grey matter atrophy, loss of white matter integrity, and functional connectivity with range of 5 to 30 years before the estimated age of symptom onset.…”

Section: Discussionsupporting

confidence: 91%

“…Our findings are consistent with the trajectories reported in a recent longitudinal study of converters with MAPT and GRN mutations, demonstrating that loss of white matter integrity and grey matter volume were present 2 years before symptom onset. 11 In addition, previous cross-sectional studies in asymptomatic MAPT mutation carriers report presence of 1 H MRS metabolite ratio abnormalities, 3 grey matter atrophy, 12 loss of white matter integrity, 13 and functional connectivity 14 with range of 5 to 30 years before the estimated age of symptom onset. It should be noted that the cross-sectional studies estimated the age of onset by the information available from the carriers of the MAPT mutation type.…”

Section: Discussionmentioning

confidence: 95%

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Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

Chen

Boeve

Tosakulwong

et al. 2019

Journal of Neuroimaging

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BACKGROUND AND PURPOSE The objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow‐up, and to determine the time at which the neurochemical alterations accelerated during disease progression. METHODS We identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow‐up. All participants were longitudinally followed with an average of 7.75 years (range 4‐11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope. RESULTS The decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset. CONCLUSIONS Our findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

Chen

Boeve

Tosakulwong

et al. 2019

Journal of Neuroimaging

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“…Previous cross-sectional MRI studies demonstrated atrophy in the anteromedial temporal lobe and orbitofrontal cortex in asymptomatic MAPT mutation carriers (6,19,20), while others found no difference between asymptomatic MAPT mutation carriers and controls (6,7,33). Recently, two longitudinal studies from a cohort of asymptomatic MAPT mutation carriers have reported that hippocampal volumes decline during a 2-year follow-up, but no cortical atrophy was found in longitudinal analysis with 4 years of follow-up (21,22). During a 10year follow-up, the rates of temporal lobe atrophy were accelerated in asymptomatic MAPT mutation carriers who were asymptomatic during follow-up, while accelerated atrophy rates in the temporal, parietal and frontal lobes were reported in MAPT mutation carriers who became symptomatic compared to non-carriers (23).…”

Section: Mapt_smrimentioning

confidence: 98%

“…Structural magnetic resonance imaging (sMRI) has captured cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers (6,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Studies of sMRI using different analysis methods, such as region of interest (ROI) in specific brain regions, cortical thickness analysis and voxel-based morphometry (VBM), could capture the gray matter and white matter volumes, cortical thickness, and the subcortical gray matter volume.…”

Section: Structural Mrimentioning

confidence: 99%

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Chen

Kantarci

2020

Front. Neurol.

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Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral changes, language abnormality, as well as executive function deficits and motor impairment. In about 30-50% of FTLD patients, an autosomal dominant pattern of inheritance was found with major mutations in the MAPT, GRN, and the C9orf72 repeat expansion. These mutations could lead to neurodegenerative pathology years before clinical symptoms onset. With potential disease-modifying treatments that are under development, non-invasive biomarkers that help determine the early brain changes in presymptomatic FTLD patients will be critical for tracking disease progression and enrolling the right participants into the clinical trials at the right time during the disease course. In recent years, there is increasing evidence that a number of imaging biomarkers show the abnormalities during the presymptomatic stage. Imaging biomarkers of presymptomatic familial FTLD may provide insight into the underlying neurodegenerative process years before symptom onset. Structural magnetic resonance imaging (MRI) has demonstrated cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers. In addition, diffusion tensor imaging (DTI) has shown the loss of white matter microstructural integrity in the presymptomatic stage of familial FTLD. Furthermore, proton magnetic resonance spectroscopy ( 1 H MRS), which provides a non-invasive measurement of brain biochemistry, has identified early neurochemical abnormalities in presymptomatic MAPT mutation carriers. Positron emission tomography (PET) imaging with [ 18 F]-fluorodeoxyglucose (FDG) has demonstrated the glucose hypometabolism in the presymptomatic stage of familial FTLD. Also, a novel PET ligand, 18 F-AV-1451, has been used in this group to evaluate tau deposition in the brain. Promising imaging biomarkers for presymptomatic familial FTLD have been identified and assessed for specificity and sensitivity for accurate prediction of symptom onset and tracking disease progression during the presymptomatic stage when clinical measures are not useful. Furthermore, identifying imaging biomarkers for the presymptomatic stage is important for the design of disease-modifying trials. We review the recent progress in imaging biomarkers of the presymptomatic phase of familial FTLD and discuss the imaging techniques and analysis methods, with a focus on the potential implication of these imaging techniques and their utility in specific mutation types.

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“…Longitudinal studies are crucial to identify genetic and environmental factors that influence the rate of these brain changes throughout development (Giedd et al, 1999;Gogtay et al, 2004;Shaw, Gogtay, & Rapoport, 2010) and aging (Raz et al, 2005). Interindividual differences in brain development are associated with general cognitive function (Ramsden et al, 2011;Schnack et al, 2015;Oschwald et al, 2019), and risk for psychiatric disorders (Shaw et al, 2009;Liberg et al, 2016) and neurological diseases (Reiter et al, 2017;Eshaghi et al, 2018;Jiskoot et al, 2019). Genetic factors involved in brain development and aging overlap with those for cognition (Brans et al, 2010;Brouwer et al, 2014) and risk for neuropsychiatric disorders (Brans et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

Brouwer¹,

Haren²,

Forti³

et al. 2020

Preprint

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We identified common genetic variants associated with the rate of brain development and aging, in longitudinal MRI scans worldwide. AbstractHuman brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. While heritable, specific loci in the genome that influence these rates are largely unknown. Here, we sought to find common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association analysis of longitudinal changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 10,163 individuals aged 4 to 99 years, on average 3.5 years apart, were used to compute rates of morphological change for 15 brain structures. We discovered 5 genome-wide significant loci and 15 genes associated with brain structural changes. Most individual variants exerted age-dependent effects. All identified genes are expressed in fetal and adult brain tissue, and some exhibit developmentally regulated expression across the lifespan. We demonstrate genetic overlap with depression, schizophrenia, cognitive functioning, height, body mass index and smoking. Several of the discovered loci are implicated in early brain development and point to involvement of metabolic processes. Gene-set findings also implicate immune processes in the rates of brain changes. Taken together, in the world's largest longitudinal imaging genetics dataset we identified genetic variants that alter agedependent brain growth and atrophy throughout our lives. a Position based on build hg19. Study-wide significant hits are displayed in bold. *This gene also showed a genome-wide significant quadratic age effect. The most parsimonious model is listed in this table.Genome-wide significant gene sets based on gene ontology. Study-wide significant gene sets are displayed in bold. a See Supplementary Table S9 for genes included in the gene set. Genes included in GO_INTERLEUKIN_1_RECEPTOR_ACTIVITY and GO_RESPONSE_TO_INTERLEUKIN_2 do not overlap.

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Longitudinal multimodal MRI as prognostic and diagnostic biomarker in presymptomatic familial frontotemporal dementia

Cited by 80 publications

References 81 publications

Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

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