Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD (original) (raw)
Related papers
Journal of Alzheimer's disease : JAD, 2016
In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: 1) to identify target regions in different disease stages and 2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low fre...
Background: Monogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase. Objective: To define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia). Methods: Thirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy. Results: Asymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found. Conclusions: GRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies.
Disease-related cortical thinning in presymptomatic granulin mutation carriers
NeuroImage: Clinical, 2021
Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.
Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers
2014
Background: To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin (GRN) mutation carriers. Methods: Ten cognitively normal subjects (five mutation carriers, GRN1; years to estimated disease onset: 12 6 7; five mutation noncarriers, GRN2) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. Results: GRN1 showed smaller cortical thickness than GRN2 in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. Conclusion: Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.
NeuroImage, 2010
Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate-prefrontal-insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.
Cognitive Reserve in Granulin-Related Frontotemporal Dementia: from Preclinical to Clinical Stages
PLoS ONE, 2013
Objective: Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+).
Understanding phenotype variability in frontotemporal lobar degeneration due to granulin mutation
Neurobiology of Aging, 2014
Phenotype in patients with granulin (GRN) mutations is unpredictable, ranging from behavioral variant frontotemporal dementia (bvFTD) to agrammatic variant of primary progressive aphasia (avPPA). To date the wide clinical variability of FTLD-GRN remains unexplained. The aim of the study was to identify genetic pathways differentiating phenotypic expression in patients carrying GRN mutations. Patients carrying the same GRNT272SfsX10 mutation were enrolled, a careful clinical assessment was carried out, and the diagnosis of either bvFTD (n ¼ 10, age ¼ 63.9 AE 9.4) or avPPA (n ¼ 6, age ¼ 58.8 AE 4.7) was done. Microarray gene expression analysis on leukocytes was performed. Genes differentially expressed between the groups were validated by real time polymerase chain reaction considering an age-matched healthy controls group (n ¼ 16, age ¼ 58.4 AE 10.7). We further considered a group of FTD with no GRN mutations (GRN-) (n ¼ 21, 13 bvFTD, and 8 avPPA) for comparisons. Real-time polymerase chain reaction (PCR) confirmed a significant decrease in leukocytes mRNA messenger RNA (mRNA) levels of RAP1GAP in bvFTD patients as compared with avPPA (p ¼ 0.049). This finding was specific for patients with GRN mutations, as we did not observe this pattern in FTD GRN-patients (p ¼ 0.99). The alteration of RAP1GAP mRNA levels may explain the clinical variability of GRN-FTLD patients. This is the first report linking a molecular pathway to specific phenotype expression in FTLD-GRN. To understand the clinical relevance of our early results it will be mandatory to extend the observation to other clinical and neuropathological series.
Human Mutation, 2008
Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), 1373-1386, 2008. r r 2008 Wiley-Liss, Inc.
Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN
Neurology, 2009
Objective: To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene. Methods: We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group. Results: Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects. Conclusion: These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers. Neurology ® 2009;72:813-820 GLOSSARY AD ϭ Alzheimer disease; ADPR ϭ Alzheimer's Disease Patient Registry; ADRC ϭ Alzheimer's Disease Research Center; bvFTD ϭ behavioral variant frontotemporal dementia; bvFTD؉P ϭ bvFTD with parkinsonism; CBS ϭ corticobasal syndrome; CDR-SB ϭ Clinical Dementia Rating scale sum of boxes; DRS ϭ Dementia Rating Scale; FTLD ϭ frontotemporal lobar degeneration; MAPT ϭ microtubule-associated protein tau; MCI ϭ mild cognitive impairment; MMSE ϭ Mini-Mental State Examination; PGRN ϭ progranulin; PPA ϭ primary progressive aphasia; STMS ϭ Short Test of Mental Status; VBM ϭ voxel-based morphometry.