Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Miocene magmatism in the Western Nyainqentanglha mountains of southern Tibet: An exhumed bright spot?

The Western Nyainqentanglha (WNT) mountain range of south-central Tibet predominantly comprises granitoids that intrude into metasedimentary strata, and was exhumed from ~ 15 to 20 km depth in the footwall of the Yangbajain graben during the late Neogene. The range provides a rare exposure of deeper crustal levels of Tibet, which can be used to gain insight into processes that may be occurring beneath the plateau. Field, petrological, thermobarometric and U–Pb geochronological analyses are applied to determine the magmatic and metamorphic history of the WNT, revealing three tectonothermal events: (1) 213–201 Ma magmatism and amphibolite-facies metamorphism associated with north–south Lhasa terrane accretion, (2) 140–52 Ma magmatism resulting from subduction of Neotethys preceding India–Asia collision, and (3) 25–8 Ma magmatism that we suggest to have resulted from partial melting of the thickened Tibetan plateau crust. The latter is correlated with seismic bright spots imaged in the region at ~ 15–18 km depth, indicating that restricted partial melting at mid-crustal levels may have been ongoing since 25 Ma, in accordance with observations from xenolith data and predictions made by thermal modelling of thickened crust

Two-stage cooling history of pelitic and semi-pelitic mylonite (sensu lato) from the Dongjiu-Milin shear zone, northwest flank of the eastern Himalayan syntaxis

The Dongjiu–Milin shear zone located on the northwest flank of the eastern Himalayan syntaxis, southeast Tibet, separates Indian and Asian plate rocks. It is characterized by a thick sequence of highly strained and ductilely deformed mylonite (sensu stricto and sensu lato) bound between a pair of sub-parallel transtensive brittle normal faults. An integrated geochronological, petrographic, and thermobarometric study of three samples of pelitic and semi-pelitic mylonite (sensu lato) from the shear zone provides new insights into its thermal and structural evolution, and hence the tectonic processes operating in the region since the India–Asia collision. U–Th–Pb in-situ dating of monazite, garnet–ilmenite thermometry, and textural relationships show that mylonitization and peak-thermal staurolite-grade metamorphism occurred at 23.4 ± 0.7 Ma at a temperature of at least ~ 610 ± 30 °C. Cooling of these units through 420–500 °C occurred at c. 11–8 Ma, as constrained by the retrograde breakdown of allanite to form monazite. These data show that the cooling history of mylonite (sensu lato) in the shear zone and the tectonic evolution of the syntaxis region can be divided into two distinct stages. Slow cooling at a rate of 6–12 °C/Myr during c. 23–8 Ma is attributed to exhumation during ductile deformation and mylonitization caused by the ongoing India–Asia collision. This was followed by a period of significantly faster cooling at a minimum rate of 57 °C/Myr since c. 8 Ma, most likely associated with brittle normal faulting that facilitated the final stages of excavation to the surface. These new thermochronological data provide evidence of deep-seated exhumation-related cooling processes occurring in a convergent margin orogenic setting

Monazite geochronology and petrology of kyanite- and sillimanite-grade migmatites from the northwestern flank of the eastern Himalayan syntaxis

A combined geochronological and petrological study of pelitic migmatites from the northwestern flank of the eastern Himalayan syntaxis has constrained the timing and P–T conditions of two high-grade metamorphic events that affected the south Lhasa block (Asian margin) and provides new insight into the tectonothermal evolution of the India–Asia collision. U(–Th)–Pb dating of in situ monazite shows that upper amphibolite-facies sillimanite-grade metamorphism and consequent partial melting occurred between c. 71 and 50 Ma at P–T conditions above 6.3 ± 1.2 kbar and 750 ± 30 °C. Further partial melting at upper amphibolite-facies kyanite-grade conditions occurred between c. 44 and 33 Ma at minimum P–T conditions of 10.4 ± 1.0 kbar and 698 ± 20 °C. These data are interpreted to record a south Lhasa block mid-crustal sillimanite-grade melting event in the Late Cretaceous to Early Eocene related to regional heat advection caused by coeval and prolonged emplacement of Gangdese batholith units. This was followed by a higher pressure and lower temperature kyanite-grade melting event during the Middle Eocene to Early Oligocene associated with deformation and crustal thickening in the south Lhasa block, coeval with kyanite-grade metamorphism along the Himalaya, as a result of the on-going India–Asia collision. These partially-melted crustal lithologies offer potential sources (or otherwise analogs for sources) for the Miocene emplacement of adakitic intrusions previously documented in the eastern Himalayan syntaxis region

Monazite geochronology and petrology of kyanite- and sillimanite-grade migmatites from the northwestern flank of the eastern Himalayan syntaxis

A combined geochronological and petrological study of pelitic migmatites from the northwestern flank of the eastern Himalayan syntaxis has constrained the timing and P–T conditions of two high-grade metamorphic events that affected the south Lhasa block (Asian margin) and provides new insight into the tectonothermal evolution of the India–Asia collision. U(–Th)–Pb dating of in situ monazite shows that upper amphibolite-facies sillimanite-grade metamorphism and consequent partial melting occurred between c. 71 and 50 Ma at P–T conditions above 6.3 ± 1.2 kbar and 750 ± 30 °C. Further partial melting at upper amphibolite-facies kyanite-grade conditions occurred between c. 44 and 33 Ma at minimum P–T conditions of 10.4 ± 1.0 kbar and 698 ± 20 °C. These data are interpreted to record a south Lhasa block mid-crustal sillimanite-grade melting event in the Late Cretaceous to Early Eocene related to regional heat advection caused by coeval and prolonged emplacement of Gangdese batholith units. This was followed by a higher pressure and lower temperature kyanite-grade melting event during the Middle Eocene to Early Oligocene associated with deformation and crustal thickening in the south Lhasa block, coeval with kyanite-grade metamorphism along the Himalaya, as a result of the on-going India–Asia collision. These partially-melted crustal lithologies offer potential sources (or otherwise analogs for sources) for the Miocene emplacement of adakitic intrusions previously documented in the eastern Himalayan syntaxis region