White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

Abstract

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers.336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function).Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers – in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load – a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year.In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome mea...

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

“…Intriguingly, demyelination that is observed as white matter hyperintensities (WMH) on MRI brain scans is a frequent and specific occurrence in FTD cases caused by GRN mutations [20,107,128]. Our data provide additional support to the idea that FTD-GRN cases are especially vulnerable to demyelination and loss of white matter, although the exact mechanism is unclear.…”

Regionconnect: Rapidly extracting standardized brain connectivity information in voxel-wise neuroimaging studies

“…The online interactive version of regionconnect that allows the user to easily select and update a white matter region of interest has been used in education for exploring healthy adult brain connectivity. The tractogram can be used to identify streamlines that traverse a white matter region of interest, and this was done recently in older adults with progranulin-associated frontotemporal dementia to determine streamlines affected by white matter hyperintensities ( Sudre et al, 2019 ). The tractogram can also be used to visualize the group of streamlines connecting two gray matter regions.…”

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

“…If microglia are more vulnerable to dysfunction or senescence in white matter, this may predispose individuals to onset of pathology in white matter due to lack of axonal support, or influence spread of pathology through white matter tracts. FTLD cases with GRN mutations show early, region-specific white matter neuroimaging abnormalities on MRI, such as white matter hyperintensities (WMH), which are not due to vascular disease and occur presymptomatically [54,58]. As microglial function varies regionally with age [14], the regional differences in dystrophy observed across pathological and genetic FTLD subtypes suggest that regional variations in senescence may determine focal onset of certain neurodegenerative pathologies.…”

“…These results support early descriptions of white matter microgliosis in FTLD [ 33 – 35 , 37 , 38 ] and recent studies showing more phagocytic microglia in white matter than grey matter of FTLD cases [ 39 , 44 ]. Neuroimaging studies of FTD demonstrate early, widespread loss of white matter integrity, preceding grey matter atrophy, which varies regionally by clinical and genetic phenotype [ 49 , 56 , 57 ], occurs presymptomatically [ 48 , 58 ] and progresses over time [ 58 , 59 ]. This could be a primary process, occurring prior to protein aggregation, or a secondary process, in response to retrograde axonal degeneration from neuronal loss due to cortical pathology.…”

“…Although many antigen-presenting microglia were present in FW, these were not well activated. Dysfunctional presentation and targeting of self-antigens in white matter (such as myelin) could contribute to the prominent, early, white matter damage seen in FW of GRN mutation carriers, including demyelination and white matter hyperintensities [ 54 , 57 , 58 ]. FTLD- C9orf72 cases had abundant phagocytic microglia within frontotemporal white matter, and many Iba1-positive microglia but few antigen-presenting microglia in all regions.…”