White matter lesions in FTLD: distinct phenotypes characterize
            <i>GRN</i>
            and
            <i>C9ORF72</i>
            mutations

Ameur, Fatah; Colliot, Olivier; Caroppo, Paola; Ströer, Sébastian; Dormont, Didier; Brice, Alexis; Azuar, Carole; Dubois, Bruno; Ber, Isabelle Le; Bertrand, Anne

doi:10.1212/nxg.0000000000000047

Cited by 21 publications

(21 citation statements)

References 8 publications

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“…This is consistent with correlations described in other imaging studies (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Sudre et al, 2017). Using precise anatomical correlation of cadaveric MRI brain images with tissue slices, we were also able to demonstrate that regions with the most severe WMH displayed the most severe cortical pathology on histological analysis.…”

Section: Discussionsupporting

confidence: 92%

“…WMH were most prominent in the three layers closest to the lateral ventricles within the frontal and parietal lobes, and were more homogeneous in appearance in the GRN mutation group, suggesting a different aetiology from WMH in other mutation carriers (Sudre et al, 2017). Similar patterns of WMH were observed in smaller imaging studies of WMH in GRN mutation carriers (Caroppo et al, 2014; Ameur et al, 2016). …”

Section: Discussionsupporting

confidence: 75%

“…White matter changes such as gliosis and demyelination have long been observed in histological studies of FTD (Englund & Brun, 1987) and several groups have observed significant WMH on MRI brain scans of GRN mutation carriers with FTD who lack vascular risk factors (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017). However, studies that have characterized in detail the pathological correlates of WMH in GRN mutation associated FTD have until now been lacking.…”

Section: Discussionmentioning

confidence: 99%

“…However, WMH are less commonly seen in frontotemporal dementia (FTD). Several studies have now reported prominent WMH in patients with familial FTD due to progranulin ( GRN ) mutations (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017) but the pathological changes underlying these have not previously been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

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Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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“…We could not explain the remarkable finding of DTI changes into the opposite direction in the SLF, SCR, cingulum between −30 and −16 years before EYO, and larger samples and follow‐up data (longitudinal changes within an individual) are needed to investigate whether the pattern is of pathophysiological or methodological nature. Recent literature provides evidence of WM involvement in GRN ‐related FTD, though on the contrary in our GRN mutation carriers few tracts were affected, and integrity loss was generally closer to estimated symptom onset than early presymptomatic. Previous studies demonstrated lower FA in the UF of presymptomatic GRN mutation carriers, and we did find lower FA in the presymptomatic period, but no differences in the symptomatic stage or in other diffusion parameters.…”

Section: Discussioncontrasting

confidence: 78%

Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross‐sectional diffusion tensor imaging study

Jiskoot

Bocchetta

Nicholas

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWe aimed to investigate mutation‐specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72,MAPT, and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study.MethodsOne hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72,MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers.ResultsDiffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC.InterpretationThis study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network‐based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease‐tracking and ‐staging in presymptomatic to early‐stage familial FTD.

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The imaging signature of C9orf72 hexanucleotide repeat expansions: implications for clinical trials and therapy development

Shing

McKenna

Siah

et al. 2021

Brain Imaging and Behavior

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White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations

Cited by 21 publications

References 8 publications

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross‐sectional diffusion tensor imaging study

The imaging signature of C9orf72 hexanucleotide repeat expansions: implications for clinical trials and therapy development

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