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Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset., Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Imaging biomarkers are needed to detect early brain changes in presymptomatic carriers harbouring FTD mutations. Using arterial spin labelling-MRI, Mutsaerts, Mirza et al. identify an inverse association between cerebral perfusion in frontotemporoparietal regions and expected age of onset. Cerebral perfusion may be a promising imaging biomarker for presymptomatic genetic FTD., Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

PURPOSE: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. MATERIALS AND METHODS: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. RESULTS: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). CONCLUSION: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Summary: Aceruloplasminemia is a rare autosomal recessive disorder. The lack of ceruloplasmin ferroxidase activity leads to parenchymal and reticuloendothelial iron overload, resulting in diabetes and progressive neurodegeneration with extrapyramidal disorders, ataxia, and dementia. We describe the MR imaging findings in a 40-year-old woman with hereditary aceruloplasminemia. The abnormal T2 hypointensities were more marked than those seen in any other condition, including degenerative disorders of the basal ganglia and Wilson disease, and they may be typical of aceruloplasminemia. To our knowledge, involvement of the cortex has not been described and suggests that brain iron accumulation in aceruloplasminemia is more extensive than previously believed, even in asymptomatic patients.

PURPOSE: To report the clinical and neuroradiologic findings of superficial siderosis of the CNS, due to chronic subarachnoid bleeding of unknown origin. MATERIALS AND METHODS: We observed seven cases. The main clinical manifestations were progressive deafness and ataxia. Four patients had had previous cranial or cervical trauma, with root avulsion in two, many years before onset of deafness and ataxia. Neuroradiologic studies included MR (0.5 T in four and 1.5 T in three) and angiography of the brain in all cases, CT in six cases, MR of the spine in six, and myelography in four. RESULTS: MR demonstrated a rim of marked hypointensity in T2-weighted images, consistent with hemosiderin deposits, on the surface of cerebellum, brain stem, inferior part of cerebral hemispheres, and spinal cord. CT showed cerebellar atrophy in five cases, and a rim of mild hyperdensity around the brain stem in two. Angiographic studies were negative. Myelography showed cervical nerve root avulsion in two cases and a cervicodorsal extradural cyst in one. Cerebrospinal fluid contained RBCs in all the six examined cases. CONCLUSION: Although CT may occasionally suggest the diagnosis of superficial siderosis, MR demonstrates this abnormality to better advantage.

We describe a four-generation Italian family with a novel form of juvenile-onset, slowly progressive, autosomal dominant cerebellar ataxia. Eleven affected family members have been evaluated. The mean age at onset was 19.5 years with no evidence of anticipation. The first symptoms were invariably unbalanced standing and mild gait incoordination. Gaze-evoked nystagmus was prominent at onset, while patients with longer disease duration developed slow saccades, ophthalmoparesis and, often, ptosis. Deep tendon reflexes in lower limbs were increased in 80% of the cases. Genetic analysis excluded the presence of pathological repeat expansions in spinocerebellar ataxia (SCA) types 1-3, 6-8, 10, 12 and 17, and DRPLA genes. Linkage exclusion tests showed no evidence of association with other known SCA loci. A genome-wide screen analysis identified linkage with chromosome 18 markers. A maximum two-point limit of determination score of 4.20 was found for marker D18S53. Haplotype analysis refined a critical region of 7.9 Mb between markers D18S1418 and D18S1104. This new SCA locus on 18p11.22-q11.2 has been designated SCA28. Candidate genes within the critical interval are currently screened for mutations.