Genetic Frontotemporal Dementia Initiative Research Articles

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

Association of low frequency variants with regional cortical grey matter volumes in genetic frontotemporal dementia: Results from GENFI

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative condition characterized by heterogeneous clinical, pathological, and genetic features. Mutations in three genes account for the majority of autosomal dominant FTD: GRN, MAPT, and C9orf72. We tested whether gene‐based aggregate burden of genome‐wide low‐frequency variants contribute to variation in regional cortical and subcortical grey matter volumes in the GENetic Frontotemporal dementia Initiative (GENFI), after controlling for effects of autosomal dominant mutations.MethodGENFI recruits symptomatic and presymptomatic participants from families segregating genetic FTD. We included 517 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of uncommon/rare variants by gene were used to examine the association of low‐frequency variants (minor allele frequency: 0.000001 to <0.05) with regional cortical and subcortical grey matter volumes, controlling for age, sex, total intracranial volume, mutation status, population stratification, and family membership (kinship matrix). In two separate analyses, we used the following set of annotations to account for (i) loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous, (ii) insertions, deletions, and frameshift mutations (indel‐fs).ResultOf the 517 participants (300 women), 307 were mutation carriers (symptomatic = 82). For LOF mutations (731 genes tested; significance threshold: p = 0.05/731 = 6.8×10−5), aggregate burden of variants in BSND were associated with lower volumes in: temporal (p = 6.6×10−6), left insula (p = 5.0×10−5), and ventromedial prefrontal cortical (p = 2.8×10−5) regions. For indel‐fs mutations (826 genes tested; significance threshold: p = 0.05/826 = 6.05×10−5), aggregate burden of variants in: (i) E2F2 was associated with lower volumes in occipital (p = 8.7×10−6) regions; (ii) TMEM61 was associated with lower volumes in left temporal (p = 7.8×10−7), and left cingulate regions (p = 5.5×10−5); (iii) KDM4A‐AS1 was associated with lower volumes in the right temporal (p = 3.2×10‐7) region. All genes are variably expressed in the brain.ConclusionIdentification of deleterious or protective low‐frequency variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication of results followed by functional studies are needed.

Optimising remote sampling of NfL and GFAP using blood cards in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort

AbstractBackgroundIn recent years, blood‐based biomarkers have become key measures in the study of dementia, including frontotemporal dementia (FTD), with use in diagnosis and clinical trial outcomes. Remote collection of blood samples provides a more accessible and cost‐effective alternative to regular clinic visits and allows for more frequent measures to be taken. This is particularly relevant as we progress into an era of clinical trials in FTD. The aim of this current study was to assess whether neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), markers previously shown be increased in genetic forms of FTD, can be measured using dried blood cards and to optimise the protocol for this.Method10 participants from the University College London GENFI study (three C9orf72 mutation carriers, four GRN mutation carriers and three mutation negative controls) were included in this pilot study. Blood samples were collected by venepuncture from each participant: one sample for plasma analysis and one sample which was used to pipette whole blood on to a blood card. NfL and GFAP concentrations were subsequently quantified using the Simoa multiplex Neurology 4‐Plex A (N4PA) assay in both plasma and the dried blood card. Total protein concentration was measured with the Bradford protein assay and used to correct for variable concentrations of blood card spots. The effect of incubation temperature and time as well as freeze thaw cycles were also assessed as part of the optimisation process.ResultIn this pilot cohort, blood card GFAP concentration (BSA corrected) very strongly correlated with matched plasma GFAP (r = 0.897, p = 0.0004), whilst blood card NfL concentration (BSA corrected) strongly correlated with matched plasma NfL (r = 0.721, p = 0.0234). Incubation temperature impacted total protein concentration in the blood cards, but freeze‐thaw and incubation time did not.ConclusionThis pilot study shows that NfL and GFAP concentrations can be successfully quantified using dried blood cards and results strongly correlate with plasma measures. Future work will involve investigating whether these biomarkers can be measured in blood cards obtained with capillary blood through lancet‐based fingerprick collection and assessing the feasibility of home collection.

Developing a mass spectrometric assay to measure granulin peptides in CSF for progranulin‐associated frontotemporal dementia

AbstractBackgroundPathogenic mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), inducing a reduced biofluid concentration of the progranulin protein (PGRN). PGRN is a cysteine‐rich glycoprotein with essential roles in inflammation and lysosomal function, made up of 7 granulin peptides and 1 paragranulin. The role of these peptides is unclear, but existing data suggests they may have contradictory roles to full‐length PGRN. With the development of numerous clinical trials aiming to treat progranulin‐associated FTD (FTD‐GRN) by increasing full‐length PGRN, it is important to establish effective outcome measures to assess treatment success and further our understanding of PGRN’s biology. Here, we aimed to develop an assay to quantify granulin peptides in cerebrospinal fluid (CSF) and determine whether they contribute to the pathology of FTD‐GRN.MethodBased on previously published explorative data of endogenous CSF peptides, 12 peptides spanning the progranulin sequence, were selected for the development of targeted assays using a quadrupole Orbitrap hybrid mass spectrometer (Fusion Tribrid, Thermo). An analytical protocol was optimised involving reduction, alkylation, molecular weight cut‐off filtration and solid phase extraction, and using isotope labelled heavy standards for quantification. Additionally, tandem mass tag (TMT) proteomics was used to analyse tryptic peptides spanning granulin and paragranulin sequence regions in 248 CSF samples from the Genetic FTD initiative (GENFI) including 56 GRN mutation carriers and 76 mutation‐negative controls.ResultPreliminary results reveal the presence of three endogenous peptides in CSF, which based on sequence matching, likely represent granulin 6 and 7 alongside the paragranulin peptide. TMT results showed significantly reduced relative peptide intensity across the granulin regions in GRN carriers CSF compared to controls (p<0.0001), but no significant difference in the paragranulin region (p>0.33).ConclusionThese findings indicate that two granulins and paragranulin are quantifiable in CSF and may have key roles in progranulin biology and potentially FTD pathology. This is supported by TMT results of differential CSF paragranulin levels compared to granulins. Continuing work will quantify CSF granulin concentrations in the GENFI cohort to assess whether these peptides have key roles in FTD‐GRN’s underlying biology and as potential outcome measures in trials.

A portable eye tracking experiment for the assessment of cognitive impairment in presymptomatic frontotemporal dementia

AbstractBackgroundEye tracking can be useful for measuring cognitive function in frontotemporal dementia (FTD), as the tasks do not require behavioural or verbal responses. However, most systems are highly expensive and require experiments to be conducted in artificial environments. We developed a fully portable eye tracking protocol using the Tobii Pro Nano, a small, low‐cost eye tracker. The aim was to investigate if the portable experiment can detect presymptomatic impairment in FTD using instructionless tasks of social cognition.MethodParticipants were recruited from the Genetic FTD Initiative (GENFI), including 41 mutation carriers (mean age = 43.0, standard deviation (SD) = 11.0), and 14 non‐carriers (mean age = 40.4, SD = 7.14). Participants completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and three non‐target) followed by a target emotion word and then the original four images alongside the emotion word. A dwell time change score was calculated by subtracting the percentage dwell time for the target image before the word appeared from the percentage dwell time after the word appeared. A lower dwell time change score signifies impaired performance. Linear mixed effects models were used to compare performance on each of the tests, with the dwell time change score included as the variable of interest and age, target type (target, non‐target), and genetic status (carrier, non‐carrier) included in the model as fixed effects.ResultThe average (standard deviation) mean percentage dwell time change score in the target image was lower at 52.2% (15.8) for the mutation carriers compared with 56.5% (7.01) for non‐carriers on the simple emotion task (p = 0.006), and 23.4% (11.2) for carriers compared with 27.3% (7.46) for non‐carriers on the complex emotion task (p = 0.076).ConclusionThese eye tracking tasks may be a useful tool for assessing deficits in social cognition in presymptomatic FTD, something that has been difficult to measure with pen and paper neuropsychometry. Therefore, this portable eye tracking experiment has the potential to be a low‐cost biomarker for monitoring the progression of FTD in clinical trials, both at home and in the clinic.

DTI changes of thalamic subregions in genetic frontotemporal dementia: findings from the GENFI cohort

AbstractBackgroundAtrophy of thalamic subregions has been observed across the spectrum of frontotemporal dementia (FTD). To gain better insight into underlying tissue changes, we investigated how thalamic subregional fractional anisotropy (FA) and mean diffusivity (MD) derived from diffusion tensor imaging (DTI) are altered in genetic FTD.MethodWe used our newly developed thalamus segmentation tool, which jointly combines structural and diffusion input MRI data, to segment thalami and extract thalamic subregional FA and MD values for 163 genetic mutation carriers and 126 non‐carriers with suitable 3T MRI data from the GENetic FTD Initiative (GENFI). Mutation carriers were divided according to their genetic diagnosis and CDR®+NACC FTLD global scores into presymptomatic/prodromal (≤0.5: 41 C9orf72, 59 GRN, 34 MAPT) and symptomatic (≥1: 8 C9orf72, 11 GRN, 10 MAPT) groups. Mean FA and MD values for thalamic subregions were obtained using diffusion tensors interpolated in the log domain and weighted by segmentation posterior probabilities. Thalamic subregional FA and MD values for presymptomatic and symptomatic mutation carriers within each genetic group were compared with non‐carriers using analysis of covariance with bootstrapping, where age, scanner type, and sex were covariates. We corrected for multiple comparisons and calculated percentage changes in adjusted FA and MD mean values for mutation carriers relative to non‐carriers.ResultThe only significant change at the presymptomatic stage was found for C9orf72 expansion carriers, who showed FA reduction in the intralaminar subregion (5%) (Figure 1, Table 1). In symptomatic C9orf72 expansion carriers, FA was reduced in the laterodorsal (21%), lateral posterior (13%), anteroventral (13%) and intralaminar (11%) subregions. Symptomatic MAPT mutation carriers also showed FA reduction in the laterodorsal (15%) and anteroventral (11%) subregions. No significant FA reductions were found for GRN mutation carriers and no significant MD changes were observed for any group after correction for multiple comparisons.ConclusionWe detected FA reductions of thalamic subregions only for C9orf72 expansion carriers at the presymptomatic stage, and for C9orf72 and MAPT mutation carriers at the symptomatic stage. Combined with the lack of robust MD changes, our findings may warrant further assessment of thalamic microstructure with more advanced diffusion models.

Examining longitudinal changes of disease severity scores in familial forms of frontotemporal dementia within the GENFI cohort

AbstractBackgroundThe CDR®+NACC FTLD Sum of Boxes (SB) score is a well‐established measure of disease severity in frontotemporal dementia (FTD), however, few studies have assessed longitudinal changes in score within familial forms of FTD.Method343 participants from the Genetic FTD Initiative (77 mutation‐negative controls, 109 C9orf72 expansion carriers, 105 GRN mutation carriers, and 52 MAPT mutation carriers), with available scores on the CDR®+NACC FTLD‐SB and the FTD Rating Scale (FRS) at baseline and follow‐up, were examined. Using the baseline FRS percentage scores, mutation carriers were stratified into four groups: asymptomatic/very mild (100‐97%), mild (96‐80%), moderate (79‐41%), and severe (40‐0%). Linear regression models with bootstrapping were used to assess annualised change in CDR®+NACC FTLD‐SB scores across genetic groups between participants' first and follow‐up visit.Result C9orf72 and GRN mutation carriers in the moderate and severe groups, as well as mild GRN carriers, showed significantly greater change than controls (p < 0.050). No significant differences in change scores were observed between MAPT mutation carriers and controls. Comparisons within genetic groups revealed that both the moderate and severe GRN and C9orf72 expansion carriers showed larger annualised change relative to their asymptomatic/very mild counterparts (p < 0.001 and p = 0.037; p = 0.028 and p < 0.001, respectively). The moderate GRN and severe C9orf72 groups also demonstrated greater annualised score changes than their respective mild counterparts (p < .001; p = 0.001). For MAPT mutation carriers, no significant changes were observed. Between genetic group comparisons revealed significant change score differences between the moderate individuals, with GRN mutation carriers showing a greater change than the C9orf72 and MAPT groups (both p < 0.001), and the C9orf72 group showing a larger annualised change than the MAPT mutation carriers (p = 0.041).ConclusionThe CDR®+NACC FTLD‐SB detects significant changes in disease severity from baseline to a first follow‐up visit in familial forms of FTD, with GRN mutation carriers showing the greatest annualised change.

Altered plasma protein profiles in genetic FTD – a GENFI study

BackgroundPlasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia.MethodsBlood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins.ResultsWe found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers.ConclusionWe identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

ObjectiveTo identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. ConclusionsLanguage deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.

Hypothalamic volumes predict sleep dysfunction in genetic frontotemporal dementia

AbstractBackgroundSleep dysfunction is common in neurodegenerative disorders, however, its neural correlates, remain poorly characterized in genetic frontotemporal dementia (FTD). Atrophy in two hypothalamic nuclei, the suprachiasmatic nucleus and the lateral hypothalamic area, important for sleep regulation, may be related to this dysfunction. Thus, we examined changes in cerebral and hypothalamic structure across the lifespan in genetic FTD and their relations to measures of sleep dysfunction.MethodData was retrieved from the Genetic Frontotemporal Dementia Initiative (GENFI). T1‐weighted structural MRI images and scores on the Cambridge Behavioural Inventory‐Revised (CBI‐R) sleep subscale were obtained from subjects with mutations causative of FTD (n = 491, scan number = 1029) and healthy controls (n = 321, scan number = 739). MRI images were processed for cortical thickness using CIVET 2.1 and hypothalamic volumes using a deep learning segmentation algorithm (Billot et al., NeuroImage 2020). Using linear mixed‐effects models, we examined changes in sleep dysfunction, vertex‐wise differences in cortical thickness, and volumetric changes in hypothalamic regions in mutation carriers compared to controls. Further, using linear mixed‐effects models, we examined associations between cortical and hypothalamic atrophy and changes in the CBI‐R sleep subscale while controlling for age, sex, scanning site, and disease severity based on the MMSE.ResultMutation carriers showed greater sleep dysfunction across the lifespan, and this increased closer to the predicted onset of symptoms, compared to controls (p < 0.01), with MAPT carriers having greater dysfunction overall (figure 1). All mutation carriers showed patterns of cortical thinning (figure 2) commensurate with the literature (p < 0.05, FDR corrected). Further, cortical thinning in frontal and parietal regions were associated with greater sleep disturbance in C9orf72 and GRN mutation carriers (p < 0.05, FDR corrected) (figure 3). Lastly, MAPT mutation carriers showed consistently significant hypothalamic volume loss across the lifespan (figure 4) (p < 0.01) and reduced hypothalamic volumes were related to increased sleep dysfunction (p < 0.05) (Figure 5).ConclusionThese findings suggest that while cortical thinning in C9orf72 and GRN carriers non‐specifically correlate with increased sleep dysfunction, the increased sleep dysfunction observed in MAPT carriers may be attributable to increased hypothalamic atrophy.

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia.

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPTcarriers.

Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort.

Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.

Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia.

Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.

Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

BackgroundCurrent clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage.Methods832 participants from the Genetic FTD Initiative (GENFI) were recruited:...

Magnetic resonance imaging biomarkers in genetic FTD

AbstractBackgroundMRI provides a suite of tools for safe, non‐invasive, repeatable and scalable assessment of the changes in brain structure and function associated with neurodegenerative disease. MRI has been part of the principal assessment in the international Genetic Frontotemporal Dementia Initiative since 2012 (GENFI). This presentation reviews the goals and achievements of MRI in GENFI, and considers future directions to elucidate disease mechanisms, inform clinical trials design, and provide single subject prognosis.MethodGENFI established protocols for harmonisation and standardisation of MRI, and coordinated infrastructure for curation and quality control. 3T MRI sequences have been optimised and closely approximated across diverse vendors, for whole‐brain qualification of volume (T1w), diffusion (DWI), perfusion (ASL), macro‐molecular environment (T2) and function (BOLD fMRI), with >2500 assessments from>1000 participants: including symptomatic people with mutations in MAPT, C9orf72 and GRN; pre‐symptomatic mutation‐carriers; and asymptomatic non‐carriers from the same families. There are >20 peer‐reviewed open‐access MRI‐based publications to date.ResultsGENFI MRI revealed a long pre‐symptomatic phase in people with FTD‐associated mutations, with atrophy present and progressive in frontotemporal regions >10 years before estimated onset. For some mutations, differences in mutation carriers (vs non‐carriers) are evident in early adulthood. The pre‐symptomatic structural change is associated with subtle cognitive and behavioural change. It is prognostic and non‐linear, accelerating with aging towards symptom onset. Intriguingly, functional integration is maintained in macro‐scale brain networks of pre‐symptomatic carriers, suggesting a mechanism of functional resilience to progression of underlying neuropathology. The consequences of mutations are not confined to frontotemporal regions: GENFI has highlighted behaviourally‐relevant changes in volume and shape, white‐matter hyperintensity and diffusivity in parietal lobe, basal ganglia, thalamus and cerebellum. The MRI tools can be used to identify stages and subtypes of genetic‐FTD.ConclusionOver ten years, GENFI has shown how MRI can be delivered at scale in multi‐centre studies of genetic FTD, revealing the long pre‐symptomatic phase, with gene‐specific mechanisms and consequences. The sensitivity, reliability and progression of gene‐specific changes in diverse MRI modalities are ideal to support clinical trials of novel therapeutic agents.

Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study.

The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia.

Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.

Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

BackgroundNeuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers.MethodsWe measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).ResultsCSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores.ConclusionsElevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.

Frequency and Longitudinal Course of Motor Signs in Genetic Frontotemporal Dementia.

Background and ObjectivesFrontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) gene. As motor disorders are increasingly recognized as part of the clinical spectrum, the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.MethodsWe analyzed baseline visit data of known carriers of a pathogenic variant in the c9orf72, GRN, or MAPT gene from the Genetic Frontotemporal Dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset.ResultsA total of 322 pathogenic variant carriers were included in the analysis: 122 c9orf72 (79 presymptomatic), 143 GRN (112 presymptomatic), and 57 MAPT (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 motor clusters, which we call progressive supranuclear palsy (PSP)-like, bulbar amyotrophic lateral sclerosis (ALS)-like, mixed/ALS-like, Parkinson disease (PD) like, and corticobasal syndrome–like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. Although the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction influenced motor signs. In c9orf72 pathogenic variant carriers, motor signs could be detected up to 25 years before expected symptom onset.DiscussionThese results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinicogenetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Hierarchical spectral clustering reveals brain size and shape changes in asymptomatic carriers of C9orf72.

Traditional methods for detecting asymptomatic brain changes in neurodegenerative diseases such as Alzheimer’s disease or frontotemporal degeneration typically evaluate changes in volume at a predefined level of granularity, e.g. voxel-wise or in a priori defined cortical volumes of interest. Here, we apply a method based on hierarchical spectral clustering, a graph-based partitioning technique. Our method uses multiple levels of segmentation for detecting changes in a data-driven, unbiased, comprehensive manner within a standard statistical framework. Furthermore, spectral clustering allows for detection of changes in shape along with changes in size. We performed tensor-based morphometry to detect changes in the Genetic Frontotemporal dementia Initiative asymptomatic and symptomatic frontotemporal degeneration mutation carriers using hierarchical spectral clustering and compared the outcome to that obtained with a more conventional voxel-wise tensor- and voxel-based morphometric analysis. In the symptomatic groups, the hierarchical spectral clustering-based method yielded results that were largely in line with those obtained with the voxel-wise approach. In asymptomatic C9orf72 expansion carriers, spectral clustering detected changes in size in medial temporal cortex that voxel-wise methods could only detect in the symptomatic phase. Furthermore, in the asymptomatic and the symptomatic phases, the spectral clustering approach detected changes in shape in the premotor cortex in C9orf72. In summary, the present study shows the merit of hierarchical spectral clustering for data-driven segmentation and detection of structural changes in the symptomatic and asymptomatic stages of monogenic frontotemporal degeneration.