Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results.

INTRODUCTION: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. HIGHLIGHTS: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Occupational differences in a Dutch sample of patients with primary progressive aphasia, behavioral variant frontotemporal dementia, and Alzheimer's dementia.

BACKGROUND: Cognitive reserve is a potential mechanism to cope with brain damage as a result of dementia, which can be defined by indirect proxies, including education level, leisure time activities, and occupational attainment. In this study we explored the association between dementia diagnosis and type of occupation in a retrospective Dutch outpatient memory clinic sample of patients with primary progressive aphasia (PPA), behavioral variant frontotemporal dementia (bvFTD), and Alzheimer's Dementia (AD). METHODS: We included data from 427 patients (bvFTD n = 87, PPA n = 148, AD n = 192) and compared the frequency of occupations (11 categories) between patients and data from the Dutch census using Pearson Χ2 tests and we calculated odds ratios (OR) by means of multinomial logistic regression analyses. We also investigated patient group differences in age, sex, education, disease duration, and global cognition. RESULTS: The frequency of teachers in patients with PPA was significantly higher than the frequency of teachers in patients with bvFTD [OR = 4.79, p = .007] and AD [OR = 2.04, p = .041]. The frequency of teachers in patients with PPA (16%) was also significantly higher than the frequency of teachers in the Dutch census [5.3%; OR = 3.27, p < .001]. The frequency of teachers in both bvFTD and AD groups were not significantly different from the frequency of teachers in the Dutch census (p = .078 and p = .513, respectively). CONCLUSIONS: A potential explanation for our results is the so called "wear and tear" hypothesis, suggesting that teachers have a communication-wise demanding occupation - and therefore are at higher risk to develop PPA. Alternatively, teaching requires continuous communication, hence teachers are more sensitive to subtle changes in their speech and language abilities. Our findings broaden our understanding of the relationship between occupational activity and cognitive reserve in the development of dementia.

Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia.

OBJECTIVE: Methylation of plasma cell-free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. METHODS: cfDNA was isolated from cross-sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome-wide methylation of cfDNA was determined using a high-resolution sequencing technique (MeD-seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). RESULTS: Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription-start-site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin-dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. INTERPRETATION: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.

BACKGROUND: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. METHODS: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. RESULTS: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). CONCLUSIONS: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study.

BACKGROUND: Blood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites. METHODS: Comparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer. RESULTS: NfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12±1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model. CONCLUSIONS: Our results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

Altered plasma protein profiles in genetic FTD - a GENFI study.

BACKGROUND: Plasma 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. METHODS: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. RESULTS: We 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. CONCLUSION: We 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.

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS: In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. RESULTS: We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION: NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

BACKGROUND: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. METHODS: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. RESULTS: The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. CONCLUSIONS: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

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.

Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study.

BACKGROUND: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. METHODS: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. RESULTS: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). CONCLUSIONS: This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

The ScreeLing: Detecting Semantic, Phonological, and Syntactic Deficits in the Clinical Subtypes of Frontotemporal and Alzheimer's Dementia.

The ScreeLing is a screening instrument developed to assess post-stroke aphasia, via the linguistic levels Syntax, Phonology, and Semantics. It could also be a useful test for the clinical subtypes of frontotemporal dementia (FTD) and Alzheimer's dementia (AD), as specific and often selective disorders are expected. Its ability to differentiate between the clinical subtypes of FTD and AD is, however, still unknown. We investigated differences in ScreeLing total and subscores, linguistic-level disorders' relationship with disease severity, and classification abilities, in patients with behavioral variant FTD (bvFTD; n = 46), patients with primary progressive aphasia (PPA; n = 105) (semantic variant primary progressive aphasia [svPPA], non-fluent variant primary progressive aphasia [nfvPPA], and logopenic variant primary progressive aphasia [lvPPA], AD [n = 20] and controls [n = 35]). We examined group differences in ScreeLing total and subscores, and one-, two- or three-level linguistic disorders using one-way analyses of covariance (ANCOVAs) or Quade's rank ANCOVA. We used frequency analyses to obtain the occurrence of the linguistic-level disorders. We determined sensitivity and specificity by the area under the curve by receiver-operating characteristics analyses to investigate classification abilities. The total score was lower in patients (bvFTD: 63.8 ± 8.5, svPPA: 58.8 ± 11.3, nfvPPA: 63.5 ± 8.4, lvPPA: 61.7 ± 6.6, AD: 63.8 ± 5.5) than controls (71.3 ± 1.0) (p < .001). Syntax subscores were lower in svPPA (19.4 ± 4.6; p < .001) and lvPPA (20.3 ± 3.2; p = .002) than controls (23.8 ± 0.4). Phonology subscores were lower in lvPPA (19.8 ± 2.6) than bvFTD (21.7 ± 2.8) (p = .010). Semantics subscores were lowest in svPPA (17.8 ± 5.0; p < .002). A selective phonological disorder was most prevalent in lvPPA (34.9%). The higher the disease severity, the more linguistic-level disorders. The optimal cutoff for the total score was 70, and 23 for all three subscores. Good classification abilities were found for the Semantics (svPPA vs. bvFTD), Phonology (lvPPA vs. svPPA), and Syntax (nfvPPA vs. lvPPA) subscores. This easy to administer test gives information about language processing with the potential to improve differential diagnosis in memory clinics and in the future potentially also clinical trial planning.

Addition of the FTD Module to the Neuropsychiatric Inventory improves classification of frontotemporal dementia spectrum disorders.

Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer's dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension 'frontal-behavioural symptoms'. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.

The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study.

OBJECTIVE: Sensitive cognitive markers are still needed for frontotemporal dementia (FTD). The Benson Complex Figure Test (BCFT) is an interesting candidate test, as it assesses visuospatial, visual memory, and executive abilities, allowing the detection of multiple mechanisms of cognitive impairment. To investigate differences in BCFT Copy, Recall and Recognition in presymptomatic and symptomatic FTD mutation carriers, and to explore its cognitive and neuroimaging correlates. METHOD: We included cross-sectional data from 332 presymptomatic and 136 symptomatic mutation carriers (GRN, MAPT or C9orf72 mutations), and 290 controls in the GENFI consortium. We examined gene-specific differences between mutation carriers (stratified by CDR® NACC-FTLD score) and controls using Quade's / Pearson Χ2 tests. We investigated associations with neuropsychological test scores and grey matter volume using partial correlations and multiple regression models respectively. RESULTS: No significant differences were found between groups at CDR® NACC-FTLD 0-0.5. Symptomatic GRN and C9orf72 mutation carriers had lower Copy scores at CDR® NACC-FTLD ≥2. All three groups had lower Recall scores at CDR® NACC-FTLD ≥2, with MAPT mutation carriers starting at CDR® NACC-FTLD ≥1. All three groups had lower Recognition scores at CDR® NACC FTLD ≥2. Performance correlated with tests for visuoconstruction, memory, and executive function. Copy scores correlated with frontal-subcortical grey matter atrophy, while Recall scores correlated with temporal lobe atrophy. CONCLUSIONS: In the symptomatic stage, the BCFT identifies differential mechanisms of cognitive impairment depending on the genetic mutation, corroborated by gene-specific cognitive and neuroimaging correlates. Our findings suggest that impaired performance on the BCFT occurs relatively late in the genetic FTD disease process. Therefore its potential as cognitive biomarker for upcoming clinical trials in presymptomatic to early-stage FTD is most likely limited.

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

BACKGROUND: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. METHODS: 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. RESULTS: Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. CONCLUSIONS: Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers.

While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period.

Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

Neuropsychological assessment in the multicultural memory clinic: Development and feasibility of the TULIPA battery.

Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics.Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands.The test battery included existing tests such as the Cross-Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), tests from the European Cross-Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%-100%), except for CCD Dots subtest B (58%). Although tests of the "core" TULIPA battery were administered often (median: 6 of 7, IQR: 5-7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0-3). The number of administered tests correlated with disease severity (RUDAS, ρ=.33, adjusted p < .001), but not with other patient characteristics. Complicating factors were observed frequently, e.g. suboptimal effort (29%-50%), fatigue (29%), depression (37%-57%).The TULIPA test battery is a promising new battery to assess culturally diverse populations in a feasible way, provided that complicating factors are taken into account.Supplemental data for this article is available online at https://doi.org/10.1080/13854046.2022.2043447 .

Longitudinal Brain Atrophy Rates in Presymptomatic Carriers of Genetic Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: It is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD, using normative brain volumetry software. METHODS: Presymptomatic GRN, MAPT, and C9orf72 pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib® ND which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared to reference centile curves based on a large population-derived sample of non-demented individuals (n=4951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age. RESULTS: 34 GRN, eight MAPT, and 14 C9orf72 pathogenic variant carriers were included (mean age=52.1, standard deviation=7.2; 66% female). Mean follow-up duration of the study was 64±33 months (median=52; range 13-108). GRN pathogenic variant carriers showed faster decline than the reference centile curves for all brain areas, though relative volumes remained between 5th and 75th percentile between the ages of 45-70. In MAPT pathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45, and showed further decline between the ages 50-60. Temporal lobe volume started in the 50th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5th percentile compared to the reference centile curves at age 45 for C9orf72 pathogenic variant carriers, but there was minimal decline over time until the age of 60. DISCUSSION: We provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease-tracking and staging biomarkers in genetic FTD. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response.

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

BACKGROUND: Neuroinflammation 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. METHODS: We 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). RESULTS: CSF 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. CONCLUSIONS: Elevated 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.