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.

Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-ß, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-ß (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-ß burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.

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.

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.

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.

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.

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 MAPT carriers.

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.

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia.

Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.

Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia.

INTRODUCTION: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). METHODS: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. RESULTS: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. DISCUSSION: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. HIGHLIGHTS: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.

Apolipoprotein L1 is increased in frontotemporal lobar degeneration post-mortem brain but not in ante-mortem cerebrospinal fluid.

AIMS: Frontotemporal Dementia (FTD) is caused by frontal-temporal lobar degeneration (FTLD), characterized mainly by brain protein aggregates of tau (FTLD-Tau) or TDP-43 (FTLD-TDP). The clinicopathological heterogeneity makes ante-mortem diagnosis of these pathological subtypes challenging. Our proteomics study showed increased Apolipoprotein L1 (APOL1) levels in CSF from FTD patients, which was prominently expressed in FTLD-Tau. We aimed to understand APOL1 expression in FTLD post-mortem brain tissue and to validate its potential as a CSF biomarker for FTD and its pathological subtypes. METHODS: APOL1 levels were analyzed in the frontal cortex of FTLD (including FTLD-Tau and FTLD-TDP) and non-demented controls by immunohistochemistry (FTLD total = 18 (12 FTLD-Tau and 6 FTLD-TDP); controls = 9), western blot (WB), and a novel prototype ELISA (FTLD total = 44 (21 FTLD-Tau and 23 FTLD-TDP); controls = 9). The association of APOL1 immunoreactivity with phosphorylated Tau (pTau) and TDP-43 (pTDP-43) immunoreactivity was assessed. CSF APOL1 was analyzed in confirmed FTD patients (n = 27, including 12 FTLD-Tau and 15 FTLD-TDP) and controls (n = 15) using the same ELISA. RESULTS: APOL1 levels were significantly increased in FTLD post-mortem tissue compared to controls as measured by immunohistochemistry, WB, and ELISA. However, no differences between the pathological subtypes were observed. APOL1 immunoreactivity was present in neuronal and glial cells but did not co-localize with pTau or pTDP-43. CSF APOL1 levels were comparable between FTD patients and controls and between pathological subtypes. CONCLUSION: APOL1 is upregulated in FTLD pathology irrespective of the subtypes, indicating a role of this novel protein in FTD pathophysiology. The APOL1 levels detected in brain tissue were not mirrored in the CSF, limiting its potential as a specific FTD biofluid-based biomarker using our current immunoassay.

Data-driven staging of genetic frontotemporal dementia using multi-modal MRI.

Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

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.

Isoform-specific patterns of tau burden and neuronal degeneration in MAPT-associated frontotemporal lobar degeneration.

Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0-4) and separate burden of glial and neuronal tau inclusions (i.e. 0-3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.

Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.

OBJECTIVE: A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay. METHODS: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS. RESULTS AND CONCLUSIONS: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts.

FRONTotemporal dementia Incidence European Research Study-FRONTIERS: Rationale and design.

INTRODUCTION: The incidence of Frontotemporal Lobar Degeneration (FTLD)-related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap. METHODS: FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long-lasting experience in FTLD-related disorders and comprehensive regional referral networks, enabling incidence estimation over well-defined geographical areas. ENDPOINTS: The primary endpoints are (1) the incidence of FTLD-related disorders across Europe; (2) geographic trends of FTLD-related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD-related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. EXPECTED IMPACTS: FRONTIERS will improve the understanding of FTLD-related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.

Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia.

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages.

Frontotemporal Dementia: Correlations Between Psychiatric Symptoms and Pathology.

OBJECTIVE: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features. METHODS: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors. RESULTS: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002). INTERPRETATION: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950-961.

Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions.

Since the discovery of the C9orf72 repeat expansion as the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis, it has increasingly been associated with a wider spectrum of phenotypes, including other types of dementia, movement disorders, psychiatric symptoms and slowly progressive FTD. Prompt recognition of patients with C9orf72-associated diseases is essential in light of upcoming clinical trials. The striking clinical heterogeneity associated with C9orf72 repeat expansions remains largely unexplained. In contrast to other repeat expansion disorders, evidence for an effect of repeat length on phenotype is inconclusive. Patients with C9orf72-associated diseases typically have very long repeat expansions, containing hundreds to thousands of GGGGCC-repeats, but smaller expansions might also have clinical significance. The exact threshold at which repeat expansions lead to neurodegeneration is unknown, and discordant cut-offs between laboratories pose a challenge for genetic counselling. Accurate and large-scale measurement of repeat expansions has been severely hindered by technical difficulties in sizing long expansions and by variable repeat lengths across and within tissues. Novel long-read sequencing approaches have produced promising results and open up avenues to further investigate this enthralling repeat expansion, elucidating whether its length, purity, and methylation pattern might modulate clinical features of C9orf72-related diseases.

Somatic TARDBP variants as a cause of semantic dementia.

The aetiology of late-onset neurodegenerative diseases is largely unknown. Here we investigated whether de novo somatic variants for semantic dementia can be detected, thereby arguing for a more general role of somatic variants in neurodegenerative disease. Semantic dementia is characterized by a non-familial occurrence, early onset (<65 years), focal temporal atrophy and TDP-43 pathology. To test whether somatic variants in neural progenitor cells during brain development might lead to semantic dementia, we compared deep exome sequencing data of DNA derived from brain and blood of 16 semantic dementia cases. Somatic variants observed in brain tissue and absent in blood were validated using amplicon sequencing and digital PCR. We identified two variants in exon one of the TARDBP gene (L41F and R42H) at low level (1-3%) in cortical regions and in dentate gyrus in two semantic dementia brains, respectively. The pathogenicity of both variants is supported by demonstrating impaired splicing regulation of TDP-43 and by altered subcellular localization of the mutant TDP-43 protein. These findings indicate that somatic variants may cause semantic dementia as a non-hereditary neurodegenerative disease, which might be exemplary for other late-onset neurodegenerative disorders.