Häkkinen, Suvi

Abstract Background A hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. There remains a critical need for biomarkers that track disease progression across clinical stages. Cross‐sectionally, intrinsic connectivity networks (ICNs) derived from task‐free fMRI (tf‐fMRI) detects abnormalities in C9orf72 expansion carriers ( C9orf72+ ), even when brain structural differences are subtle (Lee et al. , 2017). Few studies have examined longitudinal connectivity changes in C9orf72+ , however. Methods We analyzed longitudinal structural and tf‐fMRI data and plasma neurofilament light chain (NfL) concentrations of C9orf72+ recruited from UCSF and the ALLFTD Consortia. Mean time from first to last scan was 2.4±1.3 years. Participants included 36 asymptomatic (aSx‐ C9 ), 17 prodromal (prodromal‐ C9 ), 29 symptomatic (Sx‐ C9 ) carriers, and 107 healthy controls (HC). For structural MRI analyses, smoothed gray matter maps were parcellated into 246 regions‐of‐interest based on the Brainnetome atlas. We conducted voxelwise seed‐based tf‐fMRI analyses to examine ICNs showing alterations C9orf72+ based on previous literature: salience network (SN), sensorimotor network (SMN), default mode network (DMN), and a medial pulvinar thalamus network (pulvinar). General linear models and linear mixed models (LMM) compared C9orf72+ groups to HC in baseline and longitudinal gray matter and functional connectivity, as well as examined associations between longitudinal functional connectivity changes and baseline NfL concentrations. Results Despite a lack of longitudinal gray matter decline, aSx‐ and Sx‐ C9orf72+ showed functional connectivity changes. Compared to HC, aSx‐ C9 had baseline hypoconnectivity in the SN, SMN, and pulvinar network. Longitudinally, this group showed declines in the SN and pulvinar network, alongside DMN increases. Prodromal‐ C9 exhibited baseline SMN hypoconnectivity and hyperconnectivity in the DMN and pulvinar network, but no significant longitudinal changes. Sx‐ C9 showed baseline hypoconnectivity in SN, SMN, and DMN, with additional regions of DMN hyperconnectivity, while longitudinally, SN and SMN connectivity increased. In aSx‐ C9 , higher baseline NfL concentrations correlated with regions of SMN decreases over time and both increases and decreases in the pulvinar network. In prodromal‐ C9 and Sx‐ C9 combined, higher NfL was associated with DMN increases longitudinally. Conclusions Though gray matter declines were undetectable over a span of several years, functional connectivity networks changed dynamically in C9orf72+ .

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.

AbstractBackgroundPresymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking.MethodLeveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only).ResultWe found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN.ConclusionDespite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers.

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.

ObjectiveMicrotubule‐associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task‐free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross‐sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed‐based analyses to examine connectivity within networks associated with the 4 most common MAPT‐associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole‐brain connectivity analyses. We applied K‐means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole‐brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT‐syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole‐brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632–646

AbstractBackgroundClinical trials for tauopathies require novel biomarkers for disease detection and monitoring. One previous study found functional connectivity (FC) alterations in presymptomatic (preSx) MAPT mutation carriers (Whitwell et al., 2011), yet studies have not examined FC networks along the MAPT disease continuum. We hypothesized that both symptomatic (Sx) and preSx MAPT mutation carriers would show FC alterations compared to healthy controls (HC).MethodLeveraging task‐free fMRI data from the UCSF Memory and Aging Center and the ARTFL/LEFFTDS Consortia (Boeve et al., 2019), we compared 14 Sx and 33 preSx to 80 HC to characterize their FC profiles. Using a seed‐based approach, we studied FC within networks associated with different MAPT clinical syndromes (i.e., salience network [SN] for behavioral variant frontotemporal dementia, default mode network [DMN] for Alzheimer’s‐like amnestic syndrome, corticobasal syndrome [CBS] and progressive supranuclear palsy [PSP] networks). Complementing the seed‐based approach, we next calculated whole‐brain intra‐/inter‐network FC matrices for 14 networks (Brown et al., 2019), and applied K‐means clustering to assess whether preSx displayed heterogeneous connectivity profiles. ComBat was applied to harmonize multi‐site imaging data (Fortin et al., 2017, 2018). Thresholding was set at a joint height and extent threshold of p<0.05 (uncorrected) with age, sex, education and handedness as nuisance covariates.ResultCompared to HC, Sx featured disrupted FC within key hubs of all four networks, and regions of cerebellar and pontine hyperconnectivity within CBS and PSP networks. As seen in Sx vs. HC, preSx had similar anatomical patterns of SN/CBS network hypoconnectivity and CBS/PSP network hyperconnectivity vs. HC. In contrast to Sx, who had DMN disruption, preSx showed DMN hyperconnectivity vs. HC.Whole‐brain analyses revealed that Sx had disrupted intra‐/inter‐network FC in networks involving the insula/anterior temporal lobe. Clustering analysis identified two preSx subgroups. Compared to HC, preSx1 principally had disrupted FC across networks including those disrupted in Sx, whereas preSx2 mainly demonstrated hyperconnectivity.ConclusionSx and preSx both demonstrated robust FC alterations. Future studies will investigate whether the preSx subgroup whose whole‐brain FC was similar to Sx in that it showed principally FC disruption may be at greater risk for imminent symptom conversion and/or neurodegeneration.

AbstractBackgroundProgranulin (GRN) mutations cause autosomal dominant frontotemporal lobar degeneration. Clinical trials for GRN‐targeted therapies are underway, yet reliable biomarkers to predict onset and track disease progression remain elusive. Task‐free functional MRI (tf‐fMRI) connectivity may be more sensitive than structural measures for detecting presymptomatic changes (Dopper, 2014; Premi, 2016). Presymptomatic GRN feature tf‐fMRI hyperconnectivity that is more pronounced in older carriers presumably closer to symptom onset, suggesting hyperconnectivity may be a harbinger of disease (Lee, 2019). To aid the interpretation of hyperconnectivity, we explored relationships of structural and tf‐fMRI measures with candidate fluid biomarkers for GRN: CSF complement proteins C3b and C1q, which drive neurodegeneration in GRN ‐/‐ mice (Lui, 2016) and plasma neurofilament light chain (NfL), a marker of axonal injury.MethodWe studied 20 symptomatic GRN (Sx), 39 presymptomatic GRN (preSx), and 67 healthy‐controls (HC). Cross‐sectional CSF C3b, C1q, and plasma NfL concentrations were compared between groups. Correlations controlling for age assessed relationships between fluid biomarkers and symptom severity (CDR®+NACC‐FTLD box score). Voxelwise multiple regression models examined interactions between fluid biomarkers and gene status on grey matter probability maps (GM) and voxelwise tf‐fMRI whole‐brain weighted degree (WBD) maps.ResultComplement concentrations were similar between Sx, preSx, and HC. Across all GRN, C3b concentrations increased with symptom severity (r=0.34, p=0.04). In Sx, but not preSx, higher C3b was associated with increased WBD in medial‐frontal regions, left insula, and thalamus compared to HC. Sx had higher NfL concentrations compared to preSx and HC. Across all GRN and in Sx, higher NfL was associated with greater symptom severity (r=0.60, p<0.001; r=0.72, p<0.001). In Sx, higher NfL was associated with lower GM in precuneus and bilateral frontoinsular cortices, but not WBD, compared to HC. In preSx, higher NfL was associated with increased WBD in thalamus and right temporal regions, but not GM, compared to HC.ConclusionC3b and NfL concentrations correlated with symptom severity. C3b concentrations were associated with tf‐fMRI connectivity alterations in Sx while NfL concentrations were associated with connectivity alterations in preSx. Longitudinal studies are needed to determine temporal relationships between altered connectivity, atrophy, complement, NfL rise, and symptom onset.