Borderline personality disorder (BPD) is characterized by grey matter (GM) alterations in areas related to emotion regulation, impulsivity and metacognitive abilities. Dysfunction of specific neurotransmitters, including serotoninergic and dopaminergic systems, is thought to be involved, but evidence is currently limited. In this exploratory study, we tested for associations between GM alterations in BPD, the spatial distribution of neurotransmitter systems, and clinical features in a sample of 58 patients with BPD and 28 healthy controls (HC). GM volume alterations were assessed on 3T MRI using voxel-based morphometry (i) in BPD patients compared to HC and (ii) between BPD subgroups defined based on clinical features followed by spatial correlations between regional GM differences and atlas-based neurotransmitter maps. We observed smaller GM volumes in BPD patients compared to HC in the limbic, temporo-parietal, frontal medial, olfactory, and cerebellar regions (pFDR<0.05), but no association between these GM abnormalities and neurotransmitter maps of serotoninergic, dopaminergic, noradrenergic, glutamatergic, GABAergic, opioid and endocannabinoid systems (pFDR>0.05). Our results do not support the notion of a direct relationship between BPD-related GM alterations and specific major neurotransmitter systems, highlighting the need for additional studies to determine the pathophysiologic mechanisms underlying structural changes.

BACKGROUND:Individuals carrying Progranulin (GRN) mutations show asymmetrical grey matter atrophy, which could be used for early detection in the long asymptomatic phase. To capture these alterations, we employed both conventional Surface-Based Morphometry (SBM) and Mode-Based Morphometry (MBM). While the former provides high-resolution, location-specific estimates of cortical thickness (CT) differences, the latter has recently been introduced as a novel framework that decomposes CT maps into geometric eigenmodes, allowing a multiscale characterization of brain structural variability. Using both approaches enables the detection of complementary aspects of GRN-related neurodegeneration across spatial scales. METHODS:SBM and MBM were applied to CT maps to quantify structural alterations in individuals, 15 presymptomatic and 27 symptomatic, compared to 19 healthy controls (HC). SBM was used to assess vertex-wise CT differences, whereas MBM was used to decompose individual CT maps into geometric eigenmodes and quantify alterations across spatial scales. From both pipelines asymmetry indices (SBM-AI and MBM-AI) were computed. Associations between SBM/MBM-derived measures and domain-specific cognitive performance as well as global disease severity scores were then assessed. RESULTS:Compared with HC, symptomatic GRN showed significant alterations in seven eigenmodes in the left hemisphere, while only two modes contributed to CT differences in the right hemisphere. For MBM-AI and SBM-AI symptomatic GRN exhibited significantly different values compared to HC and presymptomatic GRN (p < 0.001). Although both asymmetry indices showed significant differences across disease stages (p = 1.3 × 10-5 SBM-AI; p = 3.5 × 10-5 MBM-AI), only the MBM-AI revealed a U-shaped trajectory across disease progression, characterized by an early increase in asymmetry followed by a partial re-symmetrisation in later stages. CONCLUSIONS:MBM revealed multiscale cortical alterations in symptomatic GRN mutation carriers, capturing both large-scale hemispheric differences and more localized regional variations in CT that are less apparent with conventional SBM. These findings indicate that GRN-related neurodegeneration involves complex spatial pattern across multiple anatomical scales. Brain asymmetry remains a core hallmark of GRN-related pathology, supporting the use of asymmetry indices (derived from both SBM and MBM) as potential markers of disease progression at the symptomatic stage.

BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) have distinct pathologies but frequently overlapping clinical presentations, making early and atypical differential diagnosis challenging. Blood-based biomarkers offer a minimally invasive alternative to cerebrospinal fluid and neuroimaging measures, yet their diagnostic performance-alone and in combination-remains to be fully established.ObjectiveTo quantify the discriminative ability of plasma biomarkers for differentiating AD, FTD, and healthy controls (HC).MethodsWe used a fully Bayesian classification framework, estimating Bayesian logistic regression models for all single, pairwise, and triplet combinations of six plasma biomarkers-phosphorylated tau at threonine 217 (pTau217), brain-derived tau (BD-Tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β40 (Aβ40), and amyloid-β42 (Aβ42)-in AD (n = 97), FTD (n = 255), and HC (n = 70). Models were fitted across three contrasts (AD versus HC, FTD versus HC, AD versus FTD) and evaluated via posterior distributions of cross-validated AUC, precision, recall, F1 score, and Brier score.ResultsAcross 41 candidate models, NfL was the top single biomarker (mean AUC = 0.85), achieving strong discrimination for FTD versus HC (AUC = 0.94). The best two-marker panel (pTau217 + NfL) improved AD versus HC (AUC = 0.96) and AD versus FTD (AUC = 0.90). Adding Aβ42 produced the highest-ranked triplet (AUC = 0.95) with modest, consistent gains. Posterior coefficients were biologically coherent (AD-specific pTau217 effects; severity-linked NfL), and calibration was satisfactory, with minor overconfidence only at extreme probabilities.ConclusionsA parsimonious pTau217 + NfL panel captures most diagnostic information in the full plasma profile, providing an accurate probabilistic classifier with interpretable uncertainty to support differential diagnosis and clinical triage in precision neurology.

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables carriers of pathogenic variants to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic carriers of pathogenic variants associated with FTD using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without pathogenic variants. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy is associated with enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology.

BACKGROUND:What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. METHODS:In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. FINDINGS:Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. INTERPRETATION:Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. FUNDING:Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.

BACKGROUND:Despite recent advances, the pathophysiology of functional neurological disorder (FND) remains incompletely understood. Structural neuroimaging studies have identified gray matter alterations in somatomotor-, salience-, limbic-, and default mode network-associated areas, although findings have been inconsistent. Mega-analyses, which combine individual-level data across studies, can help clarify structural alterations. METHODS:We conducted a mega-analysis of brain structural morphometrics derived from T1-weighted magnetic resonance imaging scans from 15 international research groups. After across-site harmonization with ComBat, we compared 493 patients with functional motor disorder and functional seizures with 564 healthy control participants. Euler numbers were included to account for head motion. RESULTS:The FND cohort showed reduced cortical thickness in the bilateral superior frontal gyri (left d = 0.22, right d = 0.21) and sulci (d = 0.22 and 0.23), bilateral superior precentral sulcus (d = 0.22 and 0.26), right precentral gyrus (d = 0.25), right paracentral gyrus and sulcus (d = 0.23), right cuneus (d = 0.23), and right inferior opercular gyrus (d = 0.21); we also found reduced left postcentral gyrus surface area (d = 0.25) and right hippocampal volume (d = 0.22). No regions were different in relative surface area. There were no associations between morphometrics and illness duration or lifetime history of depression or anxiety. Differences between motor and seizure variants were not identified. CONCLUSIONS:This large mega-analysis suggests subtle morphometric differences, particularly in prefrontal and motor regions. This may represent predisposing vulnerabilities, compensatory mechanisms, or FND-specific alterations. Improved neuropsychiatric characterization of FND research cohorts will help further contextualize the biological relevance of structural alterations.

This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.

BACKGROUND:The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking. METHODS:We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data. RESULTS:Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA. CONCLUSIONS:This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.

Individuals with autosomal dominant frontotemporal dementia (FTD) exhibit considerable variability in disease onset and progression. Both modifiable and non-modifiable factors-such as sex, educational attainment or geographic region of residence-may contribute to this heterogeneity, potentially through their influence on cognitive reserve. The aim of the present study was to investigate the role of cognitive reserve modulators within the Genetic Frontotemporal dementia Initiative (GENFI) cohort. To this end, we used functional MRI (i.e. spatial chronnectome measures) and neurodegenerative markers (i.e. plasma neurofilament light chains levels) to determine disease stage using a Discriminative Event-Based Model (DEBM). We then examined how potential modulators influence the relationship between disease stage and cognitive performance. We analysed a total of 711 participants, including 106 patients with genetic FTD, 325 presymptomatic mutation carriers and 280 non-carriers healthy controls. Female participants showed a weaker association between disease stage and cognitive performance compared to males (P < 0.001), with difference becoming progressively more pronounced across symptomatic stages. Educational attainment exhibited a similar effect: individuals with higher education demonstrated an attenuated association compared to those with secondary or primary schooling (P < 0.001), with differences already detectable at prodromal disease stages. The effect of geographical region of residence was associated with education levels, but appeared to have an indirect and less strong influence. In summary, sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD. These findings underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.

Background:Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD. Methods:This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452). Findings:A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group. Interpretation:Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials. Funding:This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease. Its variability in pathology and symptoms makes individual prognosis and diagnosis difficult. Most neuroimaging research assumes homogeneity within cohorts, but novel neuroanatomical modelling now allows for the estimation of individual deviations in brain regions from the norm. For the first time, this study aims to quantify patterns of neuroanatomical dissimilarity in patients with sporadic FTD. T1-weighted brain MR images of 355 participants (healthy controls - HC: n = 116, 78 females, mean age=51.16 years; patients with behavioural variant FTD – bvFTD: n = 197, 78 females, mean age=66.43 years; patients with semantic variant primary progressive aphasia – svPPA: n = 42, 23 females, mean age=63.85 years) were processed using FreeSurfer v.6.0.0, and the output was visually inspected. Cortical thickness and subcortical volumes across 187 regions were extracted and used as input for a normative model, with a reference dataset of ∼58,000 healthy individuals. 70% of HCs were used to adapt the Bayesian linear regression algorithm, accounting for age, sex, and site. The remaining 30% of HCs and all patients were used as testing data. Regions with a z-score <-1.96 were classified as outliers. Normative modelling steps were completed using PCNtoolkit (v.0.31), and statistical analyses were performed using R Studio v.4.4.2. Mean (SD) cortical thickness z-scores were -2.01(2.18), -2.04(1.94), 0.16(1.22) for bvFTD, svPPA and HCs (Figure 1). bvFTD and svPPA groups exhibited significantly more dissimilarity in cortical and subcortical regions compared to HCs (one-way ANOVAs F(2,271)=100.62; 123.81, respectively; Tukey post hoc tests both p <0.001) (Figure 2 and 3). Regions with the highest proportion of outliers were the right inferior temporal gyrus for bvFTD (54%), and the left anterior, inferior and superior-lateral temporal gyri for svPPA (>83%). The left amygdala and hippocampus were the subcortical structures with the most outliers (45% and 47% in bvFTD; 64% and 67% in svPPA, respectively). These results demonstrate that bvFTD and svPPA patients exhibit greater heterogeneity in subcortical and cortical regions compared to HCs, particularly in the right inferior temporal gyrus and left lateral temporal gyrus, respectively. Analysis of other FTD variants and correlations with cognitive and clinical data are ongoing.

The present study investigated spatial dynamic functional network connectivity (dFNC) in patients with functional hemiparesis (i.e., functional stroke mimics, FSM). The aim of this work was to assess static functional connectivity (large-scale) networks and dynamic brain states, which represent distinct dFNC patterns that reoccur in time and across subjects. Resting-state fMRI data were collected from 15 patients with FSM (mean age = 42.3 ± 9.4, female = 80 %) and 52 age-matched healthy controls (HC, mean age = 42.1 ± 8.6, female = 73 %).Each patient underwent a resting-state functional MRI scan for spatial dFNC evaluation and transcranial magnetic stimulation protocols for indirect assessment of GABAergic and glutamatergic transmission. We considered three dynamic brain networks, i.e., the somatomotor network (SMN), the default mode network (DMN) and the salience network (SN), each summarized into four distinct recurring spatial configurations. Compared to HC, patients with FSM showed significant decreased dwell time, e.g. the time each individual spends in each spatial state of each network, in state 2 of the SMN (HC vs. FSM, 13.5 ± 27.1 vs. 1.9 ± 4.1, p = 0.044). Conversely, as compared to HC, FSM spent more time in state 1 of the DMN (10.8 ± 14.9 vs. 27.3 ± 38.9, p = 0.037) and in state 3 of the SN (23.1 ± 23.0 vs. 38.8 ± 38.2, p = 0.002). We found a significant correlation between the dwell time of impaired functional state of the SMN and measures of GABAergic neurotransmission (r = 0.581, p = 0.037). Specifically, longer impaired dwell time was associated with greater GABAergic inhibition. These findings demonstrate that FSM present altered functional brain network dynamics, which correlate with measures of GABAergic neurotransmission. Both dFNC and GABAergic neurotransmission may serve as potential targets for future intervention strategies.

The non-fluent/agrammatic variant of primary progressive aphasia is a neurodegenerative disorder characterized by effortful language production and impaired comprehension of grammatically complex sentences. Recently, interest in non-pharmacological interventions has increased, particularly regarding techniques that allow for non-invasive brain stimulation, such as transcranial direct current stimulation. The main purpose of this study was to investigate whether the use of anodal transcranial direct current stimulation applied to the dorsolateral prefrontal cortex during individualized language training for 25 min a day at 5 days a week for 2 weeks would lead to significant oral naming improvements in patients with agrammatic variant of primary progressive aphasia. Specifically, we hypothesized that anodal transcranial direct current stimulation plus individualized language training may improve the oral naming of treated and untreated objects compared with both placebo transcranial direct current stimulation plus individualized language therapy and anodal transcranial direct current stimulation combined with computerized cognitive training. Forty-seven agrammatic variant of primary progressive aphasia patients were consecutively enrolled and randomized into one of three groups that received the following treatments: (i) anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex during individualized language rehabilitation treatment; (ii) placebo transcranial direct current stimulation during individualized language rehabilitation treatment; or (iii) anodal transcranial direct current stimulation with computerized cognitive training. Clinical, neuropsychological and language assessments were recorded at baseline (T0), post-treatment (T1, 2 weeks) and at 12 weeks from T0 (T2). Magnetic resonance imaging data, functional magnetic resonance imaging data and blood samples were collected at T0 and T1. All of the groups demonstrated improvements in oral object naming at T1, with maintenance effects being observed at T2. At T1, the enhancement in the oral naming of treated and untreated objects was significantly greater in patients who underwent anodal transcranial direct current stimulation during individualized language rehabilitation treatment. There were no significant changes observed across the groups regarding the magnetic resonance imaging, functional magnetic resonance imaging or blood biochemical marker data. Our results support the beneficial effects of individualized language rehabilitation treatment in combination with anodal transcranial direct current stimulation in agrammatic variant of primary progressive aphasia patients.

Functional network integrity is important for maintaining cognitive performance during the 10-20 year presymptomatic period of frontotemporal dementia (FTD), conferring resilience to advancing neuropathology and atrophy. The extent to which functional integrity relies on preserved structural connectivity is unclear. Here, we test the relationship between functional connectivity and structural connectivity, termed structure-function coupling, against genetic risk for FTD and disease progression. We studied 56 symptomatic and 165 pre-symptomatic FTD-mutation carriers, and 141 family members without mutations, from the GENFI cohort. Diffusion weighted imaging and functional magnetic resonance imaging (Siemens MR platforms) were acquired and analysed using established approaches to quantify participant-level structural and functional connectomes (Figure 1-(1)). Connectomes were defined in the Brainnetome Atlas and re-mapped onto a subcortical network and seven resting-state networks based on the Yeo Networks (Figure 1-(2)). An inter-subject regularized canonical correlation analysis (CCA) with permutation-based cross-validation was used to jointly analyse the structural and functional connectomes (Figure 1-(3-4)). Second-level analysis with robust multiple linear regression models tested for differences between non-carriers, pre-symptomatic carriers and symptomatic carriers in the strength of association between structural and functional CCA subject scores. Age, sex, head motion and scanner site were included as covariates. Canonical correlation analysis identified significant components linking structural and functional connectivity. The first component (r=0.656, p  <0.001) reflected a structural connectivity pattern with high within- and between-networks loadings (Figure 1-(5)) with strong within-networks functional connectivity and weak-to-negative between-network functional connectivity (Figure 1-(6)). This component associated structural integrity with function segregation, whereby individuals with high structural connectivity within and between networks exhibit greater functional network segregation as shown by strong within-network functional connectivity and weak between network connectivity. The strength of this structure-function coupling was greater for non-carriers compared to pre-symptomatic carriers (Figure 1-(7)). Symptomatic carriers showed minimal relationship between structural and functional scores, indicating structure-function decoupling, consistent with the hypothesis that cognitive decline is triggered by critical decoupling of previously synergistic neural systems. Our findings demonstrate progressive de-coupling between structural connectivity and functional segregation over the course of genetic frontotemporal dementia. These results have implications for designing pre-symptomatic disease-modifying ‘preventative’ trials, supported by imaging-based surrogate markers of neural system dynamics.

Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies. To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD. This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate. Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up. The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging. Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale–cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study–Activities of Daily Living (−0.55; 95% CI, −0.89 to −0.21; P = .02), and Face-Name Association Test (−1.14; 95% CI, −1.66 to −0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale–cognitive subscale (−0.59; 95% CI, −1.02 to −0.16; P = .007), Alzheimer Disease Cooperative Study–Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration. In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD. ClinicalTrials.gov Identifier: NCT05643326

Importance:Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies. Objective:To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD. Design, Setting, and Participants:This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate. Intervention:Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up. Main Outcomes and Measures:The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging. Results:Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration. Conclusions and Relevance:In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD. Trial Registration:ClinicalTrials.gov Identifier: NCT05643326.

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables mutation carriers to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic FTD-mutation carriers using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without mutations. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy arises from enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology. ### Competing Interest Statement All authors have no conflicts of interest. Untreated to this there are several disclosures. JBR is a non-remunerated trustee of the Guarantors of Brain, Darwin College, and the PSP Association; he provides consultancy to Alzheimer Research UK, Asceneuron, Alector, Biogen, CuraSen, CumulusNeuro, UCB, SV Health, and Wave, and has research grants from AZ-Medimmune, Janssen, Lilly as industry partners in the Dementias Platform UK. Prof. Lebouvier receives consultancy fees from Roche, Lilly, Biogen, and Eisai, which are directed entirely to his institution. M.M. has acted as a consultant for Astex Pharmaceuticals. ### Funding Statement K.A.T. was supported by Fellowship awards from the Guarantors of Brain (G101149) and the Alzheimer's Society, UK (Grant number 602). J.B.R was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312: BRC-1215-20014), NIHR funding to the NIHR BioResource (RG94028 & RG85445), Wellcome Trust (220258), Medical Research Council (SUAG/051G101400; SUAG/010 RG91365; MC\_UU\_00030/14 and MR/T033371/1), the Holt Fellowship and by the Addenbrookes Charitable Trust. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. The views expressed are those of the author(s) and not necessarily those of the NHS or the NIHR. J.C.V.S., L.C.J. and H.S. are supported by the Dioraphte Foundation grant 09-02-03-00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), ZonMw Onderzoeksprogramma Dementie (YOD-INCLUDED, project number10510032120002), EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Alzheimer Nederland and the Bluefield Project. C.G. received funding from EU Joint Programme-Neurodegenerative Disease Research-Prefrontals Vetenskapsrådet Dnr 529-2014-7504, EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Vetenskapsrådet 2019-0224, Vetenskapsrådet 2015-02926, Vetenskapsrådet 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation; Vetenskapsrådet (Swedish Research Council) JPND Prefrontals, 2015-02926, 2018-02754, and JPND-GENFI-PROX 2019 02248; Swedish Alzheimer Foundation, ALF-project Region Stockholm, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Swedish Brain Foundation. D.G. received support from the EU Joint Programme Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia (Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie). J.L. received funding for this work by the Deutsche Forschungsgemeinschaft German Research Foundation under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy ID 390857198). E.F. has received funding from a Canadian Institute of Health Research grant #327387. MM was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also Canadian Institutes of Health Research operating grants (Grant #s: MOP-371851 and PJT-175242) and funding from the Weston Brain Institute to Mario Masellis. FM is supported by the Tau Consortium and has received funding from the Carlos III Health Institute (PI19/01637). Several authors of this publication (J.C.V.S., M.S., R.V., A.d.M., M.O., R.V., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) – Project ID No 739510. This work was also supported by the EU Joint Programme-Neurodegenerative Disease Research GENFI-PROX grant [2019 02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S. RS-V was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundaci ó Marat ó TV3, Spain (grant code 20143810 to RSV). RL is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. This work was funded by Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. SD receives salary funding from the Fonds de Recherche du Québec-Santé. This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains, Healthy Lives initiative. This work was supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. This work was supported by the JPND grant ′GENFI-prox′ (by DLR/BMBF to M.S, joint with J.R. , JvS, M.O., B.B. and C.G.). FM is supported by the Tau Consortium and has received funding from the Carlos III Health Institute (PI19/01637). BB is supported by JPND grant ′GENFI-prox′ (2019 02248). JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI PROX grant (2019 02248). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was given a favorable opinion by the Cambridge 2 Research Ethics Committee REC 17/EE/0032 IRAS ID 204052. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data were acquired from GENFI data freeze 5. Anonymized data not published within this article will be made available by request from any qualified investigator and can be requested via the GENFI website (https://www.genfi.org/contact-us-2) or via Dementias Platform UK (https://portal.dementiasplatform.uk/Apply).

Background: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by gray matter (GM) changes, such as amyloid-beta (Aβ) plaques and neurofibrillary tangles. While GM alterations are well-established, the fine-grained, spatially distinct patterns of homogeneous Aβ uptake and their changes remain poorly understood. Additionally, white matter (WM) pathology is less explored. This study addresses these gaps by leveraging high-model-order independent component analysis (ICA) to identify spatially granular amyloid networks in both GM and WM. Methods: We analyzed [18F]Florbetapir (FBP) PET images from 716 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), classified as cognitively normal (CN), mild cognitive impairment (MCI), or AD dementia. High-model-order ICA was applied to identify 80 GM and 13 WM FBP-related networks, which were labeled using terms from the Neuromark 2.2 Atlas. Statistical analyses assessed diagnostic effects and relationships between these networks and cognitive and neuropsychiatric variables. Results: Significant diagnostic differences were observed across GM and WM networks, revealing a continuous pattern of change from CN to MCI to AD. The analysis showed that the extended hippocampal, extended thalamic, basal ganglia, and frontal subdomains displayed an MCI profile closer to AD than to CN. In contrast, other subdomains exhibited a more mixed pattern, with MCI sometimes aligning more closely with CN and other times with AD. Notably, the hippocampal-entorhinal complex (HEC) within the extended hippocampal subdomain and the precuneus within the default mode subdomain were consistently associated with cognitive decline, highlighting their roles in disease progression. Additionally, WM networks, particularly the retrolenticular internal capsule (RICap), also demonstrated significant relationships with cognitive measures, suggesting that AD pathology extends beyond GM and disrupts broader network connectivity. These findings were validated in an independent replication dataset. Conclusion: High-model-order ICA effectively captures distinct fine-grained amyloid distributions, offering a network- level perspective that enhances our understanding of AD neurobiology. By decomposing complex PET signal patterns into distinct networks, this approach underscores the critical role of both GM and WM integrity in AD pathology. The consistent associations of the HEC, precuneus, and WM networks with cognitive decline highlight the widespread impact of AD-related pathology, emphasizing the value of this methodology in advancing AD research. ### Competing Interest Statement The authors have declared no competing interest.