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Background Alzheimer’s disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated. Methods We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses. Results Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (pp=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation). Conclusions A low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components.

Background Increasing evidence links the gut microbiota (GM) to Alzheimer’s disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD. Methods We included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1β, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman’s rho were used to validate the study hypothesis. Results CI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia (p p p p [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group, [Ruminococcus]_gnavus_group and Oscillibacter (p p p Conclusions Specific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, 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., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of non-invasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD.

Funder: Fondation Brain Canada; Id: http://dx.doi.org/10.13039/100009408, Funder: Fonds de Recherche du Québec ‐ Santé; Id: http://dx.doi.org/10.13039/501100000156, Funder: Health Canada; Id: http://dx.doi.org/10.13039/501100000008, Funder: Brain Canada Foundation; Id: http://dx.doi.org/10.13039/100009408, 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.

Background Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00809-w.

Background Subjective cognitive decline (SCD) is the subjective perception of a decline in memory and/or other cognitive functions in the absence of objective evidence. Some SCD individuals however may suffer from very early stages of neurodegenerative diseases (such as Alzheimer’s disease, AD), minor psychiatric conditions, neurological, and/or somatic comorbidities. Even if a theoretical framework has been established, the etiology of SCD remains far from elucidated. Clinical observations recently lead to the hypothesis that individuals with incipient AD may have overestimated metacognitive judgements of their own cognitive performance, while those with psychiatric disorders typically present underestimated metacognitive judgements. Moreover, brain connectivity changes are known correlates of AD and psychiatric conditions and might be used as biomarkers to discriminate SCD individuals of different etiologies. The aim of the COSCODE study is to identify metacognition, connectivity, behavioral, and biomarker profiles associated with different etiologies of SCD. Here we present its rationale and study design. Methods COSCODE is an observational, longitudinal (4 years), prospective clinical cohort study involving 120 SCD, and 80 control study participants (40 individuals with no cognitive impairment, and 40 living with mild cognitive impairment - MCI, or dementia due to AD), all of which will undergo diffusion magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) as well as behavioral and biomarker assessments at baseline and after 1 and 2 years. Both hypothesis-driven and data-driven cluster analysis approaches will be used to identify SCD sub-types based on metacognition, connectivity, behavioral, and biomarker features. Conclusion COSCODE will allow defining and interpreting the constellation of signs and symptoms associated with different etiologies of SCD, paving the way to the development of cost-effective risk assessment and prevention protocols.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

© Author(s) (or their employer(s)). No commercial re-use. See rights and permissions. Published by BMJ., Background: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials., The GENFI study has been supported by the Medical Research Council UK (MR/M023664/1), the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation as well as an Alzheimer's Society grant (AS-PG-16-007). The biomarker measurements were funded in part by the UK Dementia Research Institute at UCL and by a Wellcome Trust Multi-User Equipment Grant. KM has received funding from an Alzheimer’s Society PhD studentship. IOCW is supported by a MRC Clinical Research Training Fellowship (MR/M018288/1). RS-V is supported by an Alzheimer's Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2). JCVS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG received support from the EU Joint Programme—Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. RS-V has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). JBR has received funding from the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MO has received funding from BMBF (FTLDc). MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. HZ is a Wallenberg Academy Fellow. JR is a MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration.

Objective C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD). We examined aging trajectories of cortical thickness (CTh) and surface area in C9orf72 expansion adult carriers compared to healthy controls to characterize preclinical cerebral changes leading to symptoms. Methods Data were obtained from the Genetic Frontotemporal Dementia Initiative. T1-weighted magnetic resonance imaging scans were processed with CIVET 2.1 to extract vertex-wide CTh and cortical surface area (CSA). Symptomatic and presymptomatic subjects were compared to age-matched controls using mixed-effects models, controlling for demographic variables. Aging trajectories were compared between carriers and noncarriers by testing the "age by genetic status" interaction. False discovery rate corrections were applied to all vertex-wide analyses. Results The sample included 640 scans from 386 subjects, including 54 symptomatic C9orf72 carriers (72.2% behavioral variant FTD), 83 asymptomatic carriers, and 249 controls (age range = 18-86 years). Symptomatic carriers showed fairly symmetric reduction in CTh/CSA in most of the frontal lobes, in addition to large temporoparietal areas. Presymptomatic subjects had reduced CTh/CSA in more restricted areas of the medial frontoparietal lobes, in addition to scattered lateral frontal, parietal, and temporal areas. These differences were explained by faster cortical thinning linearly throughout adulthood in a similar anatomical distribution, with differences emerging in the early 30s. CSA reduction was also faster in mutation carriers predominantly in the ventrofrontal regions. Interpretation C9orf72 mutation carriers have faster cortical thinning and surface loss throughout adulthood in regions that show atrophy in symptomatic subjects. This suggests that the pathogenic effects of the mutation lead to structural cerebral changes decades prior to symptoms. ANN NEUROL 2020 ANN NEUROL 2020;88:113-122.

© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Objective: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Interpretation: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD., W. and M.S. are members of the European Reference Network for Rare Neurological Diseases Project ID No. 739510. This work was supported by the Horizon 2020 research and innovation program (grant 779257 Solve-RD to M.S.), the National Ataxia Foundation (grant to C.W. and M.S.), the Wilhelm Vaillant Stiftung (grant to C.W.), the EU Joint Programme – Neurodegenerative Disease Research (JPND) “GENFI-prox” through participating national funding agencies (by DLR/BMBF to M.S., J.D.R., B.B., C.G., and M.O.), and the European Union's Horizon 2020 research and innovation programme under grant agreement No. 643417. J.C.S. and H.S. received funding by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813 and 733050103) in the Netherlands and the Bluefield Project to Cure Frontotemporal Dementia. J.B.R. was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and the Medical Research Council (SUAG/051 G101400). C.B. is supported by a postdoctoral fellowship from the Swiss National Science Foundation (P400PM_191077). J.D.R. 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).

Advanced MRI findings in two patients with probable chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) are presented. Diffusion tensor imaging indices (fractional anisotropy and mean diffusivity), evaluated in both patients at baseline MRI examination before treatment and during follow-up, indicated white matter structural changes not only affecting the brainstem, which represents the primary site of inflammatory damage, but also projection (corona radiata) and associative tracts in both patients, while alterations within the corpus callosum were detected in patient 1# at follow-up. Susceptibility weighted imaging (SWI) revealed hypointense lesions in both patients, MRI spectroscopy (MRS) indicated a mildly increased Cho/NAA ratio with no evidence of lipids/lactate peaks, indicating that it may be used as a non-invasive marker to identify CLIPPERS cases suspected for progression to lymphoma.

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ., Introduction: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. Methods: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. Results: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. Conclusion: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database., Data collection and sharing for this project was funded by the Frontotemporal Lobar Degeneration Neuroimaging Initiative (National Institutes of Health Grant R01 AG032306). The study is coordinated through the University of California, San Francisco, Memory and Aging Center. FTLDNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Brain scan acquisition at the McConnell Brain Imaging was supported by the Brain Canada Foundation with support from Health Canada and the Canada Foundation for Innovation (CFI Project 34874). This work was supported by Italian Ministry of Health (CoEN015 and Ricerca Corrente).

WOS: 000428233700003 PubMed ID: 29407464 Previous evidence showed abnormal posterior sources of resting-state delta (< 4 Hz) and alpha (8-12 Hz) rhythms in patients with Alzheimer's disease with dementia (ADD), Parkinson's disease with dementia (PDD), and Lewy body dementia (DLB), as cortical neural synchronization markers in quiet wakefulness. Here, we tested the hypothesis of additional abnormalities in functional cortical connectivity computed in those sources, in ADD, considered as a "disconnection cortical syndrome", in comparison with PDD and DLB. Resting-state eyes-closed electroencephalographic (rsEEG) rhythms had been collected in 42 ADD, 42 PDD, 34 DLB, and 40 normal healthy older (Hold) participants. Exact low-resolution brain electromagnetic tomography (eLORETA) freeware estimated the functional lagged linear connectivity (LLC) from rsEEG cortical sources in delta, theta, alpha, beta, and gamma bands. The area under receiver operating characteristic (AUROC) curve indexed the classification accuracy between Nold and diseased individuals (only values > 0.7 were considered). Interhemispheric and intrahemispheric LLCs in widespread delta sources were abnormally higher in the ADD group and, unexpectedly, normal in DLB and PDD groups. Intrahemispheric LLC was reduced in widespread alpha sources dramatically in ADD, markedly in DLB, and moderately in PDD group. Furthermore, the interhemispheric LLC in widespread alpha sources showed lower values in ADD and DLB than PDD groups. At the individual level, AUROC curves of LLC in alpha sources exhibited better classification accuracies for the discrimination of ADD versus Nold individuals (0.84) than for DLB versus Nold participants (0.78) and PDD versus Nold participants (0.75). Functional cortical connectivity markers in delta and alpha sources suggest a more compromised neurophysiological reserve in ADD than DLB, at both group and individual levels. (C) 2017 Elsevier Inc. All rights reserved. H2020 Marie S. Curie ITN-ETN project The present study was developed based on the data of the informal European Consortium PDWAVES and European Consortium of Dementia with Lewy Body. The members and institutional affiliations of the consortia are reported in the cover page of this manuscript. The research activities of the Unit of University of Rome "La Sapienza" were partially supported by the H2020 Marie S. Curie ITN-ETN project with the short title "BBDiag" (http://bddiag-itn-etn.eu). We thank Mrs. Jessica Janson and Mrs. Marina Selivanova for their support to those activities in the framework of the BBDiag project.

WOS: 000450412900002 PubMed ID: 30312790 We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (

Age at symptom onset (AAO) underlies different Alzheimer's disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.

WOS: 000427485900009 PubMed ID: 29448151 Objective: This study tested the hypothesis that markers of functional cortical source connectivity of resting state eyes-closed electroencephalographic (rsEEG) rhythms may be abnormal in subjects with mild cognitive impairment due to Alzheimer's (ADMCI) and Parkinson's (PDMCI) diseases compared to healthy elderly subjects (Nold). Methods: rsEEG data had been collected in ADMCI, PDMCI, and Nold subjects (N = 75 for any group). eLORETA freeware estimated functional lagged linear connectivity (LLC) from rsEEG cortical sources. Area under receiver operating characteristic (AUROC) curve indexed the accuracy in the classification of Nold and MCI individuals. Results: Posterior interhemispheric and widespread intrahemispheric alpha LLC solutions were abnormally lower in both MCI groups compared to the Nold group. At the individual level, AUROC curves of LLC solutions in posterior alpha sources exhibited moderate accuracies (0.70-0.72) in the discrimination of Nold vs. ADMCI-PDMCI individuals. No differences in the LLC solutions were found between the two MCI groups. Conclusions: These findings unveil similar abnormalities in functional cortical connectivity estimated in widespread alpha sources in ADMCI and PDMCI. This was true at both group and individual levels. Significance: The similar abnormality of alpha source connectivity in ADMCI and PDMCI subjects might reflect common cholinergic impairment. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved. H Marie S. Curie ITN-ETN project The present study was developed based on the data of the informal European Consortium PDWAVES and European Consortium of Dementia with Lewy Body. The members and institutional affiliations of the Consortia are reported in the cover page of this manuscript. Dr. Erol Basar passed away due to health problems on October 28th (November 18th 1938-October 28th 2017) in Istanbul, during the editorial processing of this manuscript. Until the end of his life, he had been working to the development of EEG science and its application in Clinical Neurophysiology. He leaves to all us an invaluable scientific legacy in the Science of Brain Rhythms and Human Cognition. He also leaves a permanent reminder of scientific passion, academic soul, and social responsibility to all fortunate people who met and knew him during his intense life. The research activities of the Unit of University of Rome "La Sapienza" were partially supported by the H2020 Marie S. Curie ITN-ETN project with the short title "BBDiag" (http://bbdiag-ITNetn.eu). We thank Mrs. Jessica Janson and Mrs. Marina Selivanova for their support to those activities in the framework of the BBDiag project.

In Alzheimer's disease (AD) research, both 2-deoxy-2-(18F)fluoro-D-glucose (FDG) positron emission tomography (PET) and electroencephalography (EEG) are reliable investigational modalities. The aim of this study was to investigate the associations between EEG High-alpha/Low-alpha (H-alpha/L-alpha) power ratio and cortical glucose metabolism. A total of 23 subjects with mild cognitive impairment (MCI) underwent FDG-PET and EEG examinations. H-alpha/L-alpha power ratio was computed for each subject and 2 groups were obtained based on the increase of the power ratio. The subjects with higher H-alpha/L-alpha power ratio showed a decrease in glucose metabolism in the hub brain areas previously identified as typically affected by AD pathology. In subjects with higher H-alpha/L-alpha ratio and lower metabolism, a “double alpha peak” was identified in the EEG spectrum and a U-shaped correlation between glucose metabolism and increase of H-alpha/L-alpha power ratio has been found. Moreover, in this group, a conversion rate of 62.5% at 24 months was detected, significantly different from the chance percentage expected. The neurophysiological meaning of the interplay between alpha oscillations and glucose metabolism and the possible interest of the H-alpha/L-alpha power ratio as a clinical biomarker in AD have been discussed.

Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset., Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.

Imaging biomarkers are needed to detect early brain changes in presymptomatic carriers harbouring FTD mutations. Using arterial spin labelling-MRI, Mutsaerts, Mirza et al. identify an inverse association between cerebral perfusion in frontotemporoparietal regions and expected age of onset. Cerebral perfusion may be a promising imaging biomarker for presymptomatic genetic FTD., Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Orjinal Makale: Functional cortical source connectivity of resting state electroencephalographic alpha rhythms shows similar abnormalities in patients with mild cognitive impairment due to Alzheimer's and Parkinson's diseases. 129(4), 766-782. https://doi.org/10.1016/j.clinph.2018.01.009

BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; pINTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.FUNDING: ZonMw and the Bluefield project.

The aim of the study was to investigate the association between postoperative delirium (POD) and in vivo markers of Alzheimer's disease pathology in nondemented hip fracture surgery patients. POD was assessed with the Confusion Assessment Method. Amyloid load was quantified on (18)F-Flutemetamol positron emission tomography images as standardized uptake value ratio. Secondary outcome measures were gray matter volumes, white matter integrity, and functional connectivity at rest. All the patients with POD (POD+, N = 5) were amyloid negative (standardized uptake value ratio

IMPORTANCE Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS The Incremental Diagnostic Value ofAmyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairmentwere evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15%and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosiswas made, diagnostic confidencewas estimated, and drug treatmentwas provided. At the time of thisworkup, an amyloid PET/computed tomographic scanwas performed, and the resultwas communicated to physicians afterworkup completion. Physicianswere asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The studywas conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES Primary outcomeswere prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2%in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9%in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Background: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). Objective: To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. Methods: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. Results: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. Conclusions: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended.

We investigated patterns of white matter (WM) loss in 18 early onset (EO) and 24 late onset (LO) Alzheimer's disease (AD) patients compared with 42 healthy controls (HC), and explored relationships of WM atrophy and apolipoprotein E (ApoE) genotype. Subjects underwent magnetic resonance imaging (MRI). Patterns of WM were assessed using voxel-based morphometry. Compared with healthy controls, LOAD patients had a selective parahippocampal WM loss, while EOAD patients experienced a more widespread pattern of posterior WM atrophy. The distinct regional distribution of WM atrophy reflected the topography of gray matter (GM) loss. ApoE ε4 status was associated with a greater parahippocampal WM loss in both AD groups. The greater WM atrophy in EOAD than LOAD fits with the evidence that EOAD is a more aggressive form of the disease. The ApoE ε4 effect on WM damage in AD is restricted to specific WM regions and does not seem to be related to age of onset.

Objective: To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD). Methods: Seventeen patients with PD with FOG (PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry. Results: In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally. Conclusions: GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.

Diffusion tensor MRI‐based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico‐cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto‐occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimer's disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas‐based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto‐occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico‐cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico‐cortical association pathways in aMCI and AD patients. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

WOS: 000405068100016 PubMed ID: 28454845 The aim of this retrospective exploratory study was that resting state eyes-closed electroencephalographic (rsEEG) rhythms might reflect brain arousal in patients with dementia due to Alzheimer's disease dementia (ADD), Parkinson's disease dementia (PDD), and dementia with Lewy body (DLB). Clinical and rsEEG data of 42 ADD, 42 PDD, 34 DLB, and 40 healthy elderly (Nold) subjects were available in an international archive. Demography, education, and Mini-Mental State Evaluation score were not different between the patient groups. Individual alpha frequency peak (IAF) determined the delta, theta, alpha 1, alpha 2, and alpha 3 frequency bands. Fixed beta 1, beta 2, and gamma bands were also considered. rsEEG cortical sources were estimated by means of the exact low-resolution brain electromagnetic source tomography and were then classified across individuals, on the basis of the receiver operating characteristic curves. Compared to Nold, IAF showed marked slowing in PDD and DLB and moderate slowing in ADD. Furthermore, all patient groups showed lower posterior alpha 2 source activities. This effect was dramatic in ADD, marked in DLB, and moderate in PDD. These groups also showed higher occipital delta source activities, but this effect was dramatic in PDD, marked in DLB, and moderate in ADD. The posterior delta and alpha sources allowed good classification accuracy (approximately 0.85-0.90) between the Nold subjects and patients, and between ADD and PDD patients. In quiet wakefulness, delta and alpha sources unveiled different spatial and frequency features of the cortical neural synchronization underpinning brain arousal in ADD, PDD, and DLB patients. Future prospective cross-validation studies should test these rsEEG markers for clinical applications and drug discovery. project "GRIDCORE" (Italian Ministry of Health, Finalized Research program) [RF-2010-2319113] The present study was developed based on the data of the informal European Consortium PDWAVES. The members and institutional affiliations of the Consortium are reported in the cover page of this manuscript. The activities for this study of Dr. Claudio Babiloni, Claudio Del Percio, and Roberta Lizio performed in the framework of the project "GRIDCORE" (Italian Ministry of Health, Finalized Research program, prot. RF-2010-2319113).