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Background and Objectives: The AT(N) classification system stratifies patients based on biomarker profiles, including amyloid-beta deposition (A), tau pathology (T), and neurodegeneration (N). This study aims to apply the AT(N) classification to a hospital-based cohort of patients with cognitive decline and/or dementia, within and outside the Alzheimer's disease (AD) continuum, to enhance our understanding of the multidimensional aspects of AD and related disorders. Furthermore, we wish to investigate how many cases from our cohort would be eligible for the available disease modifying treatments, such as aducanemab and lecanemab., Methods: We conducted a retrospective evaluation of 429 patients referred to the Memory Center of IRCCS San Raffaele Hospital in Milan. Patients underwent clinical/neuropsychological assessments, lumbar puncture, structural brain imaging, and positron emission tomography (FDG-PET). Patients were stratified according to AT(N) classification, group comparisons were performed and the number of eligible cases for anti-β amyloid monoclonal antibodies was calculated., Results: Sociodemographic and clinical features were similar across groups. The most represented group was A + T + N + accounting for 38% of cases, followed by A + T - N + (21%) and A - T - N + (20%). Although the clinical presentation was similar, the A + T + N + group showed more severe cognitive impairment in memory, language, attention, executive, and visuospatial functions compared to other AT(N) groups. Notably, T + patients demonstrated greater memory complaints compared to T -  cases. FDG-PET outperformed MRI and CT in distinguishing A + from A -  patients. Although 61% of the observed cases were A + , only 17% of them were eligible for amyloid-targeting treatments., Discussion: The AT(N) classification is applicable in a real-world clinical setting. The classification system provided insights into clinical management and treatment strategies. Low cognitive performance and specific regional FDG-PET hypometabolism at diagnosis are highly suggestive for A + T + or A - T + profiles. This work provides also a realistic picture of the proportion of AD patients eligible for disease modifying treatments emphasizing the need for early detection., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Neurogenesis decline with aging may be associated with brain atrophy. Subventricular zone neuron precursor cells possibly modulate striatal neuronal activity via the release of soluble molecules. Neurogenesis decay in the subventricular zone may result in structural alterations of brain regions connected to the caudate, particularly to its medial component. The aim of this study was to investigate how the functional organization of caudate networks relates to structural brain changes with aging. One hundred and fifty-two normal subjects were recruited: 52 young healthy adults (≤35 years old), 42 middle-aged (36 ≤ 60 years old) and 58 elderly subjects (≥60 years old). In young adults, stepwise functional connectivity was used to characterize regions that connect to the medial and lateral caudate at different levels of link-step distances. A statistical comparison between the connectivity of medial and lateral caudate in young subjects was useful to define medial and lateral caudate connected regions. Atrophy of medial and lateral caudate connected regions was estimated in young, middle-aged and elderly subjects using T 1 -weighted images. Results showed that middle-aged and elderly adults exhibited decreased stepwise functional connectivity at one-link step from the caudate, particularly in the frontal, parietal, temporal and occipital brain regions, compared to young subjects. Elderly individuals showed increased stepwise functional connectivity in frontal, parietal, temporal and occipital lobes compared to both young and middle-aged adults. Additionally, elderly adults displayed decreased stepwise functional connectivity compared to middle-aged subjects in specific parietal and subcortical areas. Moreover, in young adults, the medial caudate showed higher direct connectivity to the basal ganglia (left thalamus), superior, middle and inferior frontal and inferior parietal gyri (medial caudate connected region) relative to the lateral caudate. Considering the opposite contrast, lateral caudate showed stronger connectivity to the basal ganglia (right pallidum), orbitofrontal, rostral anterior cingulate and insula cortices (lateral caudate connected region) compared to medial caudate. In elderly subjects, the medial caudate connected region showed greater atrophy relative to the lateral caudate connected region. Brain regions linked to the medial caudate appear to be more vulnerable to aging than lateral caudate connected areas. The adjacency to the subventricular zone may, at least partially, explain these findings. Stepwise functional connectivity analysis can be useful to evaluate the role of the subventricular zone in network disruptions in age-related neurodegenerative disorders., Competing Interests: S.B. and E.C. receive or have received research supports from the Italian Ministry of Health. M.Z., G.R., G.S., C.C., L.C., M.B. and G.M. report no disclosures. M.F. is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. F.A. is Associate Editor of NeuroImage: Clinical, has received speaker honoraria from Biogen Idec, Italfarmaco, Roche, Zambon and Eli Lilly, and receives or has received research supports from the Italian Ministry of Health, the Italian Ministry of University and Research, AriSLA (Fondazione Italiana di Ricerca per la SLA), the European Research Council, the EU Joint Programme – Neurodegenerative Disease Research (JPND), and Foundation Research on Alzheimer Disease (France)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: To assess whether dual-task gait/balance training with action observation training (AOT) and motor imagery (MI) ameliorates cognitive performance and resting-state (RS) brain functional connectivity (FC) in Parkinson's disease (PD) patients with postural instability and gait disorders (PIGD)., Methods: 21 PD-PIGD patients were randomized into 2 groups: (1) DUAL-TASK + AOT-MI group performed a 6-week training consisting of AOT-MI combined with practicing observed-imagined gait and balance exercises; and (2) DUAL-TASK group performed the same exercises combined with landscape-videos observation. At baseline and after training, all patients underwent a computerized cognitive assessment, while 17 patients had also RS-fMRI scans. Cognitive and RS-FC changes (and their relationships) over time within and between groups were assessed., Results: After training, all PD-PIGD patients improved accuracy in a test assessing executive-attentive (mainly dual-task) skills. DUAL-TASK + AOT-MI patients showed increased RS-FC within the anterior salience network (aSAL), and reduced RS-FC within the anterior default mode network (aDMN), right executive control network and precuneus network. DUAL-TASK patients showed increased RS-FC within the visuospatial network, only. Group × Time interaction showed that, compared to DUAL-TASK group, DUAL-TASK + AOT-MI cases had reduced RS-FC within the aDMN, which correlated with higher accuracy in a dual-task executive-attentive test., Conclusions: In PD-PIGD patients, both trainings promote cognitive improvement and brain functional reorganization. DUAL-TASK + AOT-MI training induced specific functional reorganization changes of extra-motor brain networks, which were related with improvement in dual-task performance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Most of DYT genotypes follow an autosomal dominant inheritance pattern with reduced penetrance; the mechanisms underlying the disease development remain unclear. The objective of the study was to investigate cortical thickness, grey matter (GM) volumes and white matter (WM) alterations in asymptomatic (DYT-A) and symptomatic dystonia (DYT-S) mutation carriers., Methods: Eight DYT-A (four DYT-TOR1A and four DYT-THAP1), 14 DYT-S (seven DYT-TOR1A, and seven DYT-THAP1), and 37 matched healthy controls underwent 3D T1-weighted and diffusion tensor (DT) MRI to study cortical thickness, cerebellar and basal ganglia GM volumes and WM microstructural changes., Results: DYT-S showed thinning of the frontal and motor cortical regions related to sensorimotor and cognitive processing, together with putaminal atrophy and subcortical microstructural WM damage of both motor and extra-motor tracts such as cerebral peduncle, corona radiata, internal and external capsule, temporal and orbitofrontal WM, and corpus callosum. DYT-A had cortical thickening of middle frontal areas and WM damage of the corona radiata., Conclusions: DYT genes phenotypic expression is associated with alterations of both motor and extra-motor WM and GM regions. Asymptomatic genetic status is characterized by a very subtle affection of the WM motor pathway, together with an increased cortical thickness of higher-order frontal regions that might interfere with phenotypic presentation and disease manifestation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Evaluating the neural correlates of sensorimotor control deficits in cervical dystonia (CD) is fundamental to plan the best treatment. This study aims to assess kinematic and resting-state functional connectivity (RS-FC) characteristics in CD patients relative to healthy controls., Methods: Seventeen CD patients and 14 age-/sex-matched healthy controls were recruited. Electromagnetic sensors were used to evaluate dystonic pattern, mean/maximal cervical movement amplitude and joint position error with eyes open and closed, and movement quality during target reaching with the head. RS-fMRI was acquired to compare the FC of brain sensorimotor regions between patients and controls. In patients, correlations between motion analysis and FC data were assessed., Results: CD patients relative to controls showed reduced mean and maximal cervical range of motion (RoM) in rotation both towards and against dystonia pattern and reduced total RoM in rotation both with eyes open and closed. They had less severe dystonia pattern with eyes open vs eyes closed. CD patients showed an altered movement quality and sensorimotor control during target reaching and a higher joint position error. Compared to controls, CD patients showed reduced FC between supplementary motor area (SMA), occipital and cerebellar areas, which correlated with lower cervical RoM in rotation both with eyes open and closed and with worse movement quality during target reaching., Conclusions: FC alterations between SMA and occipital and cerebellar areas may represent the neural basis of cervical sensorimotor control deficits in CD patients. Electromagnetic sensors and RS-fMRI might be promising tools to monitor CD and assess the efficacy of rehabilitative interventions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elisabetta Sarasso reports a relationship with Italian Ministry of Health that includes: funding grants. Daniele Emedoli reports a relationship with Khymeia Group S.R.L that includes: consulting or advisory and speaking and lecture fees. Andrea Gardoni reports a relationship with none that includes:. Lucia Zenere reports a relationship with None that includes:. Elisa Canu reports a relationship with Italian Ministry of Health that includes: funding grants. Silvia Basaia reports a relationship with Italian Ministry of Health that includes: funding grants. Alberto Doretti reports a relationship with AbbVie Inc, Eli Lilly, TEVA, Lundbeck that includes: consulting or advisory. Nicola Ticozzi reports a relationship with None that includes:. Sandro Iannaccone reports a relationship with None that includes:. Stefano Amadio reports a relationship with None that includes:. Ubaldo Del Carro reports a relationship with None that includes:. Massimo Filippi reports a relationship with Alexion, Almirall, Bayer, Biogen, BMS, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, TEVA, Italian Ministry of Health, Italian Ministry of University and Research, FISM that includes: consulting or advisory, funding grants, and speaking and lecture fees. Federica Agosta reports a relationship with Biogen Idec, Italfarmaco, Roche, Zambon, Ely Lilli, Italian Ministry of Health, Italian Ministry of University and Research, AriSLA, the European Research Council, the EU JPND, and Foundation Research on Alzheimer Disease (France) that includes: funding grants and speaking and lecture fees. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; F. Agosta is Associate Editor of NeuroImage: Clinical If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status., Methods: Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables., Results: When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole-connectome showed greater node degree (P < 0.001), while sensorimotor cortices resulted isolated in C9orf72+., Interpretation: Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: The 3 clinical presentations of primary progressive aphasia (PPA) reflect heterogenous neuropathology, which is difficult to be recognized in vivo. Resting-state (RS) EEG is promising for the investigation of brain electrical substrates in neurodegenerative conditions. In this study, we aim to explore EEG cortical sources in the characterization of the 3 variants of PPA., Methods: This is a cross-sectional, single-center, memory center-based cohort study. Patients with PPA and healthy controls were consecutively recruited at the Neurology Unit, IRCCS San Raffaele Scientific Institute (Milan, Italy). Each participant underwent an RS 19-channel EEG. Using standardized low-resolution brain electromagnetic tomography, EEG current source densities were estimated at voxel level and compared among study groups. Using an RS functional MRI-driven model of source reconstruction, linear lagged connectivity (LLC) values within language and extra-language brain networks were obtained and analyzed among groups., Results: Eighteen patients with logopenic PPA variant (lvPPA; mean age = 72.7 ± 6.6; % female = 52.4), 21 patients with nonfluent/agrammatic PPA variant (nfvPPA; mean age = 71.7 ± 8.1; % female = 66.6), and 9 patients with semantic PPA variant (svPPA; mean age = 65.0 ± 6.9; % female = 44.4) were enrolled in the study, together with 21 matched healthy controls (mean age = 69.2 ± 6.5; % female = 57.1). Patients with lvPPA showed a higher delta density than healthy controls ( p < 0.01) and patients with nfvPPA ( p < 0.05) and svPPA ( p < 0.05). Patients with lvPPA also displayed a greater theta density over the left posterior hemisphere ( p < 0.01) and lower alpha2 values ( p < 0.05) over the left frontotemporal regions than controls. Patients with nfvPPA showed a diffuse greater theta density than controls ( p < 0.05). LLC was altered in all patients relative to controls ( p < 0.05); the alteration was greater at slow frequency bands and within language networks than extra-language networks. Patients with lvPPA also showed greater LLC values at theta band than patients with nfvPPA ( p < 0.05)., Discussion: EEG findings in patients with PPA suggest that lvPPA-related pathology is associated with a characteristic disruption of the cortical electrical activity, which might help in the differential diagnosis from svPPA and nfvPPA. EEG connectivity was disrupted in all PPA variants, with distinct findings in disease-specific PPA groups., Classification of Evidence: This study provides Class IV evidence that EEG analysis can distinguish PPA due to probable Alzheimer disease from PPA due to probable FTD from normal aging.

Background and Objectives: There is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease stratification in ALS is fundamental for study design definition and inclusion of homogenous patient cohorts into clinical trials. Our aim was to assess the rearrangements of structural and functional brain connectivity underlying the clinical stages of ALS, to suggest objective, reproducible measures provided by MRI connectomics mirroring disease staging., Methods: In this observational study, patients with ALS and healthy controls (HCs) underwent clinical evaluation and brain MRI on a 3T scanner. Patients were classified into 4 groups, according to the King's staging system. Structural and functional brain connectivity matrices were obtained using diffusion tensor and resting-state fMRI data, respectively. Whole-brain network-based statistics (NBS) analysis and comparisons of intraregional and inter-regional connectivity values using analysis of covariance models were performed between groups. Correlations between MRI and clinical/cognitive measures were tested using Pearson coefficient., Results: One hundred four patients with ALS and 61 age-matched and sex-matched HCs were included. NBS and regional connectivity analyses demonstrated a progressive decrease of intranetwork and internetwork structural connectivity of sensorimotor regions at increasing ALS stages in our cohort, compared with HCs. By contrast, functional connectivity showed divergent patterns between King's stages 3 (increase in basal ganglia and temporal circuits [ p = 0.04 and p = 0.05, respectively]) and 4 (frontotemporal decrease [ p = 0.03]), suggesting a complex interplay between opposite phenomena in late stages of the disease. Intraregional sensorimotor structural connectivity was correlated with ALS Functional Rating Scale-revised (ALSFRS-r) score ( r = 0.31, p < 0.001) and upper motor neuron burden ( r = -0.25, p = 0.01). Inter-regional frontal-sensorimotor structural connectivity was also correlated with ALSFRS-r ( r = 0.24, p = 0.02). No correlations with cognitive measures were found., Discussion: MRI of the brain allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor networks in ALS, mirroring disease stages. Frontotemporal functional disconnection seems to characterize only advanced disease phases. Our findings support the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which may mirror clinical progression.

Multifactorial models integrating brain variables at multiple scales are warranted to investigate aging and its relationship with neurodegeneration. Our aim was to evaluate how aging affects functional connectivity of pivotal regions of the human brain connectome (i.e., hubs), which represent potential vulnerability 'stations' to aging, and whether such effects influence the functional and structural changes of the whole brain. We combined the information of the functional connectome vulnerability, studied through an innovative graph-analysis approach (stepwise functional connectivity), with brain cortical thinning in aging. Using data from 128 cognitively normal participants (aged 20-85 years), we firstly investigated the topological functional network organization in the optimal healthy condition (i.e., young adults) and observed that fronto-temporo-parietal hubs showed a highly direct functional connectivity with themselves and among each other, while occipital hubs showed a direct functional connectivity within occipital regions and sensorimotor areas. Subsequently, we modeled cortical thickness changes over lifespan, revealing that fronto-temporo-parietal hubs were among the brain regions that changed the most, whereas occipital hubs showed a quite spared cortical thickness across ages. Finally, we found that cortical regions highly functionally linked to the fronto-temporo-parietal hubs in healthy adults were characterized by the greatest cortical thinning along the lifespan, demonstrating that the topology and geometry of hub functional connectome govern the region-specific structural alterations of the brain regions., (© 2023. The Author(s).)

Introduction: Motor imagery (MI) skills can be affected in Parkinson's disease (PD). We aimed at assessing MI and brain functional changes after action observation and MI training (AOT-MI) associated with gait/balance exercises in PD patients with postural instability and gait disorders (PD-PIGD)., Methods: Twenty-five PD-PIGD patients were randomized into two groups: DUAL-TASK + AOT-MI group performed 6-week gait/balance training combined with AOT-MI; DUAL-TASK group performed the same exercises without AOT-MI. Before and after training, MI was assessed using Kinesthetic-and-Visual-Imagery Questionnaire (KVIQ) and a MI functional MRI (fMRI) task. During fMRI, subjects were asked to watch first-person perspective videos representing gait/balance tasks and mentally simulate their execution. At baseline patients were compared with 23 healthy controls., Results: PD groups did not differ in the MI scores. Both patient groups increased kinesthetic KVIQ score after training, while only DUAL-TASK + AOT-MI group improved visual and total KVIQ scores. At baseline, both PD groups showed reduced fMRI activity of sensorimotor, temporal and cerebellar areas relative to controls. After training, DUAL-TASK + AOT-MI patients increased activity of anterior cingulate, fronto-temporal and motor cerebellar areas, and reduced the recruitment of cognitive cerebellar regions. DUAL-TASK group showed increased recruitment of occipito-temporal areas and reduced activity of cerebellum crus-I. DUAL-TASK + AOT-MI relative to DUAL-TASK group had increased activity of cerebellum VIII-IX. In DUAL-TASK + AOT-MI group, KVIQ improvement correlated with increased activity of cerebellum IX and anterior cingulate, and with reduced activity of crus-I., Conclusions: AOT-MI improves MI abilities in PD-PIGD patients, promoting the functional plasticity of brain areas involved in MI processes and gait/balance control., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: In amyotrophic lateral sclerosis (ALS), verbal fluency index (V fi ) is used to investigate fluency accounting for motor impairment. This study has three aims: (1) to provide V fi reference values from a cohort of Italian healthy subjects; (2) to assess the ability of V fi reference values ( vs standard verbal fluency test [VFT]) in distinguishing ALS patients with and without executive dysfunction; and (3) to investigate the association between V fi and brain structural features of ALS patients. Methods: We included 180 healthy subjects and 157 ALS patients who underwent neuropsychological assessment, including VFT and V fi , and brain MRI. Healthy subjects were split into four subgroups according to sex and education. For each subgroup, we defined the 95th percentile of V fi as the cutoff. In ALS, the distributions of "abnormal" cases based on V fi and standard VFT cutoffs were compared using Fisher's exact test. Using quantile regressions in patients, we assessed the association between V fi and VFT scores, separately, with gray matter volumes and white matter (WM) tract integrity. Results: Applying V fi and VFT cutoffs, 9 and 13% of ALS cases, respectively, had abnormal scores ( p  < 0.001). In ALS, while higher V fi scores were associated with WM changes of callosal fibers linking supplementary motor area, lower VFT performances related to corticospinal tract alterations. Discussion: We provided Italian reference values for the spoken V fi . Compared to VFT, V fi s are critical to disentangle motor and cognitive deficits in ALS. In patients, abnormal V fi s were associated with damage to WM tracts specifically involved in ideational information processing.

The hypothesis that the effectiveness of neurosurgical procedures in Parkinson's disease (PD) would be related to connectivity dysfunctions between the site of the stimulation and other brain regions is growing. This study aimed to assess resting-state functional connectivity between thalamic ventral intermediate nucleus (Vim) and the rest of the brain before and after thalamotomy in PD. A 76-year-old right-handed woman with refractory tremor-dominant PD was selected as a candidate for left Vim radiosurgery thalamotomy. Clinical and motion sensor evaluation and brain resting-state functional MRI (rs-fMRI) were carried out before treatment and 3, 6, and 12 months later. Targeted Vim was selected as region of interest and a seed-based rs-fMRI analysis was performed in the patient and ten age- and sex-matched controls at baseline and over time. Furthermore, a correlation analysis between functional connectivity and tremor data was carried out. Both clinical and motion sensor measurements showed a progressive tremor improvement over time on right side after radiosurgery. In the patient, seed-based analysis showed a significantly increased functional connectivity between targeted Vim and ipsilateral visual areas relative to controls before treatment. Over 1 year, a normalization of aberrant pre-therapeutic functional connectivity between Vim and visual areas was obtained. At correlation analysis, the reduction of tremor metrics over time, assessed by clinical evaluation and wearable motion sensors, was related to the reduction of the left Vim-left visual cortex functional connectivity. Our findings support the evidence that fMRI was able to detect targeted Vim connectivity and its changes over time after thalamotomy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: To evaluate the diagnostic value of combined semiquantitative and quantitative assessment of brain atrophy in the diagnostic workup of the behavioural-variant of frontotemporal dementia (bvFTD)., Methods: Three neuroradiologists defined brain atrophy grading and identified atrophy pattern suggestive of bvFTD on 3D-T1 brain MRI of 112 subjects using a semiquantitative rating scale (Kipps'). A quantitative atrophy assessment was performed using two different automated software (Quantib® ND and Icometrix®). A combined semiquantitative and quantitative assessment of brain atrophy was made to evaluate the improvement in brain atrophy grading to identify probable bvFTD patients., Results: Observers' performances in the diagnosis of bvFTD were very good for Observer 1 (k value = 0.881) and 2 (k value = 0.867), substantial for Observer 3 (k value = 0.741). Semiquantitative atrophy grading of all the observers showed a moderate and a poor correlation with the volume values calculated by Icometrix® and by Quantib® ND, respectively. For the definition of neuroradiological signs presumptive of bvFTD, the use of Icometrix® software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.971 (p-value < 0.001). The use of Quantib® ND software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.977 (p-value < 0.001). No improvement was observed for Observer 2., Conclusion: Combining semiquantitative and quantitative brain imaging evaluation allows to reduce discrepancies in the neuroradiological diagnostic workup of bvFTD by different readers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: MRI connectomics is an ideal tool to test a network-based model of pathologic propagation from a disease epicenter in neurodegenerative disorders. In this study, we used a novel graph theory-based MRI paradigm to explore functional connectivity reorganization, discerning between direct and indirect connections from disease epicenters, and its relationship with neurodegeneration across clinical presentations of the frontotemporal dementia (FTD) spectrum, including behavioral variant of FTD (bvFTD), nonfluent variant of primary progressive aphasia (nfvPPA), and semantic variant of primary progressive aphasia (svPPA)., Methods: In this observational cross-sectional study, disease epicenters were defined as the peaks of atrophy of a cohort of patients with high confidence of frontotemporal lobar degeneration pathology (Mayo Clinic). These were used as seed regions for stepwise functional connectivity (SFC) analyses in an independent (Milan) set of patients with FTD to assess connectivity in regions directly and indirectly connected to the epicenters. Correlations between SFC architecture in healthy conditions and atrophy patterns in patients with FTD were also tested., Results: As defined by comparing the 42 Mayo Clinic patients with 15 controls, disease epicenters were the left anterior insula for bvFTD, left supplementary motor area for nfvPPA, and left inferior temporal gyrus (ITG) for svPPA. Compared with 94 age-matched controls, patients with bvFTD (n = 64) and nfvPPA (n = 34) of the Milan cohort showed widespread decreased SFC in bilateral cortical regions with direct/indirect connections with epicenters and increased SFC either in directly connected regions, physically close to the respective seed region, or in more distant cortical/cerebellar areas with indirect connections. Across all link steps, svPPA (n = 36) showed SFC decrease mostly within the temporal lobes, with co-occurrent SFC increase in cerebellar regions at indirect link steps. The average stepwise topological distance from the left ITG in a reference group of 50 young healthy controls correlated with regional gray matter volume in svPPA, consistent with network-based degeneration., Discussion: Our findings demonstrate that each FTD syndrome is associated with a characteristic interplay of decreased and increased functional connectivity with the disease epicenter, affecting both direct and indirect connections. SFC revealed novel insights regarding the topology of functional disconnection across FTD syndromes, holding the promise to be used to model disease progression in future longitudinal studies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Few studies interrogated the involvement of cerebellum in modulating gait in Parkinson's disease (PD) patients with postural instability and gait disorders (PD-PIGD). This study aimed at assessing cerebellar atrophy and activity alterations during functional MRI (fMRI) gait-simulating motor- and dual-tasks in PD-PIGD., Methods: Twenty-one PD-PIGD and 23 healthy controls underwent clinical assessment, structural MRI, and fMRI including a motor-task (foot anti-phase movements) and a dual-task (foot anti-phase movements while counting backwards by threes). Grey matter cerebellar volumes were assessed using SUIT atlas. FMRI activations were extracted from each cerebellar lobule, and we correlated cerebellar and basal ganglia activity., Results: PD-PIGD patients had reduced volumes of cerebellar motor and non-motor areas relative to controls. During fMRI motor-task, patients showed greater activation of cognitive cerebellar areas (VI and Crus I-II) vs controls. During fMRI dual-task, PD-PIGD patients showed increased activity of cognitive areas (Crus II) and reduced activity of motor areas (I-IV). Cerebellar structural alterations correlated with increased fMRI activity of cerebellar cognitive areas and with lower executive-attentive performance. The increased activity of Crus I during the motor-task correlated with a better motor performance in PD-PIGD. Moreover, the increased activity of cerebellum correlated with a reduced activity of putamen., Conclusions: In PD-PIGD, the increased activity of non-motor cerebellar areas during gait-simulating tasks may be a consequence of grey matter atrophy or an attempt to compensate the functional failure of cerebellar motor areas and basal ganglia. Cerebellar MRI metrics are useful to characterize brain correlates of motor and dual-task abilities in PD-PIGD patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Neurodegenerative diseases can be considered as 'disconnection syndromes,' in which a communication breakdown prompts cognitive or motor dysfunction. Mathematical models applied to functional resting-state MRI allow for the organization of the brain into nodes and edges, which interact to form the functional brain connectome., Areas Covered: The authors discuss the recent applications of functional connectomics to neurodegenerative diseases, from preclinical diagnosis, to follow up along with the progressive changes in network organization, to the prediction of the progressive spread of neurodegeneration, to stratification of patients into prognostic groups, and to record responses to treatment. The authors searched PubMed using the terms 'neurodegenerative diseases' AND 'fMRI' AND 'functional connectome' OR 'functional connectivity' AND 'connectomics' OR 'graph metrics' OR 'graph analysis.' The time range covered the past 20 years., Expert Opinion: Considering the great pathological and phenotypical heterogeneity of neurodegenerative diseases, identifying a common framework to diagnose, monitor and elaborate prognostic models is challenging. Graph analysis can describe the complexity of brain architectural rearrangements supporting the network-based hypothesis as unifying pathogenetic mechanism. Although a multidisciplinary team is needed to overcome the limit of methodologic complexity in clinical application, advanced methodologies are valuable tools to better characterize functional disconnection in neurodegeneration.

Background: The hypothesis that the effectiveness of deep brain stimulation (DBS) in Parkinson's disease (PD) would be related to connectivity dysfunctions between the site of stimulation and other brain regions is growing., Objective: To investigate how the subthalamic nucleus (STN), the most frequently used DBS target for PD, is functionally linked to other brain regions in PD patients according to DBS eligibility., Methods: Clinical data and resting-state functional MRI were acquired from 60 PD patients and 60 age- and sex-matched healthy subjects within an ongoing longitudinal project. PD patients were divided into 19 patients eligible for DBS and 41 non-candidates. Bilateral STN were selected as regions of interest and a seed-based functional MRI connectivity analysis was performed., Results: A decreased functional connectivity between STN and sensorimotor cortex in both PD patient groups compared to controls was found. Whereas an increased functional connectivity between STN and thalamus was found in PD patient groups relative to controls. Candidates for DBS showed a decreased functional connectivity between bilateral STN and bilateral sensorimotor areas relative to non-candidates. In patients eligible for DBS, a weaker STN functional connectivity with left supramarginal and angular gyri was related with a more severe rigidity and bradykinesia whereas a higher connectivity between STN and cerebellum/pons was related to poorer tremor score., Conclusion: Our results suggest that functional connectivity of STN varies among PD patients eligible or not for DBS. Future studies would confirm whether DBS modulates and restores functional connectivity between STN and sensorimotor areas in treated patients.

This study investigated longitudinal clinical, structural and functional brain alterations in Parkinson's disease patients with freezing of gait (PD-FoG) and in those developing (PD-FoG-converters) and not developing FoG (PD-non-converters) over two years. Moreover, this study explored if any clinical and/or MRI metric predicts FoG development. Thirty PD-FoG, 11 PD-FoG-converters and 11 PD-non-converters were followed for two years. Thirty healthy controls were included at baseline. Participants underwent clinical and MRI visits. Cortical thickness, basal ganglia volumes and functional network graph metrics were evaluated at baseline and over time. In PD groups, correlations between baseline MRI and clinical worsening were tested. A ROC curve analysis investigated if baseline clinical and MRI measures, selected using a stepwise model procedure, could differentiate PD-FoG-converters from PD-non-converters. At baseline, PD-FoG patients had widespread cortical/subcortical atrophy, while PD-FoG-converters and non-converters showed atrophy in sensorimotor areas and basal ganglia relative to controls. Over time, PD-non-converters accumulated cortical thinning of left temporal pole and pallidum without significant clinical changes. PD-FoG-converters showed worsening of disease severity, executive functions, and mood together with an accumulation of occipital atrophy, similarly to PD-FoG. At baseline, PD-FoG-converters relative to controls and PD-FoG showed higher global and parietal clustering coefficient and global local efficiency. Over time, PD-FoG-converters showed reduced parietal clustering coefficient and sensorimotor local efficiency, PD-non-converters showed increased sensorimotor path length, while PD-FoG patients showed stable graph metrics. Stepwise prediction model including dyskinesia, postural instability and gait disorders scores and parietal clustering coefficient was the best predictor of FoG conversion. Combining clinical and MRI data, ROC curves provided the highest classification power to predict the conversion (AUC = 0.95, 95%CI: 0.86-1). Structural MRI is a useful tool to monitor PD progression, while functional MRI together with clinical features may be helpful to identify FoG conversion early., (© 2022. The Author(s).)

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). In patients and controls, correlations were investigated between each emotion construct and rs-FC changes within critical networks. Mean rs-FC of the clusters significantly associated with CATS scoring were compared among FTLD groups. FTLD patients had pathological CATS scores compared with controls. In controls, increased rs-FC of the cerebellar and visuo-associative networks correlated with better scores in emotion-matching and discrimination tasks, respectively; while decreased rs-FC of the visuo-spatial network was related with better performance in the affect-matching and naming. In FTLD, the associations between rs-FC and CATS scores involved more brain regions, such as orbitofrontal and middle frontal gyri within anterior networks (i.e., salience and default-mode), parietal and somatosensory regions within visuo-spatial and sensorimotor networks, caudate and thalamus within basal-ganglia network. Rs-FC changes associated with CATS were similar among all FTLD groups. In FTLD compared to controls, the pattern of rs-FC associated with emotional processing involves a larger number of brain regions, likely due to functional specificity loss and compensatory attempts. These associations were similar across all FTLD groups, suggesting a common physiopathological mechanism of emotion processing breakdown, regardless the clinical presentation and pattern of atrophy., (© 2022. The Author(s).)

Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instability-and-gait-disorder (PIGD) motor subtypes. PIGD represents a more aggressive form of the disease that TD patients have a potentiality of converting into. This study investigated functional alterations within the cerebro-cerebellar system in PD-TD and PD-PIGD patients using stepwise functional connectivity (SFC) analysis and identified neuroimaging features that predict TD to PIGD conversion. Thirty-two PD-TD, 26 PD-PIGD patients and 60 healthy controls performed clinical/cognitive evaluations and resting-state functional MRI (fMRI). Four-year clinical follow-up data were available for 28 PD-TD patients, who were classified in 10 converters (cTD-PD) and 18 non-converters (ncTD-PD) to PIGD. The cerebellar seed-region was identified using a fMRI motor task. SFC analysis, characterizing regions that connect brain areas to the cerebellar seed at different levels of link-step distances, evaluated similar and divergent alterations in PD-TD and PD-PIGD. The discriminatory power of clinical data and/or SFC in distinguishing cPD-TD from ncPD-TD patients was assessed using ROC curve analysis. Compared to PD-TD, PD-PIGD patients showed decreased SFC in temporal lobe and occipital lobes and increased SFC in cerebellar cortex and ponto-medullary junction. Considering the subtype-conversion analysis, cPD-TD patients were characterized by increased SFC in temporal and occipital lobes and in cerebellum and ponto-medullary junction relative to ncPD-TD group. Combining clinical and SFC data, ROC curves provided the highest classification power to identify conversion to PIGD. These findings provide novel insights into the pathophysiology underlying different PD motor phenotypes and a potential tool for early characterization of PD-TD patients at risk of conversion to PIGD., (© 2022. The Author(s).)

Background: Mutations in the GBA gene cause Gaucher's disease (GD) and constitute the most frequent genetic risk factor for idiopathic Parkinson's disease (iPD). Nonmanifesting carriers of GBA mutations/variants (GBA-NMC) constitute a potential PD preclinical population, whereas PD patients carrying some GBA mutations/variants (GBA-PD) have a higher risk of a more aggressive disease course. Different neuroimaging techniques are emerging as potential biomarkers in PD and have been used to study GBA-associated parkinsonism., Objective: The aim is to critically review studies applying neuroimaging to GBA-associated parkinsonism., Methods: Literature search was performed using PubMed and EMBASE databases (last search February 7, 2022). Studies reporting neuroimaging findings in GBA-PD, GD with and without parkinsonism, and GBA-NMC were included., Results: Thirty-five studies were included. In longitudinal studies, GBA-PD patients show a more aggressive disease than iPD at both structural magnetic resonance imaging and 123-fluoropropylcarbomethoxyiodophenylnortropane single-photon emission computed tomography. Fluorodeoxyglucose-positron emission tomography and brain perfusion studies reported a greater cortical involvement in GBA-PD compared to iPD. Overall, contrasting evidence is available regarding GBA-NMC for imaging and clinical findings, although subtle differences have been reported compared with healthy controls with no mutations., Conclusions: Although results must be interpreted with caution due to limitations of the studies, in line with previous clinical observations, GBA-PD showed a more aggressive disease progression in neuroimaging longitudinal studies compared to iPD. Cognitive impairment, a "clinical signature" of GBA-PD, seems to find its neuroimaging correlate in the greater cortical burden displayed by these patients as compared to iPD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objectives: To explore cognitive, EEG, and MRI features in COVID-19 survivors up to 10 months after hospital discharge., Methods: Adult patients with a recent diagnosis of COVID-19 and reporting subsequent cognitive complaints underwent neuropsychological assessment and 19-channel-EEG within 2 months (baseline, N = 49) and 10 months (follow-up, N = 33) after hospital discharge. A brain MRI was obtained for 36 patients at baseline. Matched healthy controls were included. Using eLORETA, EEG regional current densities and linear lagged connectivity values were estimated. Total brain and white matter hyperintensities (WMH) volumes were measured. Clinical and instrumental data were evaluated between patients and controls at baseline, and within patient whole group and with/without dysgeusia/hyposmia subgroups over time. Correlations among findings at each timepoint were computed., Results: At baseline, 53% and 28% of patients showed cognitive and psychopathological disturbances, respectively, with executive dysfunctions correlating with acute-phase respiratory distress. Compared to healthy controls, patients also showed higher regional current density and connectivity at delta band, correlating with executive performances, and greater WMH load, correlating with verbal memory deficits. A reduction of cognitive impairment and delta band EEG connectivity were observed over time, while psychopathological symptoms persisted. Patients with acute dysgeusia/hyposmia showed lower improvement at memory tests than those without. Lower EEG delta band at baseline predicted worse cognitive functioning at follow-up., Discussion: COVID-19 patients showed interrelated cognitive, EEG, and MRI abnormalities 2 months after hospital discharge. Cognitive and EEG findings improved at 10 months. Dysgeusia and hyposmia during acute COVID-19 were related with increased vulnerability in memory functions over time., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Functional movement disorders include a wide spectrum of clinically documented movement disorders without an apparent organic substrate., Objective: To explore the functional connectivity (FC) of the primary motor (M1) cortex in functional dystonia (FD) patients relative to healthy controls, with a focus on different clinical phenotypes., Methods: Forty FD patients (12 fixed [FixFD]; 28 mobile [MobFD]) and 43 healthy controls (14 young FixFD-age-matched [yHC]; 29 old MobFD-age-matched [oHC]) underwent resting state fMRI. A seed-based FC analysis was performed using bilateral M1 as regions of interest., Results: Compared to controls, FD patients showed reduced FC between left M1 and left dorsal anterior cingulate cortex, and between right M1 and left M1, premotor/supplementary motor area (SMA), dorsal posterior cingulate cortex (PCC), and bilateral precuneus. Relative to yHC, FixFD patients showed reduced FC between M1 and precuneus bilaterally. Compared to oHC, MobFD patients revealed reduced FC between right M1 and left M1, premotor/SMA, dorsal-PCC, bilateral primary sensory cortices and parieto-occipital areas, and increased FC of right M1 with right associative visual cortex and bilateral ventral-PCC. FixFD patients, relative to MobFD, showed lower FC between the right M1 and right associative visual area, and bilateral precuneus and ventral-PCC., Conclusions: This study suggests an altered brain FC of the motor circuit with areas involved in emotional processes and sense of agency in FD. FixFD patients showed FC abnormalities mainly in areas related to sense of agency, while MobFD in regions involved in sensorimotor functions (reduced FC) and emotional processing (increased FC)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: To study the longitudinal disease course of Parkinson's disease (PD) patients with glucocerebrosidase (GBA) mutation (GBA-positive) compared to PD non-carriers (GBA-negative) along a 5-year follow-up, evaluating changes in clinical and cognitive outcomes, cortical thickness, and gray-matter (GM) volumes., Methods: Ten GBA-positive and 20 GBA-negative PD patients underwent clinical, neuropsychological, and MRI assessments (cortical thickness and subcortical, hippocampal, and amygdala volumes) at study entry and once a year for 5 years. At baseline and at the last visit, each group of patients was compared with 22 age-matched healthy controls. Clinical, cognitive, and MRI features were compared between groups at baseline and over time., Results: At baseline, GBA-positive and GBA-negative PD patients had similar clinical and cognitive profiles. Compared to GBA-negative and controls, GBA-positive patients showed cortical thinning of left temporal, parietal, and occipital gyri. Over time, compared to GBA-negative, GBA-positive PD patients progressed significantly in motor and cognitive symptoms, and showed a greater pattern of cortical thinning of posterior regions, and frontal and orbito-frontal cortices. After 5 years, compared to controls, GBA-negative PD patients showed a pattern of cortical thinning similar to that showed by GBA-positive cases at baseline. The two groups of patients showed similar patterns of subcortical, hippocampal, and amygdala volume loss over time., Conclusions: Compared to GBA-negative PD, GBA-positive patients experienced a more rapid motor and cognitive decline together with a greater, earlier and faster cortical thinning. Cortical thickness measures may be a useful tool for monitoring and predicting PD progression in accordance with the genetic background., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial., Objective: To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD., Methods: A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models., Results: At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment., Conclusions: Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background and Objectives: A significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic, and pathologic levels. Within this continuum of presentations, the presence of mild cognitive or behavioral symptoms in patients with ALS has been consistently reported, although it is unclear whether this is to be considered a distinct phenotype or rather a natural evolution of ALS. Here, we used mathematical modeling of MRI connectomic data to decipher common and divergent neural correlates across the ALS-frontotemporal dementia (FTD) spectrum., Methods: We included 83 patients with ALS, 35 patients with bvFTD, and 61 healthy controls, who underwent clinical, cognitive, and MRI assessments. Patients with ALS were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive or behavioral involvement (ALS-ci/bi), and 8 ALS with bvFTD (ALS-FTD). First, we assessed the functional and structural connectivity patterns across the ALS-FTD spectrum. Second, we investigated whether and where MRI connectivity alterations of patients with ALS with any degree of cognitive impairment (i.e., ALS-ci/bi and ALS-FTD) resembled more the pattern of damage of one (ALS-cn) or the other end (bvFTD) of the spectrum, moving from group-level to single-subject analysis., Results: As compared with controls, extensive structural and functional disruption of the frontotemporal and parietal networks characterized bvFTD (bvFTD-like pattern), while a more focal structural damage within the sensorimotor-basal ganglia areas characterized ALS-cn (ALS-cn-like pattern). ALS-ci/bi patients demonstrated an ALS-cn-like pattern of structural damage, diverging from ALS-cn with similar motor impairment for the presence of enhanced functional connectivity within sensorimotor areas and decreased functional connectivity within the bvFTD-like pattern. On the other hand, patients with ALS-FTD resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas., Discussion: Our findings suggest a maladaptive role of functional rearrangements in ALS-ci/bi concomitantly with similar structural alterations compared to ALS-cn, supporting the hypothesis that ALS-ci/bi might be considered as a phenotypic variant of ALS, rather than a consequence of disease worsening., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

This study aimed to identify functional neuroimaging patterns anticipating the clinical indication for deep brain stimulation (DBS) in patients with Parkinson's disease (PD). A cohort of prospectively recruited patients with PD underwent neurological evaluations and resting-state functional MRI (RS-fMRI) at baseline and annually for 4 years. Patients were divided into two groups: 19 patients eligible for DBS over the follow-up and 41 patients who did not meet the criteria to undergo DBS. Patients selected as candidates for DBS did not undergo surgery at this stage. Sixty age- and sex-matched healthy controls performed baseline evaluations. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity at baseline and at each time point. At baseline, network analysis showed a higher mean nodal strength, local efficiency, and clustering coefficient of the occipital areas in candidates for DBS over time relative to controls and patients not eligible for DBS. The occipital hyperconnectivity pattern was confirmed by regional analysis. At baseline, a decreased functional connectivity between basal ganglia and sensorimotor/frontal networks was found in candidates for DBS compared to patients not eligible for surgery. In the longitudinal analysis, patient candidate for DBS showed a progressively decreased topological brain organization and functional connectivity, mainly in the posterior brain networks, and a progressively increased connectivity of basal ganglia network compared to non-candidates for DBS. RS-fMRI may support the clinical indication to DBS and could be useful in predicting which patients would be eligible for DBS in the earlier stages of PD., (© 2022. The Author(s).)

The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To assess magnetic resonance imaging (MRI) alterations occurring in patients with trigeminal neuralgia (TN) and to explore the predictive ability of MRI for initial surgical outcome and long-term pain relief/recurrence after Gamma Knife radiosurgery (GKS)., Methods: Thirty patients with idiopathic or classic TN, who underwent GKS and were followed for at least 24 months, were retrospectively included. Pre-treatment structural MRI and pre- and serial, postoperative clinical features were investigated. Fifteen age- and sex-matched healthy controls were also enrolled. Cortical thickness and gray matter (GM) volumes were assessed in TN patients relative to controls, as well as between patient subgroups according to treatment outcomes (initial responders/non-responders, patients with pain recurrence/long-lasting pain relief at the last follow-up). Clinical and MRI predictors of treatment outcomes were explored., Results: Cortical thinning of temporal, prefrontal, cingulate, somatosensory and occipital areas bilaterally was found in TN patients relative to controls. No cortical thickness and GM volume differences were observed when TN initial responders and non-responders were compared. Patients who experienced TN recurrence after initial pain relief were characterized by thicker parahippocampal and temporal cortices bilaterally and greater volume of right amygdala and hippocampus compared to patients with long-lasting pain relief. In TN patients, disease duration and baseline cortical thinning of right parahippocampal, left fusiform and middle temporal cortices were associated with poor outcome after GKS at the last follow-up (R 2 =0.57, p<0.001)., Conclusion: The study provides novel insights into structural brain alterations of TN patients, which might contribute to disease development and pain maintenance., (© 2021 European Academy of Neurology.)

Background: Action observation training and motor imagery may improve motor learning in Parkinson's disease (PD)., Objectives: The objectives of this study were to assess mobility and balance (performing motor and dual tasks) and brain functional reorganization following 6 weeks of action observation training and motor imagery associated with dual-task gait/balance exercises in PD patients with postural instability and gait disorders relative to dual-task training alone., Methods: Twenty-five PD-postural instability and gait disorder patients were randomized into 2 groups: the DUAL-TASK+AOT-MI group performed a 6-week gait/balance training consisting of action observation training-motor imagery combined with practicing the observed-imagined exercises; the DUAL-TASK group performed the same exercises combined with watching landscape videos. Exercises were increasingly difficult to include the dual task. At baseline and at 6 weeks, patients underwent: mobility, gait, and balance evaluations (also repeated 2 months after training), cognitive assessment, and functional MRI, including motor and dual tasks., Results: Dual-task gait/balance training enhanced mobility, during both single- and dual-task conditions, and executive functions in PD-postural instability and gait disorders, with a long-lasting effect at 14 weeks. When exercises were preceded by action observation training-motor imagery, PD-postural instability and gait disorders showed greater improvement of balance and gait velocity both with and without the dual task, particularly during the turning phase. After training, the DUAL-TASK+AOT-MI group showed reduced recruitment of frontal areas and increased activity of cerebellum during functional-MRI motor and dual task, correlating with balance/turning velocity and executive improvements, respectively. The DUAL-TASK group showed reduced activity of supplementary motor area and increased recruitment of temporo-parietal areas during the dual task and decreased cerebellar activity during the motor task correlating with faster turning velocity. Functional MRI results were not corrected for multiple comparisons and should be interpreted carefully., Conclusions: Adding action observation training-motor imagery to dual-task gait/balance training promotes specific functional reorganization of brain areas involved in motor control and executive-attentive abilities and more long-lasting effects on dual-task mobility and balance in PD-postural instability and gait disorders. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background and Objectives: To assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations., Methods: Sixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained., Results: Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP . Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores., Discussion: Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72 -related disorders, regardless of the clinical presentation within the FTLD spectrum., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The relationship between human brain connectomics and genetic evolutionary traits remains elusive due to the inherent challenges in combining complex associations within cerebral tissue. In this study, insights are provided about the relationship between connectomics, gene expression and divergent evolutionary pathways from non-human primates to humans. Using in vivo human brain resting-state data, we detected two co-existing idiosyncratic functional systems: the segregation network, in charge of module specialization, and the integration network, responsible for information flow. Their topology was approximated to whole-brain genetic expression (Allen Human Brain Atlas) and the co-localization patterns yielded that neuron communication functionalities-linked to Neuron Projection-were overrepresented cell traits. Homologue-orthologue comparisons using dN/dS-ratios bridged the gap between neurogenetic outcomes and biological data, summarizing the known evolutionary divergent pathways within the Homo Sapiens lineage. Evidence suggests that a crosstalk between functional specialization and information flow reflects putative biological qualities of brain architecture, such as neurite cellular functions like axonal or dendrite processes, hypothesized to have been selectively conserved in the species through positive selection. These findings expand our understanding of human brain function and unveil aspects of our cognitive trajectory in relation to our simian ancestors previously left unexplored., (© 2021. The Author(s).)

Introduction: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD., Methods: 24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic., Results: DLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB., Conclusions: DLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Longitudinal connectivity studies might guide our understanding of the underlying neurodegenerative processes. We report the results of a longitudinal study in patients at different stages of Parkinson's disease (PD), who performed motor and non-motor evaluations and serial resting state (RS) functional MRI (fMRI). Cluster analysis was applied to demographic and clinical data of 146 PD patients to define disease subtypes. Brain network functional alterations were assessed at baseline in PD relative to 60 healthy controls and every year for a maximum of 4 years in PD groups. Progression of brain network changes were compared between patient clusters using RS fMRI. The contribution of network changes in predicting clinical deterioration was explored. Two main PD clusters were identified: mild PD (86 patients) and moderate-to-severe PD (60 patients), with the latter group being older and having earlier onset, longer PD duration, more severe motor, non-motor and cognitive deficits. Within the mild patient cluster, two clinical subtypes were further identified: mild motor-predominant (43) and mild-diffuse (43), with the latter being older and having more frequent non-motor symptoms. Longitudinal functional connectivity changes vary across patients in different disease stages with the coexistence of hypo- and hyper-connectivity in all subtypes. RS fMRI changes were associated with motor, cognitive and non-motor evolution in PD patients. Baseline RS fMRI presaged clinical and cognitive evolution. Our network perspective was able to define trajectories of functional architecture changes according to PD stages and prognosis. RS fMRI may be an early biomarker of PD motor and non-motor progression., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Functional brain connectivity alterations may be detectable even before the occurrence of brain atrophy, indicating their potential as early markers of pathological processes., Objective: We aimed to determine the whole-brain network topologic organization of the functional connectome in a large cohort of drug-naïve Parkinson's disease (PD) patients using resting-state functional magnetic resonance imaging and to explore whether baseline connectivity changes may predict clinical progression., Methods: One hundred and forty-seven drug-naïve, cognitively unimpaired PD patients were enrolled in the study at baseline and compared to 38 age- and gender-matched controls. Non-hierarchical cluster analysis using motor and non-motor data was applied to stratify PD patients into two subtypes: 77 early/mild and 70 early/severe. Graph theory analysis and connectomics were used to assess global and local topological network properties and regional functional connectivity at baseline. Stepwise multivariate regression analysis investigated whether baseline functional imaging data were predictors of clinical progression over 2 years., Results: At baseline, widespread functional connectivity abnormalities were detected in the basal ganglia, sensorimotor, frontal, and occipital networks in PD patients compared to controls. Decreased regional functional connectivity involving mostly striato-frontal, temporal, occipital, and limbic connections differentiated early/mild from early/severe PD patients. Connectivity changes were found to be independent predictors of cognitive progression at 2-year follow-up., Conclusions: Our findings revealed that functional reorganization of the brain connectome occurs early in PD and underlies crucial involvement of striatal projections. Connectomic measures may be helpful to identify a specific PD patient subtype, characterized by severe motor and non-motor clinical burden as well as widespread functional connectivity abnormalities. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: We evaluated the value of resting-state EEG source biomarkers to characterize mild cognitive impairment (MCI) subjects with an Alzheimer's disease (AD)-like cerebrospinal fluid (CSF) profile and to track neurodegeneration throughout the AD continuum. We further applied a resting-state functional MRI (fMRI)-driven model of source reconstruction and tested its advantage in terms of AD diagnostic accuracy., Methods: Thirty-nine consecutive patients with AD dementia (ADD), 86 amnestic MCI, and 33 healthy subjects enter the EEG study. All ADD subjects, 37 out of 86 MCI patients and a distinct group of 53 healthy controls further entered the fMRI study. MCI subjects were divided according to the CSF phosphorylated tau/β amyloid-42 ratio (MCIpos: ≥ 0.13, MCIneg: < 0.13). Using Exact low-resolution brain electromagnetic tomography (eLORETA), EEG lobar current densities were estimated at fixed frequencies and analyzed. To combine the two imaging techniques, networks mostly affected by AD pathology were identified using Independent Component Analysis applied to fMRI data of ADD subjects. Current density EEG analysis within ICA-based networks at selected frequency bands was performed. Afterwards, graph analysis was applied to EEG and fMRI data at ICA-based network level., Results: ADD patients showed a widespread slowing of spectral density. At a lobar level, MCIpos subjects showed a widespread higher theta density than MCIneg and healthy subjects; a lower beta2 density than healthy subjects was also found in parietal and occipital lobes. Evaluating EEG sources within the ICA-based networks, alpha2 band distinguished MCIpos from MCIneg, ADD and healthy subjects with good accuracy. Graph analysis on EEG data showed an alteration of connectome configuration at theta frequency in ADD and MCIpos patients and a progressive disruption of connectivity at alpha2 frequency throughout the AD continuum., Conclusions: Theta frequency is the earliest and most sensitive EEG marker of AD pathology. Furthermore, EEG/fMRI integration highlighted the role of alpha2 band as potential neurodegeneration biomarker., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In the present study we investigated emotion recognition in pure motor amyotrophic lateral sclerosis (ALS) patients and its relationship with the integrity of basal ganglia, hippocampus and amygdala. Twenty ALS patients without either cognitive or behavioural impairment, and 52 matched healthy controls performed a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. All participants underwent also a 3T brain MRI. Volumes of basal ganglia, hippocampus and amygdala bilaterally were measured using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, correlations between CATS significant findings, brain volumes, cognition, mood and behaviour were explored. ALS patients showed altered performances at the CATS total score and, among the investigated emotions, patients were significantly less able to recognize disgust compared with controls. No brain volumetric differences were observed between groups. In ALS patients, a lower performance in disgust recognition was related with a reduced volume of the left pallidum and a lower performance on the Edinburgh Cognitive and Behavioural ALS Screen. Cognitively/behaviourally unimpaired ALS patients showed impaired disgust recognition, which was associated with pallidum volume. The association with cognitive alterations may suggest impaired disgust recognition as an early marker of cognitive decline., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This study assessed brain structural alterations in two diverse clinical forms of functional (psychogenic) dystonia (FD) - the typical fixed dystonia (FixFD) phenotype and the "mobile" dystonia (MobFD) phenotype, which has been recently described in one study. Forty-four FD patients (13 FixFD and 31 MobFD) and 43 healthy controls were recruited. All subjects underwent 3D T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI). Cortical thickness, volumes of gray matter (GM) structures, and white matter (WM) tract integrity were assessed. Normal cortical thickness in both FD patient groups compared with age-matched healthy controls were found. When compared with FixFD, MobFD patients showed cortical thinning of the left orbitofrontal cortex, and medial and lateral parietal and cingulate regions bilaterally. Additionally, compared with controls, MobFD patients showed reduced volumes of the left nucleus accumbens, putamen, thalamus, and bilateral caudate nuclei, whereas MobFD patients compared with FixFD demonstrated atrophy of the right hippocampus and globus pallidus. Compared with both controls and MobFD cases, FixFD patients showed a severe disruption of WM architecture along the corpus callous, corticospinal tract, anterior thalamic radiations, and major long-range tracts bilaterally. This study showed different MRI patterns in two variants of FD. MobFD had alterations in GM structures crucial for sensorimotor processing, emotional, and cognitive control. On the other hand, FixFD patients were characterized by a global WM disconnection affecting main sensorimotor and emotional control circuits. These findings may have important implications in understanding the neural substrates underlying different phenotypic FD expression levels.

Objective: To investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA)., Methods: A total of 173 patients with sporadic ALS, 38 patients with PLS, 28 patients with PMA, and 79 healthy controls were recruited from 3 Italian centers. Participants underwent clinical, neuropsychological, and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topologic network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical and cognitive data was investigated., Results: Compared with healthy controls, patients with ALS and patients with PLS showed altered structural global network properties, as well as local topologic alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal, and parietal areas. Patients with PMA showed preserved global structure. Patient groups did not show significant alterations of functional network topologic properties relative to controls. Increased local functional connectivity was observed in patients with ALS in the precentral, middle, and superior frontal areas, and in patients with PLS in the sensorimotor, basal ganglia, and temporal networks. In patients with ALS and patients with PLS, structural connectivity alterations correlated with motor impairment, whereas functional connectivity disruption was closely related to executive dysfunction and behavioral disturbances., Conclusions: This multicenter study showed widespread motor and extramotor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extramotor brain changes, and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The objectives of this study were to investigate progressive cortical thinning and volume loss in Parkinson's disease (PD) patients with different longitudinal patterns of cognitive decline: with stable normal cognition, with stable mild cognitive impairment, with conversion to mild cognitive impairment, and with conversion to dementia., Methods: We recruited 112 patients (37 Parkinson's disease with stable normal cognition, 20 Parkinson's disease with stable mild cognitive impairment, 36 Parkinson's disease with conversion to mild cognitive impairment, 19 Parkinson's disease with conversion to dementia) and 38 healthy controls. All patients underwent at least 2 visits within 4 years including clinical/cognitive assessments and structural MRI (total visits, 393). Baseline cortical thickness and gray matter volumetry were compared between groups. In PD, gray matter changes over time were investigated and compared between groups., Results: At baseline, compared with Parkinson's disease with stable normal cognition cases, Parkinson's disease with conversion to mild cognitive impairment patients showed cortical atrophy of the parietal and occipital lobes, similar to Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia patients. The latter groups (ie, patients with cognitive impairment from the study entry) showed additional involvement of the frontotemporal cortices. No baseline volumetric differences among groups were detected. The longitudinal analysis (group-by-time interaction) showed that, versus the other patient groups, Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia cases accumulated the least cortical damage, with Parkinson's disease with conversion to dementia showing unique progression of right thalamic and hippocampal volume loss; Parkinson's disease with conversion to mild cognitive impairment patients showing specific cortical thinning accumulation in the medial and superior frontal gyri, inferior temporal, precuneus, posterior cingulum, and supramarginal gyri bilaterally; and Parkinson's disease with stable normal cognition patients showing cortical thinning progression, mainly in the occipital and parietal regions bilaterally., Conclusions: Cortical thinning progression is more prominent in the initial stages of PD cognitive decline. The involvement of frontotemporoparietal regions, the hippocampus, and the thalamus is associated with conversion to a more severe stage of cognitive impairment. In PD, gray matter alterations of critical brain regions may be an MRI signature for the identification of patients at risk of developing dementia. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Alzheimer's disease (AD) is associated with brain network dysfunction. Network-based investigations of brain connectivity have mainly focused on alterations in the strength of connectivity; however, the network breakdown in AD spectrum is a complex scenario in which multiple pathways of connectivity are affected. To integrate connectivity changes that occur under AD-related conditions, here we developed a novel metric that computes the connectivity distance between cortical regions at the voxel level (or nodes). We studied 114 individuals with mild cognitive impairment, 24 with AD, and 27 healthy controls. Results showed that areas of the default mode network, salience network, and frontoparietal network display a remarkable network separation, or greater connectivity distances, from the rest of the brain. Furthermore, this greater connectivity distance was associated with lower global cognition. Overall, the investigation of AD-related changes in paths and distances of connectivity provides a novel framework for characterizing subjects with cognitive impairment; a framework that integrates the overall network topology changes of the brain and avoids biases toward unreferenced connectivity effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes., Competing Interests: The authors declare no competing interest.

Objective: To investigate the progression of resting-state functional connectivity (rs-FC) changes in patients with amyotrophic lateral sclerosis (ALS) and their relationship with frontal cognitive alterations., Methods: This is a multicentre, observational and longitudinal study. At baseline and after six months, 25 ALS patients underwent 3D T1-weighted MRI, resting-state functional MRI (rs-fMRI), and the computerized Test of Attentional Performance (TAP). Using independent component analysis, rs-FC changes of brain networks involving connections to frontal lobes and their relationship with baseline cognitive scores and cognitive changes over time were assessed. With a seed-based approach, rs-FC longitudinal changes of the middle frontal gyrus (MFG) were also explored., Results: After six months, ALS patients showed an increased rs-FC of the left anterior cingulate, left middle frontal gyrus (MFG) and left superior frontal gyrus within the frontostriatal network, and of the left MFG, left supramarginal gyrus and right angular gyrus within the left frontoparietal network. Within the frontostriatal network, a worse baseline performance at TAP divided attention task was associated with an increased rs-FC over time in the left MFG and a worse baseline performance at the category fluency index was related with increased rs-FC over time in the left frontal superior gyrus. After six months, the seed-based rs-FC analysis of the MFG with the whole brain showed decreased rs-FC of the right MFG with frontoparietal regions in patients compared to controls., Conclusions: Rs-FC changes in ALS patients progressed over time within the frontostriatal and the frontoparietal networks and are related to frontal-executive dysfunction. The MFG seems a potential core region in the framework of a frontoparietal functional breakdown, which is typical of frontotemporal lobar degeneration. These findings offer new potential markers for monitoring extra-motor progression in ALS., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Clinical manifestations and evolution are very heterogeneous among individuals with Parkinson's disease (PD). The aims of this study were to investigate the pattern of progressive brain atrophy in PD according to disease stage and to elucidate to what extent cortical thinning and subcortical atrophy are related to clinical motor and non-motor evolution. 154 patients at different PD stages were assessed over time using motor, non-motor and structural MRI evaluations for a maximum of 4 years. Cluster analysis defined clinical subtypes. Cortical thinning and subcortical atrophy were assessed at baseline in patients relative to 60 healthy controls. Longitudinal trends of brain atrophy progression were compared between PD clusters. The contribution of brain atrophy in predicting motor, non-motor, cognitive and mood deterioration was explored. Two main PD clusters were defined: mild (N = 87) and moderate-to-severe (N = 67). Two mild subtypes were further identified: mild motor-predominant (N = 43) and mild-diffuse (N = 44), with the latter group being older and having more severe non-motor and cognitive symptoms. The initial pattern of brain atrophy was more severe in patients with moderate-to-severe PD. Over time, mild-diffuse PD patients had the greatest brain atrophy accumulation in the cortex and the left hippocampus, while less distributed atrophy progression was observed in moderate-to-severe and mild motor-predominant patients. Baseline and 1-year cortical thinning was associated with long-term progression of motor, cognitive, non-motor and mood symptoms. Cortical and subcortical atrophy is accelerated early after the onset of PD and becomes prominent in later stages of disease according to the development of cognitive, non-motor and mood dysfunctions. Structural MRI may be useful for monitoring and predicting disease progression in PD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was two-fold: (i) to investigate structural and functional brain network architecture in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), stratified in converters (c-aMCI) and non-converters (nc-aMCI) to AD; and to assess the relationship between healthy brain network functional connectivity and the topography of brain atrophy in patients along the AD continuum. Ninety-four AD patients, 47 aMCI patients (25 c-aMCI within 36 months) and 53 age- and sex-matched healthy controls were studied. Graph analysis and connectomics assessed global and local, structural and functional topological network properties and regional connectivity. Healthy topological features of brain regions were assessed based on their connectivity with the point of maximal atrophy (epicenter) in AD and aMCI patients. Brain network graph analysis properties were severely altered in AD patients. Structural brain network was already altered in c-aMCI patients relative to healthy controls in particular in the temporal and parietal brain regions, while functional connectivity did not change. Structural connectivity alterations distinguished c-aMCI from nc-aMCI cases. In both AD and c-aMCI, the point of maximal atrophy was located in left hippocampus (disease-epicenter). Brain regions most strongly connected with the disease-epicenter in the healthy functional connectome were also the most atrophic in both AD and c-aMCI patients. Progressive degeneration in the AD continuum is associated with an early breakdown of anatomical brain connections and follows the strongest connections with the disease-epicenter. These findings support the hypothesis that the topography of brain connectional architecture can modulate the spread of AD through the brain.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.