Caudate functional networks influence brain structural changes with aging.

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 T1-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.

EEG Correlates in the 3 Variants of Primary Progressive Aphasia.

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.

Structural and Functional Brain Network Connectivity at Different King's Stages in Patients With Amyotrophic Lateral Sclerosis.

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.

Age-related vulnerability of the human brain connectome.

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.

Altered Functional Connectivity of the Subthalamic Nucleus in Parkinson's Disease: Focus on Candidates for Deep Brain Stimulation.

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.

Functional Connectivity From Disease Epicenters in Frontotemporal Dementia.

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.

The human functional connectome in neurodegenerative diseases: relationship to pathology and clinical progression.

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.

Brain structural abnormalities and cognitive changes in a patient with 17q21.31 microduplication and early onset dementia: a case report.

OBJECTIVES: We describe brain structural damage and cognitive profile evolution of an adult patient with 17q21.31 microduplication, a rare condition associated with psychomotor delay, behavioural disturbances and poor social interaction. METHODS: A.B., 57 years old, male, displayed obsessive and repetitive behaviours, irritability, scarce hygiene and memory loss at disease onset. He had strong familiarity for adult-onset behavioural alterations (his father and sister) and neuropsychiatric conditions (his son). Blood and cerebrospinal fluid (CSF) samples revealed 17q21.31 microduplication, shared also by his son and sister, and raised CSF tau, respectively. He was hospitalized 1 year after disease onset and underwent an MRI scan and a neuropsychological assessment, the latter being repeated 7 months later. To quantitatively investigate patient's grey matter (GM) volume, 16 age- and education-matched male controls were selected and voxel-based morphometry analysis was performed. RESULTS: During hospitalization, his behavioural profile was characterized by anosognosia, impulsivity, apathy and aggressiveness. Cognitive testing revealed main attentive-executive disturbances and difficulties in understanding non-literal language. Compared to controls, A.B. had greater GM atrophy mainly in the right hemisphere, involving amygdala, hippocampus, inferior/superior temporal gyri and temporal pole. He received a diagnosis of early onset dementia. After 7 months, he developed empathy loss, perseverative behaviour, changes in eating habits and worsening in executive-attentive abilities. CONCLUSIONS: In A.B., 17q21.31 microduplication caused a neurodegenerative condition with prevalent right temporal damage, raised CSF tau level, behavioural disturbances, memory impairment, attentive-executive and abstract language dysfunctions and fast disease progression, thus reflecting the complex interaction between such genetic substrate and clinical phenotypes.

MRI biomarkers of freezing of gait development in Parkinson's disease.

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.

Cerebro-cerebellar motor networks in clinical subtypes of Parkinson's disease.

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.

Cognitive, EEG, and MRI features of COVID-19 survivors: a 10-month study.

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.

Functional connectivity in Parkinson's disease candidates for deep brain stimulation.

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.

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia: Shared and Divergent Neural Correlates Across the Clinical Spectrum.

OBJECTIVES: A significant overlap between amyotrophic lateral sclerosis (ALS) and behavioral variant of frontotemporal dementia (bvFTD) has been observed at clinical, genetic and pathological levels. Within this continuum of presentations, the presence of mild cognitive and/or behavioral symptoms in ALS patients 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-FTD spectrum. METHODS: We included 83 ALS patients, 35 bvFTD patients and 61 healthy controls, who underwent clinical, cognitive and MRI assessments. ALS patients were classified according to the revised Strong criteria into 54 ALS with only motor deficits (ALS-cn), 21 ALS with cognitive and/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 ALS patients 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, ALS-FTD patients resembled both structurally and functionally the bvFTD-like pattern of damage with, in addition, the structural ALS-cn-like damage in the motor areas. CONCLUSIONS: 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.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum.

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.

Resting-state electroencephalographic biomarkers of Alzheimer's disease.

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/ß 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.

Functional Connectomics and Disease Progression in Drug-Naïve Parkinson's Disease Patients.

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.

Progression of cognitive and behavioral disturbances in motor neuron diseases assessed using standard and computer-based batteries.

Objective: Detecting and monitoring cognitive and behavioral deficits in motor neuron diseases (MND) is critical due to their considerable clinical impact. In this scenario, computer-based batteries may play an important role. In this study, we investigated the progression of cognitive and behavioral deficits in MND patients using both standard and computer-based neuropsychological batteries. Methods: This is a retrospective study on 74 MND patients (52 amyotrophic lateral sclerosis [ALS], 12 primary lateral sclerosis [PLS], and 10 progressive muscular atrophy [PMA]) who were followed up for 12 months and underwent up to three cognitive/behavioral assessments, 6 months apart, including standard and/or computerized based (the Test of Attentional Performance [TAP]) batteries. Behavioral/cognitive changes were investigated over time using generalized linear model for longitudinal data accounting for time and revised-ALS Functional Rating Scale. Results: Over 12 months, ALS patients showed a global cognitive decline (Mini Mental State Examination) at the standard battery and reduced performance in the alertness, sustained and divided attention, go/nogo, cross-modal and incompatibility TAP tasks. Most of these findings remained significant when ALSFRS-R changes over time were included as covariate in the analyses. ALS patients did not show significant behavioral abnormalities over time. No cognitive and behavioral changes were found in PLS and PMA cases. Conclusions: Computer-based neuropsychological evaluations are able to identify subtle cognitive changes in ALS, unique to this condition. This study highlights the need of specific, accurate and well-tolerated tools for the monitoring of cognitive deficits in MND.

Structural and functional brain connectome in motor neuron diseases: A multicenter MRI study.

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.