Interregional Correlation Analysis Research Articles

Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer’s Disease: Clues from [18F]FDG PET Voxel-Wise Analysis

Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Alterations via inter-regional connective relationships in Alzheimer's disease.

Disruptions in the inter-regional connective correlation within the brain are believed to contribute to memory impairment. To detect these corresponding correlation networks in Alzheimer's disease (AD), we conducted three types of inter-regional correlation analysis, including structural covariance, functional connectivity and group-level independent component analysis (group-ICA). The analyzed data were obtained from the Alzheimer's Disease Neuroimaging Initiative, comprising 52 cognitively normal (CN) participants without subjective memory concerns, 52 individuals with late mild cognitive impairment (LMCI) and 52 patients with AD. We firstly performed vertex-wise cortical thickness analysis to identify brain regions with cortical thinning in AD and LMCI patients using structural MRI data. These regions served as seeds to construct both structural covariance networks and functional connectivity networks for each subject. Additionally, group-ICA was performed on the functional data to identify intrinsic brain networks at the cohort level. Through a comparison of the structural covariance and functional connectivity networks with ICA networks, we identified several inter-regional correlation networks that consistently exhibited abnormal connectivity patterns among AD and LMCI patients. Our findings suggest that reduced inter-regional connectivity is predominantly observed within a subnetwork of the default mode network, which includes the posterior cingulate and precuneus regions, in both AD and LMCI patients. This disruption of connectivity between key nodes within the default mode network provides evidence supporting the hypothesis that impairments in brain networks may contribute to memory deficits in AD and LMCI.

Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase.

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype.

Brain metabolic connectivity reconfiguration in the semantic variant of primary progressive aphasia

Functional network-level alterations in the semantic variant of Primary Progressive Aphasia (sv-PPA) are relevant to understanding the clinical features and the neural spreading of the pathology. We assessed the effect of neurodegeneration on brain systems reorganization in early sv-PPA, using advanced brain metabolic connectivity approaches. Forty-four subjects with sv-PPA and forty-four age-matched healthy controls (HC) were included. We applied two multivariate approaches to [18F]FDG-PET data – i.e., sparse inverse covariance estimation and seed-based interregional correlation analysis – to assess the integrity of (i) the whole-brain metabolic connectivity and (ii) the connectivity of brain regions relevant for cognitive and behavioral functions. Whole-brain analysis revealed a global-scale connectivity reconfiguration in sv-PPA, with widespread changes in metabolic connections of frontal, temporal, and parietal regions. In comparison to HC, the seed-based analysis revealed a) functional isolation of the left anterior temporal lobe (ATL), b) decreases in temporo-occipital connections and contralateral homologous regions, c) connectivity increases to the dorsal parietal cortex from the spared posterior temporal cortex, d) a disruption of the large-scale limbic brain networks. In sv-PPA, the severe functional derangement of the left ATL may lead to an extensive connectivity reconfiguration, encompassing several brain regions, including those not yet affected by neurodegeneration. These findings support the hypothesis that in sv-PPA the focal vulnerability of the core region (i.e., ATL) can potentially drive the widespread cerebral connectivity changes, already present in the early phase.

Exploring the functional role and neural correlates of K-complexes in isolated rapid eye movement sleep behavior disorder

Underlying neural mechanisms and cognitive implications of non-Rapid Eye Movement (NREM) sleep in isolated Rapid Eye Movement (REM) sleep behavior disorder (iRBD) are not yet fully elucidated. This study aims to evaluate brain metabolic connectivity of the anterior default mode network (ADMN) underlying a waveform that is an hallmark of NREM sleep, namely K-complex (KC) and their implication for neuropsychological functioning in iRBD patients. Combining polysomnographic and multivariate molecular imaging (FDG-PET) approaches may provide crucial insights regarding KCs role in the prodromal stages of synucleinopathies. We applied a seed-based interregional correlation analysis on FDG-PET data. iRBD patients with cognitive decline displayed a reduced KC density (KCd) in comparison to patients without cognitive impairments. KCd showed a significant positive correlation with global cognitive functioning, specifically with visuo-spatial and executive performances, two cognitive domains known to be relevant in predicting conversion into neurodegenerative disorders. Increased KCd was associated with a more preserved ADMN connectivity. Our study underlines the importance of NREM sleep in prodromal stages of synucleinopathies, and future investigations might clarify its role in iRBD.

Cuneus/precuneus as a central hub for brain functional connectivity of mild cognitive impairment in idiopathic REM sleep behavior patients.

To investigate brain functional correlates of mild cognitive impairment (MCI) in idiopathic REM sleep behavior disorder (iRBD). Thirty-nine consecutive iRBD patients, 17 with (RBD-MCI, 73.6±6.5 years), and 22 without (RBD-NC, 69.6±6.1 years) MCI underwent neuropsychological assessment, 18F-FDG-PET, and 123I-FP-CIT-SPECT as a marker of nigro-striatal dopaminergic function. Forty-two healthy subjects (69.6±8.5 years) were used as control for 18F-FDG-PET analysis. Brain metabolism was compared between the three groups by univariate analysis of variance. Post hoc comparison between RBD-MCI and RBD-NC was performed to investigate the presence of an MCI-related volume of interest (MCI-VOI). Brain functional connectivity was explored by interregional correlation analysis (IRCA), using the whole-brain normalized MCI-VOI uptake as the independent variable. Moreover, the MCI-VOI uptake was correlated with 123I-FP-CIT-SPECT specific-to-non displaceable binding ratios (SBR) and neuropsychological variables. Finally, the MCI-VOI white matter structural connectivity was analyzed by using a MRI-derived human atlas. The MCI-VOI was characterized by a relative hypometabolism involving precuneus and cuneus (height threshold p<0.0001). IRCA (height threshold p<0.0001) revealed a brain functional network involving regions in frontal, temporal, parietal, and occipital lobes, thalamus, caudate, and red nuclei in iRBD patients. In controls, the network was smaller and involved temporal, occipital, cingulate cortex, and cerebellum. Moreover, MCI-VOI metabolism was correlated with verbal memory (p=0.01), executive functions (p=0.0001), and nigro-putaminal SBR (p=0.005). Finally, MCI-VOI was involved in a white matter network including cingulate fasciculus and corpus callosum. Our data suggest that cuneus/precuneus is a hub of a large functional network subserving cognitive function in iRBD.

Premotor and fronto-striatal mechanisms associated with presence hallucinations in dementia with Lewy bodies

Introductionpresence hallucinations (PH) are frequent in dementia with Lewy bodies (DLB), but their cortico-subcortical origin is unknown. Recent studies have defined key frontal and temporal areas contributing to the occurrence of PH (PH-network) and tested their relevance in subjects with Parkinson’s disease (PD). With the present study, we aimed at disentangling the metabolic and dopaminergic correlates of pH as well as their relation to a recently defined PH brain network in DLB. Methodsfor the present study, we included 34 DLB subjects (10 with PH (PH + ); 24 without PH (PH-)), who underwent 18F-FDG PET and 123I-FP-CIT SPECT imaging. We performed 18F-FDG PET group comparisons, as well as interregional correlation analyses using 18F-FDG PH-network regions as a seed. ResultsPH + versus PH- had reduced 18F-FDG uptake in precentral, superior frontal and parietal gyri, involving ventral premotor cortex (vPMC) of the PH-network that showed strongly reduced functional connectivity with bilateral cortical regions. 18F-FDG vPMC uptake was negatively correlated with caudate 123I-FP-CIT uptake in PH+ (p = 0.028) and interregional correlation analysis seeding from the vPMC showed widespread fronto-parietal 18F-FDG decreases in PH + . Discussionthese findings uncover the pivotal role of vPMC (involved in a PH-network) and its cortico-striatal connections in association with PH in DLB, improving our understanding of psychosis in neurodegeneration.

The interplay among education, brain metabolism, and cognitive impairment suggests a role of cognitive reserve in Amyotrophic Lateral Sclerosis

We tested the Cognitive Reserve (CR) hypothesis in Amyotrophic Lateral Sclerosis (ALS), enrolling 111 patients, using education as CR proxy, 18F-FDG-PET to assess brain damage, and ECAS to measure cognition. Education was regressed out against brain metabolism, including age, sex, spinal/bulbar onset, ALSFRS-R, and ECAS as covariates. Clusters showing a significant correlation were used as seed regions in an interregional correlation analysis (IRCA) in the ALS group and in 40 controls. In the ALS group, we found a negative correlation between brain metabolism and education in the right anterior cingulate and bilateral medial frontal gyrus. In the IRCA in the ALS group, the medial frontal cluster metabolism positively correlated with that of frontotemporal regions (right > left), bilateral caudate nuclei, and right insula, and negatively correlated with that of corticospinal tracts, cerebellum, and pons. In controls, the IRCA showed significant positive correlations in the same regions but less extended. Our results agree with the CR hypothesis. The negative correlation between the medial frontal cluster and the cerebellum found only in ALS patients might reflect cerebellar compensation.

The role of anterior prefrontal cortex in prospective memory: an exploratory FDG-PET study in early Alzheimer's disease

From previous studies in healthy volunteers the prefrontal regions are deeply involved in prospective memory (PM), although little is known about the functional neural basis of PM in prodromal Alzheimer's disease (AD). To this end, we retrospectively recruited 18 patients with mild cognitive impairment caused by AD and 23 matched healthy control subjects who had undergone 18F-fluorodeoxyglucose positron emission tomography and the PM-specific paradigm test. Brain metabolism was correlated with the PM score in the 2 groups separately to find those brain areas correlated with PM performance, which were then used as a hub for an inter-regional metabolic connectivity analyses (inter-regional correlation analysis). Of note, in mild cognitive impairment caused by AD, but not in healthy control subjects, PM score positively correlated with metabolic levels in the right anterior prefrontal cortex (middle and inferior frontal gyri), which disclosed a loss of interhemispheric connectivity in the inter-regional correlation analysis. According to our findings, the functioning of the right anterior prefrontal cortex and its interhemispheric metabolic connectivity is crucial in early AD to sustain PM performance, which deteriorates along with progressive metabolic failure of the interconnected areas.

Specific occupational profiles as proxies of cognitive reserve induce neuroprotection in dementia with Lewy bodies.

Cognitive reserve (CR) delays cognitive decline due to neurodegeneration. Heterogeneous evidence suggests that education may act as CR in Dementia with Lewy Bodies (DLB). No data, however, are currently available on the role of occupation as proxy of CR in this neuropathology. Thirty-three patients with probable DLB were retrospectively included. We performed regression analyses models (TFCE p< 0.05) and seed-based interregional correlation analyses (p= 0.001, FWE-corrected at cluster-level) with brain metabolism. We aimed at exploring the relationship between brain metabolic connectivity, as assessed by FDG-PET, in the relevant resting-state networks and CR proxies (education, 6-levels occupation, and the specific O*Net occupational profiles). Education modulates executive (ECN), attentive (ATTN) and posterior default mode (PDMN) networks in the highly educated DLB subjects, as shown by an increased metabolic connectivity, acting as a compensatory mechanism. High scores of the 6-levels occupation scale were associated with a decreased connectivity in the anterior default mode (ADMN) and high visual network (HVN), suggesting brain reserve mechanisms. As for the specific O*Net occupational profiles, these modulated ADMN, PDMN, ATTN, ECN, HVN and primary visual network (PVN) connectivity according to different neuroprotection mechanisms, namely neural reserve and compensation against neurodegeneration. This study highlights the relevance of life-long occupational activities at individual level in the neural expression of compensatory and neuroprotective mechanisms in DLB.

Altered Topological Patterns of Gray Matter Networks in Tinnitus: A Graph-Theoretical-Based Study.

ObjectiveTinnitus is a prevalent hearing disorder, which could have a devastating impact on a patient’s life. Functional studies have revealed connectivity pattern changes in the tinnitus brains that suggested a change of network dynamics as well as topological organization. However, no studies have yet provided evidence for the topological network changes in the gray matter. In this research, we aim to use the graph-theoretical approach to investigate the changes of topology in the tinnitus brain using structural MRI data, which could provide insights into the underlying anatomical basis for the neural mechanism in generating phantom sounds.MethodsWe collected 3D MRI images on 46 bilateral tinnitus patients and 46 age and gender-matched healthy controls. Brain networks were constructed with correlation matrices of the cortical thickness and subcortical volumes of 80 cortical/subcortical regions of interests. Global network properties were analyzed using local and global efficiency, clustering coefficient, and small-world coefficient, and regional network properties were evaluated using the betweenness coefficient for hub connectivity, and interregional correlations for edge properties. Between-group differences in cortical thickness and subcortical volumes were assessed using independent sample t-tests, and local efficiency, global efficiency, clustering coefficient, sigma, and interregional correlation were compared using non-parametric permutation tests.ResultsTinnitus was found to have increased global efficiency, local efficiency, and cluster coefficient, indicating generally heightened connectivity of the network. The small-world coefficient remained normal for tinnitus, indicating intact small-worldness. Betweenness centrality analysis showed that hubs in the amygdala and parahippocampus were only found for tinnitus but not controls. In contrast, hubs in the auditory cortex, insula, and thalamus were only found for controls but not tinnitus. Interregional correlation analysis further found in tinnitus enhanced connectivity between the auditory cortex and prefrontal lobe, and decreased connectivity of the insula with anterior cingulate gyrus and parahippocampus.ConclusionThese findings provided the first morphological evidence of altered topological organization of the brain networks in tinnitus. These alterations suggest that heightened efficiency of the brain network and altered auditory-limbic connection for tinnitus, which could be developed in compensation for the auditory deafferentation, leading to overcompensation and, ultimately, an emotional and cognitive burden.

Lifetime sport practice and brain metabolism in Amyotrophic Lateral Sclerosis

ObjectiveTo evaluate the metabolic correlates of lifetime sport practice in ALS through brain 18F-FDG-PET. Methods131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain 18F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40). ResultsWe found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC. ConclusionsWe hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.

Exercise modulates neuronal activation in the micturition circuit of chronically stressed rats: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

BackgroundRats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS. MethodsAdult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H2O) after intravenous bolus injection of [14C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis. ResultsWAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a ‘top-down’ decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex. ConclusionOur results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS.

From metabolic connectivity to molecular connectivity: application to dopaminergic pathways

This study aims to reveal the feasibility and potential of molecular connectivity based on neurotransmission in comparison with the metabolic connectivity with an application to dopaminergic pathways. For this purpose, we propose to compare the neurotransmission connectivity findings using 123I-FP-CIT SPECT and 18F-FDOPA PET with the metabolic connectivity findings using 18F-FDG PET. 18F-FDG PET and 123I-FP-CIT SPECT images from 47 subjects and 18F-FDOPA PET images from 177 subjects, who had no neurological or psychiatric disorders, were studied. Interregional correlation analyses were performed at the group level to determine the midbrain's connectivity via glucose metabolic rate using 18F-FDG PET and via dopaminergic binding potential using 123I-FP-CIT SPECT and 18F-FDOPA PET. SPM-T maps of each radiotracer were generated, and masks used to highlight the significant differences obtained among the imaging modalities and targets. The three dopaminergic pathways (i.e., nigrostriatal, mesolimbic, and mesocortical) were identified by 18F-FDG PET (1599 voxels, with a Tmax value of 12.6), 123I-FP-CIT SPECT (1120 voxels, with Tmax value of 5.1), and 18F-FDOPA PET (6054 voxels, with Tmax value of 11.7) for a T voxel threshold of 5.10, 2.80, and 5.10, respectively. Using the same T voxel threshold of 5.10, 18F-FDOPA PET showed more specific findings than 18F-FDG PET with less voxels identified outside these pathways (- 9323 voxels), whereas no significant voxels were obtained with 123I-FP-CIT SPECT at this threshold. The present study illustrates the feasibility and interest in using molecular connectivity with 18F-FDOPA PET for dopaminergic pathways. Such analyses could be applied to specific diseases involving the dopaminergic system.

Temporal Analysis of OMI-Observed Tropospheric NO2 Columns over East Asia during 2006–2015

The study analyzed temporal variations of Ozone Monitoring Instrument (OMI)-observed NO2 columns, interregional correlation, and comparison between NO2 columns and NOx emissions during the period from 2006 to 2015. Regarding the trend of the NO2 columns, the linear lines were classified into four groups: (1) ‘upward and downward’ over six defined geographic regions in central-east Asia; (2) ‘downward’ over Guangzhou, Japan, and Taiwan; (3) ‘stagnant’ over South Korea; and (4) ‘upward’ over North Korea, Mongolia, Qinghai, and Northwestern Pacific ocean. In particular, the levels of NO2 columns in 2015 returned to those in 2006 over most of the polluted regions in China. Quantitatively, their relative changes in 2015 compared to 2006 were approximately 10%. From the interregional correlation analysis, it was found that unlike positive relationships between the polluted areas, the different variations of monthly NO2 columns led to negative relationships in Mongolia and Qinghai. Regarding the comparison between NO2 columns and NOx emission, the NOx emissions from the Copernicus Atmosphere Monitoring Service (CAMS) and Clean Air Policy Support System (CAPSS) inventories did not follow the year-to-year variations of NO2 columns over the polluted regions. In addition, the weekly effect was only clearly shown in South Korea, Japan, and Taiwan, indicating that the amounts of NOx emissions are significantly contributed to by the transportation sector.

Variant-specific vulnerability in metabolic connectivity and resting-state networks in behavioural variant of frontotemporal dementia

Brain connectivity measures represent candidate biomarkers of neuronal dysfunction in neurodegenerative diseases. Previous findings suggest that the behavioural variant of frontotemporal dementia (bvFTD) and its variants (i.e., frontal and temporo-limbic) may be related to the vulnerability of distinct functional connectivity networks. In this study, 82 bvFTD patients were included, and two patient groups were identified as frontal and temporo-limbic bvFTD variants. Two advanced multivariate analytical approaches were applied to FDG-PET data, i.e., sparse inverse covariance estimation (SICE) method and seed-based interregional correlation analysis (IRCA). These advanced methods allowed the assessment of (i) the whole-brain metabolic connectivity, without any a priori assumption, and (ii) the main brain resting-state networks of crucial relevance for cognitive and behavioural functions.In the whole bvFTD group, we found dysfunctional connectivity patterns in frontal and limbic regions and in all major brain resting-state networks as compared to healthy controls (HC N = 82). In the two bvFTD variants, SICE and IRCA analyses identified variant-specific reconfigurations of whole-brain connectivity and resting-state networks. Specifically, the frontal bvFTD variant was characterised by metabolic connectivity alterations in orbitofrontal regions and anterior resting-state networks, while the temporo-limbic bvFTD variant was characterised by connectivity alterations in the limbic and salience networks. These results highlight different neural vulnerabilities in the two bvFTD variants, as shown by the dysfunctional connectivity patterns, with relevance for the different neuropsychological profiles. This new evidence provides further insight in the variability of bvFTD and may contribute to a more accurate classification of these patients.

Vulnerability of multiple large-scale brain networks in dementia with Lewy bodies.

Aberrations of large-scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large-scale resting-state networks' integrity and their interactions. We found both local and long-distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network-level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network-level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.

Metabolic Positron Emission Tomography Response to Gamma Knife of the Ventral Intermediate Nucleus in Essential Tremor

To understand the substrates of response and nonresponse and to identify potential biomarkers for the selection and follow-up of patients with essential tremor (ET) treated with Gamma Knife (Elekta AB, Stockholm, Sweden) of the ventral intermediate nucleus (GKVIM). To characterize positron emission tomography (PET) changes in the metabolism of glucose and metabolic connectivity in patients with ET treated by GKVIM through observational study. Forty-two patients with right ET were referred to 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET) imaging before and after left GKVIM. Statistical Parametric Mapping T-score map comparisons were performed between pre- and post-GKVIM groups and between clinical responders and nonresponders. Metabolic connectivity was evaluated by the interregional correlation analysis method. After GKVIM, patients with ET exhibited decreased left thalamic metabolism, which was associated with remote metabolic decreases in the right cerebellum, left temporal gyri, and bilateral frontal gyri (P<.05, family-wise error-corrected). Additionally, nonresponders (n=7) showed metabolic decreases in the right temporo-occipital area (P<.005 corrected for cluster volume) after GKVIM. The metabolism in this area was already reduced in nonresponders before treatment in comparison to that in responders and was predictive of future response (sensitivity: 89%; specificity: 71%). In nonresponder patients, strong connectivity between the left thalamus and right temporo-occipital area was found before GKVIM and was lost after treatment, whereas this connectivity remained weak and stable in responders. These findings could lead to better knowledge of the variability in the metabolic PET profiles among patients with ET, particularly the integration of 18F-FDG PET imaging in the pretherapeutic evaluation of patients with refractory ET candidates for GKVIM.

Feeling of presence in dementia with Lewy bodies is related to reduced left frontoparietal metabolism

Feeling of presence (FOP) refers to the vivid sensation of a person’s presence near oneself and is common in Dementia with Lewy Bodies (DLB). Based on previous observations on epileptic subjects, we hypothesized that DLB subjects with FOP would harbour 18F-fluorodeoxyglucose PET hypometabolism in left parietal areas. 25 subjects (mean age 71.9 ± 6.7, disease duration at scan 1.7 ± 1.5 years) were included in the study, of whom nine (36%) experienced FOP. No significant between-group difference was observed regarding dopamine transporters striatal uptake (p = 0.64), daily dopaminergic treatment dosage (p = 0.88) and visual hallucinations (p = 0.83). Statistical parametric mapping showed that subjects with FOP had a significantly reduced glucose metabolism in several left frontoparietal areas (p < 0.001), including superior parietal lobule and precuneus. Interregional correlation analysis of these areas showed specific connectivity with right insula and putamen in the FOP subgroup and right orbitofrontal and superior frontal in subjects without FOP. This provides further evidence about the role of a left frontoparietal network and suggest a possible contribution of impaired orbitofrontal reality filtering associated with FOP.

Altered connectivity between striatal and extrastriatal regions in patients with schizophrenia on maintenance antipsychotics: an [18 F]fallypride PET and functional MRI study.

In addition to probing regional differences in receptor availability, molecular positron emission tomography (PET) is proving useful for investigating perturbations in neurotransmitter networks using interregional correlation analyses. In a multi-modal imaging study, we examined interregional correlationsof dopamine D2/3 receptor availability between striatal and extrastriatal regions using [18 F]fallypride high-resolution PET in 11 patients with schizophrenia receiving low-dose maintenance atypical antipsychotics and 14 healthy control subjects, and investigated resting-state functional connectivity in the same subjects using seed-based functional magnetic resonance imaging (fMRI) analysis. In the healthy control group, there were no significant correlations of [18 F]fallypride binding potential (BPND ) between striatal regions and any cortical areas, whereas the patient group showed significant and widespread inter-correlations. Correlations between BPND in striatum, amygdala and insula with cortex were significantly higher in patients than in controls. In seed-based resting-state fMRI analysis, the healthy controls revealed positive and negative functional connectivity patterns, while patients exhibited a pattern of exclusively positive connectivity. Functional connectivity was significantly higher between striatal regions and extrastriatal areas including cortical regions in patients compared to controls. In this first such report, molecular and functional connectivity between striatal and extrastriatal regions was primarily characterized by increased interregional relationships in treated patients with schizophrenia. The results suggest that the spatial organization of D2/3 receptor availability and related functional connectivity are significantly perturbed in stable outpatients on maintenance antipsychotics. Future studies should include antipsychotic-naïve patients to determine if these relationships are illness-related characteristics, or arising due to chronic antipsychotic treatment.