Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with ...anti-β-amyloid (Aβ) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aβ autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated.
The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aβ autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aβ-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aβ autoantibodies and AD biomarkers;
C-PK11195 PET for activated microglia.
At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation.
Our findings extend the current notion of ARIA-E by providing the first in vivo
C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.
The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers ...of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.
To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and 18FFDG-PET measures of neural dysfunction.
We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and 18FFDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For 18FFDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).
Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the 18FFDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.
This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.
•No other studies integrate measures of neurophysiology and brain metabolism in ALS.•The ALS group with normal MEPs has normal brain metabolism.•Brain metabolic patterns are contingent upon the extent of upper motor neuron burden.•Hypometabolism involving motor areas correlates with altered evoked motor potentials.
The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers ...of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.BACKGROUNDThe diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and 18FFDG-PET measures of neural dysfunction.OBJECTIVETo evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and 18FFDG-PET measures of neural dysfunction.We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and 18FFDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For 18FFDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).METHODSWe retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and 18FFDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For 18FFDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the 18FFDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.RESULTSBased on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the 18FFDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.CONCLUSIONThis study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.
The number of molecular imaging studies in the field of brain connectivity is steadily increasing.Molecular imaging is not yet widely used by the MRI-predominant neuroimaging community as tool of ...choice for studying brain connectomics.Because chemical synapses are essential to signal transduction, targeting the molecular level of brain communication is indispensable for our understanding of the brain connectome.PET as major molecular imaging tool provides various established markers of neural activity, neurotransmitter systems, and proteinopathies.Integration of connectomes produced with different neurophysiological methods, including molecular imaging, might be key for advancing the field of neuroscience.
In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.
Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset.
Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO ...(late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography.
Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction.
Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.
•EO-DLB exhibits lower metabolism in the posterior brain regions.•LO-DLB shows lower metabolism in fronto-insular cortices.•Metabolic connectivity reductions in posterior brain regions in both DLB groups.•Unique increase of connectivity of specific resting-state networks in EO-DLB.•Stronger correlation between serotonergic system and hypometabolism in EO-DLB.
Visual hallucinations (VH) are a core clinical feature of dementia with Lewy bodies (DLB), but their specific neural substrate remains elusive. We used 18F-FDG-PET to study the neural dysfunctional ...signature of VH in a group of 38 DLB patients (mean age±SD 72.9 ± 7.5) with available anamnestic records, cognitive and neurological examination and NeuroPsychiatric Inventory assessing VH. We tested the voxel-wise correlation between 18F-FDG-PET hypometabolism and VH NPI scores at the whole-group level, then adopting inter-regional correlation analysis to explore the resting-state networks (RSNs) metabolic connectivity in DLB patients with and without visual hallucinations, as compared to N = 38 age-matched healthy controls (HCs) (mean age±SD 71.5 ± 6.9). At the whole-group level, we found a negative correlation between VH NPI scores and 18F-FDG-PET hypometabolism in the right occipito-temporal cortex (p < .001 uncorrected, p < .05 Family-Wise Error cluster-corrected). Then, splitting the group according to VH presence, we found that DLB non-hallucinators presented a pattern of connectivity seeding from this occipito-temporal cluster and extending to the ventral visual stream. At difference, the DLB hallucinators showed a metabolic connectivity pattern limited to the occipital-dorsal parietal regions. As for RSNs, both the DLB subgroups showed a markedly reduced extent of attention and visual networks compared to HCs, with a variable alteration in the topography. DLB-VH patients showed a more pronounced shrinkage of the primary visual network, which was disconnected from the higher visual hubs, at difference with both HC and DLB non-hallucinators. These findings suggest that an altered brain metabolic connectivity within and beyond visual systems may promote VH in DLB. These results support the most recent neurocognitive models interpreting VH as the result of an inefficient recruitment of the ventral visual stream and of a large-scale multi-network derangement.
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.
While the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical ...disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach.
We collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data.
We found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD.
Synucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.
•Synucleinopathies as multisystem neurotransmission diseases since the early stages.•Evolution of dopaminergic dysfunction in the α-synuclein-spectrum.•Early vulnerability of the noradrenergic system.•Cholinergic networks' alterations in all the α-synuclein diseases.•IRBD and DLB share specific cholinergic dysfunction.
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