Search

Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β = –0.804; p = 0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

Background Early-onset Alzheimer’s disease (EOAD) is characterized by young age of onset ( Methods We prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [18F]-FDG PET and [11C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [18F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [11C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [11C]-PK11195 PET BP increases. Results EOAD patients showed a significant and extended microglia activation, as [11C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects. Conclusion The severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

Background and ObjectiveThis was a multicenter study aimed at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre–mild cognitive impairment [pre–MCI]).MethodsData were obtained from the Network-AD project (NET-2011-02346784). The included participants underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and amyloid PET. We used principal component analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism.ResultsA total of 105 participants (SCD = 49, pre–MCI = 56) were included. FDG-PET was normal in 45% of participants and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the participants who underwent amyloid PET (n = 60). PCA resulted in 3 neuropsychological factors: (1) executive/visuomotor, correlating with hypometabolism in frontal and occipital cortices and basal ganglia; (2) memory, correlating with hypometabolism in temporoparietal regions; and (3) visuospatial/constructional, correlating with hypometabolism in frontoparietal cortices. Two factors emerged from the neuropsychiatric PCA: (1) affective, correlating with hypometabolism in orbitofrontal and cingulate cortex and insula; (2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal, and parietal regions.DiscussionFDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre–MCI. These results indicate that SCD and pre–MCI represent heterogeneous populations. Different neuropsychological and neuropsychiatric profiles emerged, which correlated with neuronal dysfunction in specific brain regions. Long-term follow-up studies are needed to assess the risk of progression to dementia in these conditions.

The theory of generalized Nijenhuis torsions, which extends the classical notions due to Nijenhuis and Haantjes, offers new tools for the study of normal forms of operator fields. We propose a general result ensuring that, given a family of commuting operator fields whose generalized Nijenhuis torsion of level $l$ vanishes, there exists a local chart where all operators can be simultaneously block-diagonalized. We also introduce the notion of generalized Haantjes algebra, consisting of operators with a vanishing higher-level torsion, as a new algebraic structure naturally generalizing standard Haantjes algebras., Comment: 20 pages, no figures

Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.

Objective Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11 C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11 C-PK11195 and PET imaging. Methods We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11 C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels. Results Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. Interpretation In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.