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Methods: This study assessed data from two cohorts of patients with alpha‐synucleinopathies (University of Brescia and University of Rome Tor‐Vergata cohorts). Consecutive participants with video‐polysomnography‐confirmed iRBD, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and controls underwent neurological, clinical and 123I‐FP‐CIT SPECT imaging assessments. Individuals with iRBD were longitudinally monitored to collect clinical phenoconversion to PD or DLB. The main outcome was to identify whole brain 123 I‐FP‐CIT SPECT measures reflecting monoaminergic deficits in each clinical group as compared to controls. Results: The cohort (n = 184) included 45 patients with iRBD, 47 PD, 42 DLB and 50 age‐matched controls. Individuals with iRBD were categorized as RBD‐DAT− (n = 32) and RBD‐DAT+ (n = 13), according to nigrostriatal assessment used in clinical practice. Compared to controls, RBD‐DAT− showed an early involvement of the left insula, which increased in RBD‐DAT+, and was present in patients with Parkinson's disease and dementia with Lewy bodies. Longitudinal cox regression analyses revealed a higher risk of phenoconversion in individuals with iRBD and insular monoaminergic deficits [HR = 3.387; CI 95%: 1.18–10.27]. Interpretation: In this study, altered insular monoaminergic binding in iRBD was associated with phenoconversion to DLB or PD. These findings may provide a helpful stratification approach for future pharmacological or non‐pharmacological interventions. [ABSTRACT FROM AUTHOR]

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. 11C‐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 11C‐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 11C‐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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Postmortem studies reported significant microglia activation in association with neuronal apoptosis in Fatal Familial Insomnia (FFI), indicating a specific glial response, but negative evidence also exists. An in vivo study of local immune responses over FFI natural course may contribute to the understanding of the underlying pathogenesis. Methods: We included eight presymptomatic subjects (mean ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N‐129met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 11.10 years.) for comparisons. 11C‐(R)‐PK11195 PET allowed the measurement of Translocator Protein (TSPO) overexpression, indexing microglia activation. A clustering algorithm was adopted to define subject‐specific reference regions. Voxel‐wise statistical analyses were performed on 11C‐(R)‐PK11195 binding potential (BP) images both at the group and individual level. Results: The D178N‐129met/val FFI patient showed significant 11C‐(R)‐PK11195 BP increases in the midbrain, cerebellum, anterior thalamus, anterior cingulate cortex, orbitofrontal cortex, and anterior insula, bilaterally. Similar TSPO increases, but limited to limbic structures, were observed in four out of eight presymptomatic carriers. The only carrier with the codon 129met/val polymorphism was the only one showing an additional TSPO increase in the anterior thalamus. Interpretation: In comparison to nonprion neurodegenerative diseases, the observed lack of a diffuse brain TSPO overexpression in preclinical and the clinical FFI cases suggests the presence of a different microglia response. The involvement of limbic structures might indicate a role for microglia activation in these key pathologic regions, known to show the most significant neuronal loss and functional deafferentation in FFI. [ABSTRACT FROM AUTHOR]