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.

11 C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis.

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.

Individual Brain Metabolic Signatures in Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome (CBS) is the usual clinical presentation of patients with corticobasal degeneration pathology. Nevertheless, there are CBS individuals with postmortem neuropathology typical of Alzheimer's disease (AD). OBJECTIVE: In this study, we aim to detect FDG-PET metabolic signatures at the single-subject level in a CBS sample, also evaluated with cerebrospinal fluid (CSF) markers for AD pathology. METHODS: 21 patients (68.9±6.4 years; MMSE score = 21.7±6.3) fulfilling current criteria for CBS were enrolled. All underwent a clinical-neuropsychological assessment and an instrumental evaluation for biomarkers of neurodegeneration, amyloid and tau pathology (i.e., FDG-PET imaging and CSF Aß42 and tau levels) at close intervals. CBS subjects were classified according to the presence or absence of CSF markers of AD pathology (i.e., low Aß42 and high phosphorylated tau levels). Optimized voxel-based SPM procedures provided FDG-PET metabolic patterns at the single-subject and group levels. RESULTS: Eight CBS had an AD-like CSF profile (CBS-AD), while thirteen were negative (CBS-noAD). The two subgroups did not differ in demographic characteristics or global cognitive impairment. FDG-PET SPM t-maps identified different metabolic signatures. Namely, all CBS-AD patients showed the typical AD-like hypometabolic pattern involving posterior cingulate cortex, precuneus and temporo-parietal cortex, whereas CBS-noAD cases showed bilateral hypometabolism in fronto-insular cortex and basal ganglia that is typical of the frontotemporal lobar degeneration spectrum. DISCUSSION: These results strongly suggest the inclusion of FDG-PET imaging in the diagnostic algorithm of individuals with CBS clinical phenotype in order to early identify functional metabolic signatures due to different neuropathological substrates, thus improving the diagnostic accuracy.

The clinico-metabolic correlates of language impairment in corticobasal syndrome and progressive supranuclear palsy.

PURPOSE: To assess the clinical-metabolic correlates of language impairment in a large sample of patients clinically diagnosed as corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPs). METHODS: We included 70 patients fulfilling current criteria for CBS (n = 33) or PSPs (n = 37). All subjects underwent clinical-neuropsychological and FDG-PET assessments at the time of diagnosis. The whole patient's cohort was grouped into three subgroups according to the language characteristics, i.e., (a) nfv-PPA; (b) subtle language impairments, LANG-; (c) no language deficits, NOL-. FDG-PET data were analysed using an optimized voxel-based SPM method at the single-subject and group levels in order to evaluate specific hypometabolic patterns and regional dysfunctional FDG-PET commonalities in subgroups. RESULTS: 21 patients had a nfvPPA diagnosis (i.e., nfv-PPA/CBS = 12 and nfv-PPA/PSPs = 9), while 20 patients had a subtle language impairment LANG- (i.e., CBS = 12 and PSPs = 8), not fulfilling the criteria for a nfv-PPA diagnosis. The remaining sample (i.e., 9/33 CBS and 20/37 PSPs patients) did not show any language deficit. FDG-PET results in individuals with a nfv-PPA diagnosis were consistent with the typical nfv-PPA pattern of hypometabolism (i.e., left fronto-insular and superior medial frontal cortex involvement), both in CBS and PSPs. The LANG-CBS and LANG-PSPs subjects had different FDG-PET hypometabolic patterns involving, respectively, parietal and frontal regions. As expected, NOL-CBS and NOL-PSPs showed a predominant right hemisphere involvement, with selective functional metabolic signatures typical of the two syndromes. CONCLUSIONS: Language impairments, fulfilling the nfv-PPA criteria, are associated with both CBS and PSPs clinical presentations early in the disease course. Subtle language deficits may be present in an additional proportion of patients not fulfilling the nfv-PPA criteria. The topography of brain hypometabolism is a major dysfunctional signature of language deficits in CBS and PSPs clinical phenotypes.