Pilotto, Andrea

AbstractBackgroundPatterns of regional atrophy and hypometabolism have been observed in dementia with Lewy bodies (DLB). However, determinants of regional vulnerability to structural and functional neurodegeneration remain largely unexplored. First, we investigated the association between regional gene expression and grey matter volumes in probable DLB patients. Since hypometabolism presumably precedes overt brain atrophy, we additionally investigate the association between regional gene expression and hypometabolism in DLB.MethodTo investigate the association between gene expression and regional volumes, 165 DLB patients along with 165 age‐ and sex‐matched healthy controls from three European centres and the Mayo Clinic (USA) were included. Regional volumes were quantified from MRI using SPM12 in 112 cortical, subcortical, and cerebellar brain regions, and compared between groups, using w‐scores. Regional expression data of seven genes involved in the formation and degradation of pathological protein aggregates (APOE, APP, BIN1, GBA, MAPT, SNCA, TMEM175) was extracted from six healthy donors from the Allen Human Brain Atlas and correlated with regional volumetric w‐scores. To assess the predictive value of regional gene expression on regional volumes we used Gaussian stepwise backwards linear regression including all seven genes as predictors. To investigate the association between gene expression and hypometabolism, we are currently applying the same analysis pipeline to FDG‐PET data of 139 DLB patients from 8 European centres.ResultMost brain regions showed lower volumes in DLB patients compared to healthy controls, with differences being most pronounced in occipital and parietal lobes. Regional expression of APOE correlated positively with regional volumes in DLB. Conversely, regional expression of MAPT correlated negatively with regional volumes. Both APOE and MAPT gene expression were significant predictors of regional volumes in the regression analysis. None of the other gene expression values was significantly associated with regional volumes in DLB.ConclusionOur findings show that regional expression of genes associated with the abnormal accumulation of amyloid and tau, common co‐pathologies in DLB, partially account for the brain atrophy pattern observed in DLB patients. Analyses are ongoing for the hypometabolism pattern. Our finding emphasises the relevance of co‐pathologies in predicting atrophy progression and identifying potential targets for future disease‐modifying treatments.

AbstractINTRODUCTIONDementia with Lewy bodies (DLB) is typically characterized by parietal, temporal, and occipital atrophy, but less is known about the newly defined prodromal phases. The objective of this study was to evaluate structural brain alterations in prodromal DLB (p‐DLB) as compared to healthy controls (HC) and full‐blown dementia (DLB‐DEM).METHODSThe study included 42 DLB patients (n = 20 p‐DLB; n = 22 DLB‐DEM) and 27 HC with a standardized neurological assessment and 3‐tesla magnetic resonance imaging. Voxel‐wise analyses on gray‐matter and cortical thickness were implemented to evaluate differences between p‐DLB, DLB‐DEM, and HC.RESULTSp‐DLB and DLB‐DEM exhibited reduced occipital and posterior parieto‐temporal volume and thickness, extending from prodromal to dementia stages. Occipital atrophy was more sensitive than insular atrophy in differentiating p‐DLB and HC. Occipital atrophy correlated to frontotemporal structural damage increasing from p‐DLB to DLB‐DEM.DISCUSSIONOccipital and posterior‐temporal structural alterations are an early signature of the DLB continuum and correlate with a long‐distance pattern of atrophy.

AbstractIntroductionOperationalized research criteria for mild cognitive impairment with Lewy bodies (MCI‐LB) were published in 2020. The aim of this systematic review and meta‐analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI‐LB set out in the criteria.MethodsMEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI‐LB.ResultsFifty‐seven articles were included. The meta‐analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta‐iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers.DiscussionThe available evidence largely supports the current diagnostic criteria for MCI‐LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research.Highlights A meta‐analysis of the diagnostic features of MCI‐LB was carried out. The four core clinical features were more common in MCI‐LB than MCI‐AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI‐LB. More evidence is needed for the proposed biomarkers. FDG‐PET and quantitative EEG show promise as diagnostic biomarkers in MCI‐LB.

Abstract Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA‐binding protein 43 (TDP‐43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co‐pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co‐pathologies in DLB and their cross‐sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease‐specific and disease‐nonspecific biomarkers and how co‐pathologies can impact these biomarkers. We propose a framework for integrating multi‐modal biomarker fingerprints and step‐wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co‐pathologies.

Abstract Background Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis. Methods Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1β, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and β2-microglobulin). Results Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. Conclusions SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis.