Micaela Mitolo

Background: Patients with Dementia with Lewy Bodies (DLB) typically experience attentional deficits [1]. The objective of this study was to evaluate the patterns of functional activity during a sustained attention task in a group of DLB compared with healthy elderly. Method: A total of 20 DLB patients (8F; mean age (SD) = 74.1 (6.1)) and 20 age‐matched healthy controls (HC) (12F; mean age (SD) = 69 (7.6)) underwent a comprehensive neuropsychological assessment and a brain MRI protocol that included an auditory Psychomotor Vigilance Task (PVT) fMRI paradigm. Differences on neuropsychological tests between the two groups were assessed with ANCOVAs or Mann‐Whitney U tests, according to the data distribution. Results were corrected for multiple comparisons and statistical significance was set at p p = 0.01), and longer response time ( p = 0.01). The pattern of functional activity during the PVT task highlights significantly less activation in the DLB group compared with HC in the right superior lateral occipital cortex, right cuneus and right precuneus ( p Acknowledgement : This study has been supported by the Italian Ministry of Health (#GR‐2019‐12369242) and by #NEXTGENERATIONEU, project MNESYS (PE0000006).

Minor visual phenomena (MVP), such as visual illusions, pareidolias, feeling of presence, and passage hallucinations, are often experienced by patients with Lewy Body Disease (LBD), in addition to complex visual hallucinations (VH), even in the early stages of the disease. This systematic review aimed to provide an up-to-date literature review of the occurrence and prevalence of MVP in LBD and to assess their potential associations both with VH and visuoperceptual and visuospatial deficits. A systematic literature search was carried out in PubMed, Web of Science, APA PsycInfo, Scopus, and Cochrane Library, and a total of 44 articles were included. The included studies showed significant variability in the occurrence of MVP in the LBD population and in the assessment methods used, such as standardized scales (e.g., the noise pareidolia test), semi-structured interviews (e.g., the North-East Visual Hallucinations Interview), and clinical descriptions. Similarly to VH, MVP appears to be highly specific to LBD, helping in differential diagnosis from Alzheimer’s Disease. The overall relationship between MVP, VH, and visuoperceptual/visuospatial deficits remains unclear. Some studies found that MVP (especially pareidolic responses and presence of hallucinations) was positively correlated with VH, yet it is challenging to determine whether MVP can be considered a precursor of future VH development. Negative associations were reported between MVP (especially pareidolias) and visuoperceptual/visuospatial abilities. However, it is not clear whether these deficits serve as independent, exclusive factors in MVP occurrence or if they interact with VH as a contributing component. Gaining insight into the occurrence of these phenomena could prove beneficial for differential diagnosis, prognosis, and prediction of treatment outcomes in patients with LBD.

Cognitive decline in Alzheimer’s disease (AD) continuum is knowingly associated with degenerative neurobiological features; however, reliable markers for the early detection of the preclinical stages of AD are not fully established. The main goal of this study was to track ongoing brain neurodegeneration across the AD continuum by combining neuropsychological data, brain MRI features, and plasmatic ‐ brain‐derived circulating cell‐free DNA (b‐cfDNA) biomarkers. A total of 91 participants were included in this study including 28 healthy controls (HC) (mean age 66.4±9.2), 21 participants with Subjective Cognitive Decline (SCD) (mean age 70.4±8.5), 18 participants with Mild Cognitive Impairment (MCI) (mean age 72.3±7.1) and 24 patients with AD dementia (mean age 71.5±8.3). All participants underwent a neuropsychological evaluation, a brain MRI and a blood sample test to quantify the levels of brain‐derived cfDNA in plasma. ANCOVAs were used to test differences across participants. In addition, the median value of b‐cfDNA levels was set as a threshold to categorize participants into b‐cfDNA‐positive or negative. Pearson’s correlations were carried out between all variables. Results were corrected for multiple comparisons and statistical significance was set at p<0.05. Several regions in frontal, temporal and inferior parietal lobes showed progressively lower volumes going from HC to AD dementia. Although no statistical differences between mean b‐cfDNA levels were observed among groups, we found a trend of increased values in SCD and MCI participants. In addition, volumes of specific temporal regions differed significantly between b‐cfDNA‐positive and b‐cfDNA‐negative participants. Moreover, b‐cfDNA values correlated with semantic fluency scores in the AD dementia group (p = 0.038) and with the Stroop test scores in the HC group (p = 0.007). These results suggest that active neurodegeneration in the early phases of AD can be associated with a release of b‐cfDNA in plasma. Thus, this blood‐based biomarker might reveal early neurodegenerative processes even in the pre‐clinical dementia stage, when the neuropsychological and MRI changes are very subtle and difficult to detect at the individual level. Acknowledgement: This study is supported by funding obtained under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 ‐Project code PE0000006, CUP D93C22000930002, MNESYS

Background: Blood‐based biomarkers are becoming emerging tools, easily detectable and minimally invasive, to reveal neurodegeneration and neuroinflammation in Alzheimer’s disease (AD). However, a comprehensive and up‐to‐date overview of the association between blood‐based biomarkers and brain parameters as measured by MRI is not available. The aim of this review is to fill this gap and clarify the relationship between the main peripheral blood‐based protein biomarkers (i.e., Aβ, p‐tau, t‐tau, NfL and GFAP) and brain parameters derived from MRI in the AD continuum.Method: A literature search was carried out searching the PubMed and Web of Science databases for articles published up to May 2023. Articles were excluded according to the following criteria: no data on protein biomarkers; no data on the association between biomarkers and MRI data; articles not presenting novel data; articles that included only cognitively unimpaired older adults or patients with other neurological conditions; animal studies; molecular imaging studies; non‐peer reviewed articles; non‐English language articles; case reports.Result: A total of 33 articles were included in this systematic review. The findings revealed the following: hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels; p‐tau181 and p‐tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness; NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo‐inositol values in the posterior cingulate cortex/precuneus. Moreover, higher plasma GFAP levels were also negatively associated with hippocampal atrophy, lower cortical thickness, and smaller white matter volumes in temporal and parietal regions.Conclusion: Our systematic review showed strong associations between the main blood‐based protein biomarkers and MRI markers of AD, highlighting a high degree of concordance between these measurements. This suggests a possible advantage in combining multiple AD‐related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.Acknowledgement: This study is supported by funding obtained under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 ‐ Project code PE0000006, CUP D93C22000930002, “A multiscale integrated approach to the study of the nervous system in health and disease” (MNESYS).

Background: Isolated REM Sleep Behavior Disorder (iRBD) is a well‐recognized prodromal state of an underlying α‐synucleinopathy, occurring several years before an overt neurodegenerative disorder becomes fully manifest. iRBD has been related to poorer cognitive performance and higher frequency of mild cognitive impairment (MCI). The aim of this study was to explore in detail, with structural and functional MRI, frontal‐executive dysfunction in iRBD patients and to evaluate its association with cognitive performance.Method: Thirty‐two iRBD patients (24 males; age, mean±SD = 67.9±7.1 years) and thirty age‐matched healthy controls were recruited and underwent an extensive neuropsychological assessment and multiparametric MR acquisition. The MR protocol (3T) included T1‐w volumetric (isotropic 1mm³), diffusion weighted imaging (b = 2000 s/mm², 64 directions) and resting‐state (TR = 0.735s, 10 minutes) acquisitions. Brain volumetry analysis was conducted using FreeSurfer. TBSS was applied to evaluate white matter microstructural alterations. Resting state networks were investigated with ICA. Correlations between MR parameters and neuropsychological variables were explored with Spearman’s test.Result: iRBD patients, when compared with healthy controls, showed worse performance on tests related to attentive‐executive, memory, and visuospatial functions (i.e., cancellation test p = 0.041, similarities p = 0.015, 15‐words recall p = 0.004, and simple drawing copy p = 0.007); they also showed volume reduction in left rostral anterior cingulate (p = 0.005). TBSS highlighted increased anterior corpus callosum and forceps minor Radial Diffusivity in iRBD patients (p Acknowledgement: This study was supported by the Italian Ministry of Health (#GR‐2019‐12369242).

Blood-based biomarkers are minimally invasive tools to detect the pathological changes of Alzheimer’s Disease (AD). This meta-analysis aims to investigate the use of blood-derived p-tau isoforms (181, 217, 231) to predict conversion from mild cognitive impairment (MCI) to AD dementia (ADD). Studies involving MCI patients with data on blood p-tau isoforms at baseline and clinical diagnosis at follow-up (≥1 year) were included. Twelve studies on p-tau 181 (4340 MCI, conversion rate 20.6%), four on p-tau 217 (913 MCI, conversion rate 33.4%), and one on p-tau 231 (135 MCI, conversion rate 33%) were included. For p-tau 181, the pooled area under the receiver operating characteristic curve (AUC) was 0.73 (95% CI = 0.68–0.78), and for p-tau 217 was 0.85 (95% CI = 0.75–0.91). Plasma levels of p-tau 181 had good discriminatory power to identify MCI patients who will convert to ADD. Although only four studies on p-tau 217 have been included in the meta-analysis, in the last year the predictive power of p-tau 217 is emerging as superior to that of other isoforms. However, given the high heterogeneity detected in the p-tau 217 studies included in this meta-analysis, additional supportive evidence is needed. Insufficient results were available for p-tau 231. These findings support the prognostic utility of p-tau 181 and p-tau 217 measured in blood to predict progression to ADD in MCI and encourage its future implementation in clinical practice.

Background: Neuronal loss is a major pathological feature of neurodegenerative diseases. The analysis of plasma cell-free DNA (cfDNA) is an emerging approach to track cell death events in a minimally invasive way and from inaccessible areas of the body, such as the brain. Previous studies showed that DNA methylation (DNAm) profiles can be used to map the tissue of origin of cfDNA and to identify molecules released from the brain upon cell death. The aim of the present study is to contribute to this research field, presenting the development and validation of an assay for the detection of brain-derived cfDNA (bcfDNA). Methods: To identify CpG sites with brain-specific DNAm, we compared brain and non-brain tissues for their chromatin state profiles and genome-wide DNAm data, available in public datasets. The selected target genomic regions were experimentally validated by bisulfite sequencing on DNA extracted from 44 different autoptic tissues, including multiple brain regions. Sequencing data were analysed to identify brain-specific epihaplotypes. The developed assay was tested in plasma cfDNA from patients with immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor T (CAR-T) therapy. Results: We validated five genomic regions with brain-specific DNAm (four hypomethylated and one hypermethylated in the brain). DNAm analysis of the selected genomic regions in plasma samples from CAR-T patients revealed higher levels of bcfDNA in participants with ongoing neurotoxicity syndrome. Conclusions: We developed an assay for the analysis of bcfDNA in plasma. The assay is a promising tool for the early detection of neuronal loss in neurodegenerative diseases.