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Paraspinal muscle atrophy is gaining attention in spine surgery due to its link to back pain, spinal degeneration and worse postoperative outcomes. Electrical impedance myography (EIM) is a noninvasive diagnostic tool for muscle quality assessment, primarily utilized for patients with neuromuscular diseases. However, EIM's accuracy for paraspinal muscle assessment remains understudied. In this study, we investigated the correlation between EIM readings and MRI‐derived muscle parameters, as well as the influence of dermal and subcutaneous parameters on these readings. We retrospectively analyzed patients with lumbar spinal degeneration who underwent paraspinal EIM assessment between May 2023 to July 2023. Paraspinal muscle fatty infiltration (FI) and functional cross‐sectional area (fCSA), as well as the subcutaneous thickness were assessed on MRI scans. Skin ultrasound imaging was assessed for dermal thickness and the echogenicities of the dermal and subcutaneous layers. All measurements were performed on the bilaterally. The correlation between EIM readings were compared with ultrasound and MRI parameters using Spearman's correlation analyses. A total of 20 patients (65.0% female) with a median age of 69.5 years (IQR, 61.3–73.8) were analyzed. The fCSA and FI did not significantly correlate with the EIM readings, regardless of frequency. All EIM readings across frequencies correlated with subcutaneous thickness, echogenicity, or dermal thickness. With the current methodology, paraspinal EIM is not a valid alternative to MRI assessment of muscle quality, as it is strongly influenced by the dermal and subcutaneous layers. Further studies are required for refining the methodology and confirming our results. [ABSTRACT FROM AUTHOR]

The quantification of the spatial and temporal variability of crop response to controllable inputs and the relationship with their controlling factors is important for making input prescriptions. In this study, we (1) assessed the within‐field spatial variability of corn (Zea mays L.) response to nitrogen (NR) and seed (SR) rates using on‐farm precision experiments (OFPE) data and geographically weighted regression (GWR) models; (2) determined the spatial agreement between NR and SR response classes, and their temporal stability; and (3) modeled the effect of weather and site‐specific features on the spatial distribution of the responses. Response maps were estimated by fitting GWR models to yields and as‐applied NR and SR from 14 OFPE. Responses classified into positive and non‐positive response classes were spatially joined to weather, soil, and landscape covariates to train a random forest model. GWR models explained 30%–60% of yield variation. Positive responses to NR and SR represented about 46% and 33% of fields' area, respectively, with large variation across field‐year combinations. Temporal agreement was about 50%–60%, for NR and SR, respectively. The spatial agreement between NR and SR response classes suggests that factors controlling the crop response to these inputs are similar. In both cases, weather variables were the most important predictors, followed by landscape and soil attributes. Although weather variables acted at a field level, that is, field‐year, the latter reflected the effect of within‐field variability on crop response. To reduce this weather uncertainty, future research should consider conducting larger numbers of OFPE across multiple seasons. Core Ideas: We detected significant spatial variability of corn response to nitrogen and seed rates using geographically weighted regression and on‐farm precision experiments data.The temporal consistency of response zones to same input across years was inconsistent due to weather.Spatial agreement between zones for the same year was higher as they shared the same controlling factors.Seasonal conditions were the most important factors determining the changes to get positive responses to these inputs. [ABSTRACT FROM AUTHOR]

INTRODUCTION: For routine clinical implementation of Alzheimer's disease (AD) plasma biomarkers, fully automated random‐access platforms are crucial to ensure reproducible measurements. We aimed to perform an analytical validation and to establish cutoffs for AD plasma biomarkers measured with Lumipulse. METHODS: Two cohorts were included. UNIPG: n = 450 paired cerebrospinal fluid (CSF)/plasma samples from subjects along the AD‐continuum, subjects affected by other neurodegenerative diseases, and controls with known CSF profile; AMS: n = 40 plasma samples from AD and n = 40 controls. Plasma amyloid β (Aβ)42, Aβ40, and p‐tau181 were measured with Lumipulse. We evaluated analytical and diagnostic performance. RESULTS: Lumipulse assays showed high analytical performance. Plasma p‐tau181 levels accurately reflected CSF A+/T+ profile in AD‐dementia and mild cognitive impairment (MCI)‐AD, but not in asymptomatic‐AD. Plasma and CSF Aβ42/40 values were concordant across clinical AD stages. Cutoffs and probability‐based models performed satisfactorily in both cohorts. DISCUSSION: The identified cutoffs and probability‐based models represent a significant step toward plasma AD molecular diagnosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Lewy body disease, a frequently observed co‐pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α‐synuclein seed amplification assay (αS‐SAA). The prevalence and clinical impact of CSF αS‐SAA positivity in AD are still unknown. METHODS: αS‐SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS‐SAA positivity and cognitive changes were also evaluated. RESULTS: In agreement with available neuropathological studies, αS‐SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances. DISCUSSION: αS‐SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS‐SAA positivity as biomarker of synucleinopathy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales.Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods.Sex differences in gray matter measures in DLB tended to disappear with increasing age. [ABSTRACT FROM AUTHOR]

Summary We propose a multivariate regime switching model based on a Student‐t$$ t $$ copula function with parameters controlling the strength of correlation between variables and that are governed by a latent Markov process. To estimate model parameters by maximum likelihood, we consider a two‐step procedure carried out through the Expectation–Maximisation algorithm. To address the main computational burden related to the estimation of the matrix of dependence parameters and the number of degrees of freedom of the Student‐t$$ t $$ copula, we show a novel use of the Lagrange multipliers, which simplifies the estimation process. The simulation study shows that the estimators have good finite sample properties and the estimation procedure is computationally efficient. An application concerning log‐returns of five cryptocurrencies shows that the model permits identifying bull and bear market periods based on the intensity of the correlations between crypto assets. [ABSTRACT FROM AUTHOR]

Background: Monoaminergic systems are pharmacologically modulable and therefore both a target for symptomatic therapies and a window for the study of disease progression. Although these mechanisms are unclear. We explore the progression and the distribution of monoaminergic deficits in the Alzheimer's Disease (AD) continuum, along with the accumulation of misfolded pathological proteins. Method: We included 50 patients with Alzheimer's Disease (AD) and 42 Healthy Controls (HC). We acquired brain [18F]FDG‐PET images as a marker of neurodegeneration and MMSE as a measure of global cognitive functioning. We performed voxel‐based analysis between AD vs. HC. Using JuSpace toolbox we explored the correlation between [18F]FDG‐PET images and PET maps of dopamine (DAT), serotonin (SERT), noradrenaline (NAT) and choline vesicular (VAChT) transporters cortical distribution. Moreover, we evaluated relative hypometabolism in the main cholinergic nucleus (Meynert nucleus). We divided in two groups the AD patients based on MMSE score (AD Dementia ‐ADD‐ <24; MCI ≥24), to explore the association between monoaminergic disfunction and pathological proteins burden, across the AD continuum. Result: Sample characteristics are provided in Table 1. Results from voxel‐based analysis are shown in Figure 1. In the whole AD group, the distribution of relative cortical hypometabolism was associated with a significant reduction of VAChT availability (p = 0.018). This association remained significant when considering the ADD (p = 0.006), but not the MCI group. Figure 2. β‐amyloid42 levels and β‐amyloid42/40 ratio were inversely correlated with VAChT in the ADD group (p = 0.003; p = 0.038, respectively). No correlation was observed in the MCI group. Lastly, there was no correlation between Meynert nucleus relative hypometabolism and misfolded proteins levels in all groups. Conclusion: In the ADD phase we showed a significant damage in the cortical regions targeted by the cholinergic system. This result was not evident among the other systems studied, nor in the MCI phase. This provides an explanation of the reduction of the cholinesterase inhibitors efficiency in the dementia phase. Moreover, we showed that β‐amyloid accumulation was not associated with Meynert Nucleus degeneration, but that impacted on cholinergic function via damage accumulation in the cortical areas targeted by the cholinergic system. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) patients present a higher risk of developing epilepsy compared to the age‐matched general population. Neurodegenerative cognitive disorders in general are closely linked with epilepsy and subclinical Epileptiform Electroencephalographic Activity (EEA). Furthermore, AD with Mild Cognitive Impairment (MCI) patients present abnormalities in posterior cortical sources of resting‐state eyes‐closed EEG rhythms at delta (< 4 Hz) and low‐frequency alpha (8‐10 Hz) rhythms. This retrospective study tested the hypothesis that ADMCI patients with EEA (ADMCI‐EEA) may be characterized by specific disease‐related abnormalities in delta and alpha rsEEG source activities compared with ADMCI patients without EEA (ADMCI‐noEEA) and noADMCI controls. Method: We analysed data from an international database (www.pdwaves.org) comprising clinical, neuropsychological, rsEEG (25‐30 minutes), cerebrospinal fluid (CSF), and structural magnetic resonance imaging (sMRI) data in n = 42 ADMCI and n = 32 noADMCI patients without a diagnosis of epilepsy. The database also included clinical, neuropsychological, and rsEEG data of n = 38 matched cognitively unimpaired elderly (Nold) persons, used as additional controls in the present study. The rsEEG traces were reviewed by expert epileptologists blinded to the diagnostic status. EEA was detected in n = 8 ADMCI and n = 13 no‐ADMCI patients (Table 1). Individual alpha frequency peak (IAF) was used to determine the rsEEG delta, theta, and alpha bands. Regional rsEEG cortical sources were estimated using the eLORETA freeware. Result: Compared to the Nold and noADMCI‐noEEA groups, the noADMCI‐EEA group showed greater temporal rsEEG delta cortical source activity. Conversely, compared to the Nold and ADMCI‐noEEA groups, the ADMCI‐EEA group showed greater temporal and occipital rsEEG delta cortical source activity (Figure 1). Notably, CSF amyloid (but not sMRI‐based cortical atrophy) burden was greater in the ADMCI‐EEA than in ADMCI‐noEEA patients (Table 2). Conclusion: The abnormal temporal rsEEG delta cortical source activity in the ADMCI‐EEA and noADMCI‐EEA groups may reflect an unspecific susceptibility of the temporal lobe to slowing rsEEG activity for several neuropathological processes. Instead, the abnormal occipital rsEEG delta cortical source activity in the ADMCI‐EEA over the control groups may reflect a specific susceptibility of the occipital lobe to slowing rsEEG activity for AD‐related neuropathological processes in the cholinergic tract to the occipital cortex. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) and metabolic syndrome (MetS) are associated with increased risk of dementia, as well as altered gut microbiome composition (Ott et al., 1999; Ley et al., 2006). However, the extent to which gut microbiome alterations moderate brain pathology in these conditions remains unclear. Here, we examined the extent to which MetS associates with altered cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD), glial activation, and neurodegeneration, and whether MetS interacts with gut microbiome composition to impact brain pathology. Method: Cognitively unimpaired adults (n = 88, Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center; Table 1) underwent fasting blood collection and lumbar puncture, and provided a stool sample. Twenty‐six percent (n = 23) of participants met MetS criteria. Fecal microbiota composition was characterized using 16S rRNA sequencing. QIIME2 was used to denoise and classify features, followed by Phyloseq to filter rare taxa, agglomerate taxa at the phylum rank, and compute relative abundances. Analyses centered on Firmicutes:Bacteroidetes, given its previously observed alterations in T2D and MetS (Stadlbauer et al., 2015). CSF biomarkers were quantified using a robust prototype assay as part of the Roche NeuroToolKit research platform. Multiple regression models were used to determine associations between MetS and CSF biomarkers in addition to Firmicutes:Bacteroidetes, and any MetS by Firmicutes:Bacteroidetes effects on CSF biomarkers. Results are reported as significant when p < 0.05, uncorrected. Result: A significant negative association between MetS and CSF YKL‐40 was observed (Figs. 1a, 1b), but no significant association between MetS and Firmicutes:Bacteroidetes (Fig 1c), nor associations with other CSF biomarkers (Table 2). MetS showed a significant interaction with Firmicutes:Bacteroidetes on YKL‐40 (Fig. 1d), as control participants with a higher ratio showed increased YKL‐40. Conclusion: In a cognitively unimpaired cohort, MetS was associated with lower CSF YKL‐40 (a marker of astrocytic activation) and moderated the relationship between Firmicutes:Bacteroidetes and CSF YKL‐40. While the direction of the findings was unexpected, T2D is associated with inhibition of astrocyte activation (Jing et al., 2013), and astroglial function is modulated by gut microbiota. Follow‐up studies are currently testing how gut microbiome modulates neuroimmune function in the context of AD. [ABSTRACT FROM AUTHOR]

Background: Gut microbial composition is associated with Alzheimer's disease (AD) pathology, and recent findings (Heston et al, medRxiv 2022) have identified an increase in intestinal inflammation with greater age and with higher cortical amyloid burden. Although gut microbiome composition and intestinal inflammation have independently been linked to AD pathology, it remains unclear whether the microbiome and gut inflammation are interrelated in the context of preclinical AD. Here we used phylogenetically‐based mediation (PhyloMed) to test whether the gut microbiome mediates the relationship between gut inflammation and cortical amyloid burden, and to highlight bacterial clades that may be specifically implicated as mediators. Method: 78 participants (Table 1) were enrolled in the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention, collected fecal samples, and completed C11‐PiB PET. Figure 1 illustrates the processing and analysis for each data stream. Fecal calprotectin was measured to quantify intestinal inflammation, and 16S rRNA sequencing characterized the fecal microbiome. Testing the full cohort and the cognitively unimpaired (CU) subset separately (n = 73), PhyloMed was performed at every taxonomic level, resulting in 14 models. Covariates included age, sex, body mass index, Bristol Stool Scale score, cognitive diagnosis/amyloid status, pseudocontinuous APOE AD risk score, and age difference between PET scan and fecal sample. Result: For both the full and CU cohorts, models at the amplicon sequence variant (ASV) level showed that gut microbiome composition was a significant mediator (p<0.05); species‐ and genus‐level models were marginally significant (p<0.1, Benjamini‐Hochberg FDR) (Table 2). ASVs from the family Lachnospiraceae (Figure 2A) were highlighted as significantly mediating taxa (p<.05, FDR). Interestingly, these taxa were negatively associated with calprotectin, while they were positively associated with PiB DVR (Figures 2B, 2C). Conclusion: Even before cognitive decline, the gut microbiome mediated the relationship between calprotectin, a measure of gut inflammation, and cortical PiB DVR, a measure of amyloid burden. Taxa within Lachnospiraceae were implicated as specific mediators, linked with lower inflammation and higher amyloid burden. Future work will use germ‐free mouse models to functionally elucidate the role of these bacteria in inflammation and AD. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the reliability and accuracy in the assignment of the case definitions of peri‐implant health and diseases according to the 2018 Classification of Periodontal and Peri‐implant Diseases and Conditions. Methods: Ten undergraduate students, 10 general dentists, and 10 experts in implant dentistry participated in this study. All examiners were provided with clinical and radiographic documentation of 25 dental implants. Eleven out the 25 cases were also accompanied by baseline readings. Examiners were asked to define all cases using the 2018 classification case definitions. Reliability among examiners was evaluated using the Fleiss kappa statistic. Accuracy was estimated using percentage of complete agreement and quadratic weighted kappa for pairwise comparisons between each rater and a gold standard diagnosis. Results: The Fleiss kappa was 0.50 (95% CI: 0.48 to 0.51) and the mean quadratic weighted kappa value was 0.544. Complete agreement with the gold standard diagnosis was achieved in 59.8% of the cases. Expertise in implantology affected accuracy positively (p < 0.001) while the absence of baseline readings affected it negatively (p < 0.001). Conclusion: Both reliability and accuracy in assigning case definitions to dental implants according to the 2018 classification were mostly moderate. Some difficulties arose in the presence of specific challenging scenarios. [ABSTRACT FROM AUTHOR]

Introduction: Vascular cognitive impairment (VCI) is a common and heterogeneous condition, clinically and pathophysiologically, that still lacks approved treatment. Methods: We reviewed evidence from randomized and non‐randomized clinical trials in VCI to explore whether any therapeutic option warrants further investigation and to assess possible flaws in previous studies. Results: We identified 118 studies after searching PubMed and Embase, including 19,223 participants and 5 different VCI subtypes. We found 63 different types of intervention (51 pharmacologic, 5 employing physical agent application, 7 rehabilitation approaches) compared with either placebo, best medical treatment, or other interventions. Treatment efficacy was assessed through 125 outcome measures (with a clearly pre‐specified primary outcome in 50.8% of studies). Discussion: Therapeutic trials in VCI have been heterogeneous in terms of populations, types of interventions, and outcomes. Overall, a lack of clear pathophysiological rationale for tested interventions seems to emerge, together with the need to homogenize trial study design [ABSTRACT FROM AUTHOR]

During the front end of innovation, teams embody abstract meanings into product concepts. The literature on Innovation of Meaning suggests that focusing on a single product‐user interaction supports this process. This Moment of Meaning facilitates the development of shared meaning and knowledge. We explore how the Moment of Meaning acts as a Boundary Object to support the innovation process. We study six Innovation of Meaning projects in different companies to explore how the Moment of Meaning supports the transition from abstract meaning to a concrete solution. Attending company meetings and workshops, we collected extensive qualitative data on the usage of the Moment of Meaning. We identify four uses of the Moment of Meaning. Depending on its degree of abstraction and perspective, it represents a Metaphor, a Product Vision, a Core Feature or an Experience Concept. Our study sheds light on the reification of meanings in early stages of innovation. Also, we highlight the potential evolution of Boundary Objects over time. To managers, we provide actionable knowledge on how a simple boundary object could ease the transition from an innovation strategy to a concrete product concept. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease (AD). DLB is a clinically and biologically heterogeneous disease, and little is known about longitudinal trajectories of patients with DLB. Disease progression can be measured with biomarkers capturing structural, functional, and pathological processes, aiding in understanding disease mechanism and discovering potential drug targets. We aimed to perform a systematic review to explore longitudinal patterns of biomarkers in DLB. Methods: Searches were conducted within five different databases, including cohort studies and case series on DLB patients with repeated measures of fluid or imaging biomarkers, and at least six months follow‐up. Fourteen studies were included (Figure 1), reporting data on longitudinal MRI, DaT‐Scan, PiB and flortaucipir‐PET, plasma p‐tau, and HMPAO SPECT, with up to 2,5 years of follow‐up (Table 1). No data on cerebrospinal fluid biomarkers were available. We could only perform a meta‐analysis on annualized brain atrophy rates, with a random effect model and standardized mean differences (SMD). Results: Progressive putaminal atrophy is seen in DLB patients, even when DaT‐scans are initially normal. In the meta‐analysis, brain atrophy rates were not significantly higher in pure DLB compared to cognitively unimpaired controls, with the exception of accelerated ventricular expansion rates (SMD 0.57 [0.03‐1.10], p = 0.04, 2 studies, 58 patients). Autopsy‐confirmed AD copathology resulted in greater global atrophy rates compared to pure DLB (SMD 0.72 [0.21‐1.31], p = 0.006, Figure 2), similar to AD. AD copathology accelerates temporal lobe and striatal atrophy rates. In one study, brain amyloid accumulation in DLB initially accelerated and then decelerated, similar to AD and cognitively unimpaired subjects, with absolute SUVr lower than AD. In another study, brain tau accumulation rate correlated with brain atrophy rates in the middle temporal pole in DLB patients. Conclusions: Only a few studies reported longitudinal data on biomarkers in DLB. DLB patients do not have significantly higher brain atrophy rates compared to controls, while the presence of AD copathology accelerates global and regional atrophy. Future studies with longer follow‐ups and multimodal biomarkers are needed to further characterize disease progression and elucidate clinical and biological heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in cortical sources of resting‐state eyes closed electroencephalographic (rsEEG) rhythms recorded by hospital settings (10‐20 montage) with 19 scalp electrodes characterized Alzheimer's disease (AD) from preclinical to dementia stages. An intriguing rsEEG application is the monitoring and evaluating of AD progression in large populations with few electrodes in low‐cost devices. Here we assessed whether the above‐mentioned abnormalities could be observed from fewer scalp electrodes in patients with mild cognitive impairment (ADMCI) or dementia (ADD) due to AD. Method: Clinical and rsEEG data acquired in hospital settings (10‐20 montage) from 88 ADD and 75 ADMCI participants and 70 age‐, education‐, and sex‐matched normal elderly controls (Nold) were available in an Italian‐Turkish archive (PDWAVES Consortium; www.pdwaves.eu). Standard spectral Fast Fourier Transform (FFT) analysis of rsEEG data for individual delta, theta, and alpha frequency bands was computed from 6 monopolar scalp electrodes to derive bipolar C3‐P3, C4‐P4, P3‐O1, and P4‐O2 markers. Result: The ADMCI and ADD groups showed increased delta/alpha and theta/alpha power density at the C3‐P3, C4‐P4, P3‐O1, and P4‐O2 bipolar channels compared to the Nold group (Figure 1). The best classification accuracy (area under the receiver operating characteristic curve) between the ADD and ADMCI vs Nold individuals was reached using alpha2/theta power density computed at the C3‐P3 bipolar channel (AUROC for ADMCI vs Nold = 81%; AUROC for ADD vs Nold = 90%; Figure 2). Conclusion: Standard rsEEG power density computed from six posterior bipolar channels characterized AD status from preclinical to dementia stages. These results may pave the way toward diffuse clinical applications in the health monitoring of dementia using low‐cost EEG systems with a strict number of electrodes in lower‐ and middle‐income countries. [ABSTRACT FROM AUTHOR]

Background: A/T/(N) cerebrospinal fluid (CSF) biomarkers, i.e., amyloid‐β 1‐42 and 1‐40 ratio (Aβ42/Aβ40, A), tau phosphorylated at threonine 181 (p‐T181‐tau, T), and total tau (N), define molecular diagnosis of Alzheimer's disease (AD). Automated platforms have brought a significant achievement in reducing the pre‐analytical variability. Measuring such biomarkers in blood might allow longitudinal sampling for disease monitoring, in view of disease‐modifying therapies. Along with this premise, to test the agreement between CSF and plasma measurements, we assessed Aβ42, Aβ40 and p‐T181‐tau with Lumipulse® G600II automated platform in paired CSF and plasma samples from 224 patients. Method: We selected 224 plasma samples collected from subjects with different clinical diagnosis (see Table 1), for whom CSF measurements were performed between 2018 and 2021. Both plasma and CSF were collected at the time of lumbar puncture following international guidelines. ATN CSF profiles have been defined according to cutoff values measured in our lab. One‐way analysis of variance with post‐hoc Tukey test was applied to determine statistically significant differences among groups, linear regression and correlation analysis were applied to determine degree of agreement between CSF and plasma biomarkers, and ROC analysis was applied to test the ability to differentiate AD‐like CSF profiles (A+/T+) from normal CSF profiles (A‐/T‐). Result: Distributions of Aβ42/Aβ40 ratio and p‐T181‐tau for the different A/T groups are shown in Figure 1. Plasma Aβ42/Aβ40 ratio was found to be significantly decreased in A+/T‐ and A+/T+ subjects as compared with A‐/T‐ and A‐/T+; p‐T181‐tau was found to be significantly increased in A+/T+ subjects as compared with all the other A/T profiles. Plasma Aβ42/Aβ40 ratio and p‐T181‐tau showed moderate correlation with their CSF equivalents (r = 0.62 and 0.60, p << 0.001, respectively). Both biomarkers could detect AD‐like CSF profiles (A+/T+) with an area under the ROC curve > 0.8 (see Figure 2). Conclusion: The automated assessment of Aβ42/Aβ40 and p‐T181‐tau in plasma can satisfactorily reflect the CSF A+T+ status. Larger cohorts are needed to verify the concordance of plasma with CSF biomarkers [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent proteinopathies of the central nervous system. Alpha‐synuclein seed amplification assays (αS‐SAA) are the most promising techniques for the in vivo detection of synucleinopathies, ie, PD and DLB. In neuropathological studies, Lewy Bodies (LBs) have been found in 50‐60% of AD patients. In AD, concomitant LB pathology could lead to parkinsonism and to a more aggressive course of the disease. Whether concomitant LBs could be related to some clinical aspects of AD, i.e., clinical variants or clinical progression, remains to be assessed. In our work, we applied αS‐SAA to determine whether the rate of assay positivity differs in AD vs controls (CTRL), and among AD clinical variants. Method: We used αS‐SAA to test 457 CSF samples from a cohort of AD, CTRL, and patients with PD and DLB. Classical AD CSF biomarkers were used to select CTRL and AD patients according to the A/T/(N) system. All CTRL showed a CSF A‐/T‐/N‐ profile while all AD patients were A+T+. Details of the subjects included are reported in Table 1. Fisher's Exact test for count data and logistic regression (by assuming age and gender as covariates) were used to evaluate the significance of the different prevalences observed. Result: We observed significantly higher αS‐SAA positivity in PD/DLB (86%) and AD patients (30%) with respect to CTRL subjects (13%, 7% in CTRL CN and 16% in CTRL MCI subjects) (Fig‐1A). Among the AD clinical variants, patients with posterior variant exhibited significantly higher αS‐SAA positivity (Fig‐1C). Interestingly, αS‐SAA positivity increased in the diagnostic groups as they progressed to later stages of AD, with the highest percentage in the AD at dementia phase (AD‐dem) group (36%) (Fig‐1B). Conclusion: Our results show that a large portion of AD cases have concomitant synucleinopathy and αS‐SAA could allow stratification of AD cases, as assay positivity was associated with AD subtypes and progression. Further evaluation of cross‐sectional and longitudinal clinical data is needed to determine potential prognostic value of αS‐SAA in AD. Early detection of synucleinopathy in AD patients will be increasingly important for design of personalized disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

Background: Alterations in gut microbiome in individuals with Alzheimer's disease (AD) may contribute to development or exacerbation of AD pathology via the microbiota‐gut‐brain axis. Composition and diversity of gut microbiota have been studied previously in AD dementia; here we investigate the gut microbial genes involved and their association with AD pathology prior to development of dementia. Method: Cerebrospinal fluid (CSF; N = 98) and fecal samples (N = 333) were collected from participants enrolled in the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center studies. CSF biomarkers of AD, β‐amyloid (Aβ)42/Aβ40 and phosphorylated‐tau‐181 (phospho‐tau [181P]), were quantified using robust prototype assays from the Roche NeuroToolKit (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Fecal samples were analyzed by whole genome sequencing. Sequences were filtered, quality controlled, and profiled for taxonomy and functional classification at species level using MetaPhlAn 4.0/HUMAnN 3.0 software. Compositional/functional differential abundance, alpha‐/beta‐diversity, correlation between feature abundance and sample metadata, gene‐set enrichment (GSE), and network analyses were performed using R packages (phyloseq/vegan/DESeq2/NetCoMi/rstatix/clusterProfiler). Analyses compared clinical status and biomarker groups. Result: The relative abundance of phylum Firmicutes and Bacteroidetes decreased and increased, respectively, in individuals with AD versus cognitively unimpaired (CU) individuals. In CU individuals, functional profiles differed in Aβ‐positive (A+) and phospho‐tau [181P]‐positive (T+) groups versus Aβ‐ and phospho‐tau [181P]‐negative (A−T−) individuals. In the microbial metagenome, 64 genes were significantly increased (p < 0.05) in the A+T+ group versus the A−T− group; 21/64 genes had ≥1 significant correlation with the AD biomarkers (e.g., toxic protein SymE positively correlated with phospho‐tau [181P] and negatively correlated with Aβ42/Aβ40 in CU individuals, suggesting that it may be a contributor to pathophysiological metabolic pathways in AD). Three KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in GSE analyses, including fatty acid metabolism/degradation and cationic antimicrobial peptide resistance, were significantly associated (p < 0.05) with genes that were enriched in the AD population versus CU individuals. Conclusion: Individuals with AD have distinct differential abundance in microbiota composition, in addition to an increase and enrichment of genes associated with AD pathogenesis pathways. These genes were associated with AD biomarkers prior to development of AD dementia. [ABSTRACT FROM AUTHOR]

The introduction of targeted therapies represented one of the most significant advances in the treatment of BRAFV600E melanoma. However, the onset of acquired resistance remains a challenge. Previously, we showed in mouse xenografts that vascular endothelial growth factor (VEGFA) removal enhanced the antitumor effect of BRAF inhibition through the recruitment of M1 macrophages. In this work, we explored the strategy of VEGFA/BRAF inhibition in immunocompetent melanoma murine models. In BRAF mutant D4M melanoma tumors, VEGFA/BRAF targeting reshaped the tumor microenvironment, largely by stimulating infiltration of M1 macrophages and CD8+ T cells, and sensitized tumors to immune checkpoint blockade (ICB). Furthermore, we reported that the association of VEGFA/BRAF targeting with anti‐PD‐1 antibody (triple therapy) resulted in a durable response and enabled complete tumor eradication in 50% of the mice, establishing immunological memory. Neutralization and CRISPR‐Cas‐mediated editing of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) abrogated antitumor response prompted by triple therapy and identified GM‐CSF as the cytokine instrumental in M1‐macrophage recruitment. Our data suggest that VEGFA/BRAF targeting in melanoma induces the activation of innate and adaptive immunity and prepares tumors for ICB. Our study contributes to understanding the tumor biology of BRAFV600E melanoma and suggests VEGFA as therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Exploratory data analysis was performed, looking after correlations of Leg Movement (LMs) against the 22 full‐EEG polysomnography during sleep. The EEG signals were recorded with the 19 derivations from the traditional International 10/20 electrode placement, chin electromyography (EMG), and electrooculogram (EOG). Nine subjects were considered: six in the Mild Cognitive Impairment (MCI) group, and three controls (CTRL). In line with the hypothesis about phasic activity reorganizing cerebral processing, lower correlations were expected for MCI, during REM sleep. Method: For each subject, the first rotation (PC1) of the Principal Component Analysis (PCA) decomposition of the data (22 channels) was generated. This accounts for the direction of the maximal variance. The proportion of variance explained by PC1 was very high (Table 2). In view of this, pairing the LMs and the PC1 time series allowed for reliable comparisons. As expected, there was no linear relation between the LMs and each of the channels: out of 198 pairs (22 for each subject), the maximal correlation coefficient was 0.0194. Therefore, it was natural to look for nonlinear relationships. The metric considered, was the total variation, at 5‐second intervals. The total variation corresponds with the arclength of the graph and is a measure of variability of a time series. For each subject, correlation coefficients were calculated for the total variations for LM versus PC1. Result: The mean coefficients for the CTRL group were higher than those for the MCI group for all the sleep epochs (Table 1). The difference was highest for REM sleep. In Table 2, the coefficients of the PC1 for each subject and variable (PC1) are presented (variations of one subject, Fig. 1). Conclusion: Due to the small size of the sample, it is not possible to draw any actual conclusions. However, anecdotal evidence was found for differences in synchronic activity between groups. This was most notorious for REM sleep, with decreased correlations for the MCI group. It would be of interest to replicate this study with a much larger sample. [ABSTRACT FROM AUTHOR]

Introduction: Etiological diagnosis of neurocognitive disorders of middle‐old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. Methods: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. Results: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI‐mild dementia), and detailed pre‐assessment screening (clinical‐neuropsychological evaluations, brain imaging, and blood tests). Discussion: The Delphi consensus on these assumptions set the stage for the development of the first pan‐European workflow for biomarkers' use in the etiological diagnosis of middle‐old age neurocognitive disorders at MCI‐mild dementia stages. Highlights: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe.A consensus of experts will define a workflow for the rational use of biomarkers.The diagnostic workflow will be patient‐centered and based on clinical presentation.The workflow will be updated as new evidence accrues. [ABSTRACT FROM AUTHOR]

Bone quality is increasingly being recognized in the assessment of fracture risk. Nonenzymatic collagen cross‐linking with the accumulation of advanced glycation end products stiffens and embrittles collagen fibers thus increasing bone fragility. Echogenicity is an ultrasound (US) parameter that provides information regarding the skin collagen structure. We hypothesized that both skin and bone collagen degrade in parallel fashion. Prospectively collected data of 110 patients undergoing posterior lumbar fusion was analyzed. Preoperative skin US measurements were performed in the lumbar region to assess dermal thickness and echogenicity. Intraoperative bone biopsies from the posterior superior iliac spine were obtained and analyzed with confocal fluorescence microscopy for fluorescent advanced glycation endproducts (fAGEs). Pearson's correlation was calculated to examine relationships between (1) US and fAGEs, and (2) age and fAGEs stratified by sex. Multivariable linear regression analysis with adjustments for age, sex, body mass index (BMI), diabetes mellitus, and hemoglobin A1c (HbA1c) was used to investigate associations between US and fAGEs. One hundred and ten patients (51.9% female, 61.6 years, BMI 29.8 kg/m2) were included in the analysis. In the univariate analysis cortical and trabecular fAGEs decreased with age, but only in women (cortical: r = −0.32, p = 0.031; trabecular: r = −0.32; p = 0.031). After adjusting for age, sex, BMI, diabetes mellitus, and HbA1c, lower dermal (β = 1.01; p = 0.012) and subcutaneous (β = 1.01; p = 0.021) echogenicity increased with increasing cortical fAGEs and lower dermal echogenicity increased with increasing trabecular fAGEs (β = 1.01; p = 0.021). This is the first study demonstrating significant associations between skin US measurements and in vivo bone quality parameters in lumbar fusion patients. As a noninvasive assessment tool, skin US measurements might be incorporated into future practice to investigate bone quality in spine surgery patients. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: Posterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer's disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker and neuropathological correlates of PCA in a large‐scale international cohort. Method: We contacted 55 research centers conducting PCA research identified in a literature review (n=1353 papers) as well as additional sites recruited through the ISTAART Atypical AD Professional Interest Group (n=7 sites) requesting deidentified, single‐subject data from PCA patients (published and unpublished). Inclusion criteria were: 1. clinical diagnosis of PCA, 2. availability of AD biomarkers (PET or CSF) or 3. availability of autopsy diagnosis. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected. Result: As of January 2022, we have collected individual patient data from 390 participants evaluated at 14 sites in 10 countries (Table 1). In the preliminary sample, mean age at symptom onset was 63.1 ± 8.8 years, 62.3% of participants were female, and 78.3% presented with a "PCA‐pure" clinical syndrome by Crutch 2017 diagnostic criteria. APOE4 genotype was present in 45.6% (n=125). Preliminary results show that 82.9% (n=270) display predominant MRI atrophy and 91.9% (n=185) predominant FDG hypometabolism in posterior cortical regions. CSF amyloid markers were positive in 80.2% participants (n=187), while CSF phosphorylated tau markers were positive in 61.4% (n=184). Amyloid PET was positive in 85.2% (n=129) while tau PET was only available in 65 patients (positive in all, and all were amyloid positive). At autopsy (n=36, data from 4 centers), high AD neuropathologic changes were found in all but one patient, who had primary frontotemporal lobar degeneration with TDP‐43 type A pathology. Lewy bodies, argyrophilic grains and cerebral amyloid angiopathy were common co‐pathologies (Figure 1). Conclusion: In a large international cohort, PCA is strongly associated with positive AD biomarkers and neuropathology. Data collection is ongoing, and we further aim to identify clinical features associated with non‐AD underlying causes of PCA. [ABSTRACT FROM AUTHOR]

CATSPER2 (Cation channel sperm‐associated protein 2) protein, which is part of the calcium CATSPER channel located in the membrane of the flagellar principal piece of the sperm cell, is only expressed in the testis during spermatogenesis. Deletions or mutations in the Catsper2 gene are associated with the deafness‐infertility syndrome (DIS) and non‐syndromic male infertility. However, the mechanisms by which Catsper2 is regulated are unknown. Here, we report the characterization of the promoter region of murine Catsper2 and the role of CTCF and CREMτ in its transcription. We report that the promoter region has transcriptional activity in both directions, as determined by observing luciferase activity in mouse Sertoli and GC‐1 spg transfected cells. WGBS data analysis indicated that a CpG island identified in silico is non‐methylated; Chromatin immunoprecipitation (ChIP)‐seq data analysis revealed that histone marks H3K4me3 and H3K36me3 are present in the promoter and body of the Catsper2 gene respectively, indicating that Catsper2 is subject to epigenetic regulation. In addition, the murine Catsper2 core promoter was delimited to a region between −54/+189 relative to the transcription start site (TSS), where three CTCF and one CRE binding site were predicted. The functionality of these sites was determined by mutation of the CTCF sites and deletion of the CRE site. Finally, ChIP assays confirmed that CREMτ and CTCF bind to the Catsper2 minimal promoter region. This study represents the first functional analysis of the murine Catsper2 promoter region and the mechanisms that regulate its expression. [ABSTRACT FROM AUTHOR]

Background: Tooth autotransplantation is a valid method for replacing non-restorable teeth. This study aimed to assess mid-term survival and success of autotransplanted third molars and the clinical periodontal parameters and factors predicting successful periodontal attachment apparatus regeneration.Methods: In total, 36 patients who had undergone extraction and subsequent autotransplantation of 36 third molars using virtual planning and computer-aided rapid prototyping models by an oral surgeon and endodontist were eligible. Probing pocket depth (PPD), gingival recession (REC), clinical attachment level (CAL), pulpal and periapical healing, root resorption, and radiographic bone loss (RBL) were evaluated. Additionally, a questionnaire evaluated patient-reported outcomes.Results: The mean age of the participants was 30.2 years with a mean follow-up duration of 29.42 ± 14.56 months. The overall survival and success rates were 97.2% and 91.7%, respectively. No statistically significant differences were found in success and survival rates between open and closed apex groups or between compromised and intact buccal bone groups. No signs of pulp necrosis were found in the open apex group. Progressive replacement resorption was detected in one closed apex case. The mean PPD was 2.7 ± 0.45 mm for all transplanted teeth. REC was 0.13 mm higher in transplanted teeth than in previous hopeless teeth. CAL changes were neither clinically relevant (-0.17 ± 0.66 mm) nor statistically significant. The reported patient satisfaction was high.Conclusions: Autotransplantation of third molars is a predictable treatment method, with a 2.5-year cumulative tooth survival and success of 97.2% and 91.7%, respectively, which were not influenced by recipient site integrity or root development. [ABSTRACT FROM AUTHOR]

Background: Patients with Lewy body disease (LBD) often show a co‐occurring Alzheimer's disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detection in vivo of AD‐related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro‐axonal damage are correlated with the presence of AD co‐pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles. Method: We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p‐tau, t‐tau) and of synaptic (β‐synuclein, α‐synuclein, SNAP‐25, neurogranin) and neuro‐axonal proteins (NfL) in 28 cognitively unimpaired participants with non‐degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD‐MCI, and dementia stages, AD‐dem). We compared CSF biomarker levels in clinical and AT(N)‐based subgroups. Result: CSF β‐synuclein, α‐synuclein, SNAP‐25, neurogranin and NfL levels did not differ between LBD (n = 101, age: 67.2 ± 7.8 years, 27.7% females) and controls (age: 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD‐MCI n = 30, AD‐dem n = 30, age: 72.3 ± 6.0 years, 63.3% females) compared to both groups (p<0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro‐axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A‐T‐ profiles (LBD/A‐T‐) (p<0.01 for all), and β‐synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI: 0.884‐0.991). CSF β‐synuclein (p = 0.0021), α‐synuclein (p = 0.0099) and SNAP‐25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T‐ cases, which had synaptic biomarkers levels within the normal range. CSF α‐synuclein was significantly decreased only in LBD patients with T‐ profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. Conclusion: LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro‐axonal biomarkers compared to LBD/A‐T‐ and control subjects. LBD patients with AD co‐pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in the neurophysiological oscillatory mechanisms generating dominant resting‐state eyes closed electroencephalographic (rsEEG) rhythms portray the Alzheimer's disease (AD) continuum, from the preclinical to the dementia stage. Here, we tested whether these abnormalities may be reproducible by analyzing the rsEEG signals acquired in bipolar configuration with a montage consisting of only four centro‐parietal and parieto‐occipital channels (C3‐P3, C4‐P4, P3‐O1, and P4‐O2) in patients with mild cognitive impairment (MCI) due to AD (ADMCI). Method: To evaluate the study hypotheses, clinical, neuropsychological, anthropometric, genetic, cerebrospinal fluid (CSF), MRI, and rsEEG data in 70 Nold and 75 ADMCI subjects from an international archive were used in the present study. The subgroups were matched for age, gender, and education. In all subjects, rsEEG recordings lasted about 3‐5 minutes. The rsEEG data were recorded with a sampling frequency of 128‐512 Hz and related antialiasing bandpass between 0.01 Hz and 60‐100 Hz. Electrode montage included 19 scalp monopolar sensors placed following 10‐20 System. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz) bands. Result: Results confirmed previous evidence about the abnormalities of the delta, theta, and alpha rhythms in ADMCI patients compared to Nold subjects. Moreover, as compared to the Nold group, the ADMCI group showed increased delta power density and decreased alpha power density at the C3‐P3, C4‐P4, P3‐O1, and P4‐O2 bipolar channels. Increased theta power density for ADMCI patients was observed only at the C3‐P3 bipolar channel. Best classification accuracy between the ADMCI and Nold individuals reached 81% (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3‐P3 bipolar channel. Conclusion: The current findings provide evidence in the potential use of rsEEG low‐channel portable devices as a topographic biomarker of cognitive decline within the extensive screening of in elderly population at risk of developing AD‐ or other dementia‐related disorders. Moreover, the confirmation of this hypothesis would have exciting applications in the framework of telehealth home monitoring of global brain functions. [ABSTRACT FROM AUTHOR]

Background: CSF and imaging biomarkers are needed for the etiological diagnosis of neurocognitive disorders, but evidence is incomplete on their rational use in the clinic. Since October 2020, a European task force has been defining an evidence‐based diagnostic workflow, where incomplete evidence is filled by the opinion of experts. Herein, we report the preliminary results through January 2022. Method: A Delphi method was used to reach consensus. Eleven pertinent European scientific societies delegated two panelists each to join Delphi rounds and voting. Consensus was set at 70% of consistent responses. Result: In the 5 voting rounds completed so far, panelists defined clinical setting (specialist outpatient service) and stage of application (prodromal and mild dementia) of the workflow, patients' age window of biomarkers use (strongly encouraged below 70 years and of limited usefulness over 85). Workflow is configurated to be patient‐centered and structured on three levels of assessment (W): W1, definition of clinical profiles based on the combined results of MRI, neuropsychology, blood tests; W2, choice of first‐line biomarkers according to the main clinical suspicion (i.e., FDG‐PET for frontotemporal lobar degeneration and motor tauopathies, dopamine SPECT/PET for Lewy body spectrum disorders, and CSF biomarkers either for Alzheimer's disease or in cases with inconclusive neuropsychological and/or MRI findings, whereas no biomarker was indicated in suspected vascular cognitive impairment); W3, selection of a second‐line biomarker when results of first‐line biomarkers are inconsistent with diagnostic hypothesis (i.e., not typical FDG‐PET pattern) or uninformative (i.e., borderline CSF amyloid results) or not sufficient to rule out other etiologies (i.e., amyloid‐positive and tau‐negative CSF results) or when a diagnosis remains possible despite a negative first‐line biomarker (e.g., normal dopamine SPECT/PET in suspected prodromal dementia with Lewy bodies). Conclusion: The task force is currently defining the second‐line biomarkers of W3 and the project it set to deliver the final algorithm by June 2022. The workflow will promote consistency in diagnosing neurocognitive disorders across countries, and rational use of resources. The initiative has an impact in preparing clinicians to work in the upcoming clinical space where etiological disease‐modifying drugs are expected to be available. [ABSTRACT FROM AUTHOR]

Introduction and Aim: In the Dominican Republic, there is an important number of individuals affected by nonsyndromic cleft lip with or without cleft palate (NS CL/P); in the search for the etiology, this study sought to determine the inheritance pattern of NS CL/P and to establish possible associations with clinical and socioenvironmental characteristics in a group of affected patients. Materials and Methods: The type of cleft was characterized according to the general phenotypic category, the family trees were built according to Bennett et al. (2008, 10.1007/s10897-008-9169-9), the socioenvironmental factors analyzed were tobacco consumption, alcohol, and radiation exposure. Results: Seventy-eight patients were analyzed, among whom severe phenotypes were more prevalent, including complete cleft lip and palate (CLP) (61.53%) and bilateral clefts (64%). In the analysis of genealogies, it was determined that 81.5% of the families were sporadic cases, 12.3% were autosomal dominant inheritance, and 6.2% were presented with a multifactorial inheritance. The consumption of alcohol was the most common socioenvironmental factor. There were no reports on the evaluated socioenvironmental factors in cases where heredity was determined as autosomal dominant. No inbred relationships were observed. Conclusion: There were diverse inheritance models for NS CL/P in patients from the Dominican Republic. Sporadic cases constituted the most frequent condition, followed by the existing families with autosomal dominance, and multifactorial inheritance. The absence of socioenvironmental factors commonly associated with pathology in families with autosomal dominant inheritance supports the hypothesis of a more significant genetic influence in this type of inheritance. [ABSTRACT FROM AUTHOR]

Introduction: Intellectual disability, accelerated aging, and early‐onset Alzheimer‐like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. Methods: Neuronal‐derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. Results: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. Conclusions: The alteration of the insulin‐signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population. [ABSTRACT FROM AUTHOR]

This study aimed at quantifying trabecular volumetric bone mineral density (vBMD) at the external occipital protuberance (EOP) and the upper cervical spine. A retrospective review of patients who underwent non‐contrast enhanced computed tomography of the cervical spine that included the occipital bone up to the EOP between 2007 and 2020 was conducted. Measurements of trabecular vBMD were performed in the occipital midline area, with the region of interest extending 4.5 mm above and below the center of the EOP, as well as the C1 lateral masses and the C2 vertebral body using asynchronous quantitative computed tomography. Eighty‐six patients (female, 37.2%) were included for analysis. The patient population was 81.4% Caucasian with a mean ± SD age of 62.3 ± 13.1 years. Total bone thickness at the EOP was 16.7 ± 3.4 mm, with a ratio of trabecular to total bone thickness of 0.44. Trabecular vBMD (mean ± SD) was significantly higher at the EOP than at C1 and C2 (EOP = 612.3 ± 145.8 mg/cm3, C1 average = 290.3 ± 66.5 mg/cm3, C2 = 305.8 ± 78.8 mg/cm3; p < 0.001). A significant strong correlation between trabecular vBMD of C1 and C2 was observed (r = 0.744; p < 0.001), but only low correlations between the EOP and C1 (r = 0.295; p = 0.008) and C2 (r = 0.413; p < 0.001). In individuals > 65 years of age, cervical vBMD was significantly lower, but remained high at the EOP. Clinical significance: Trabecular vBMD at the EOP is significantly higher than at the upper cervical vertebrae and remains high in older populations. Together with morphological information about the occipital bone, these results might be helpful for occipitocervical fixation when deciding about uni‐ or bicortical screw placement at the EOP. [ABSTRACT FROM AUTHOR]

Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O6-methylguanine-DNA methyltransferase (MGMT) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA-seq) data from the BTC subcohort of the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Among 164 Italian cases, 18% presented MGMT promoter hypermethylation (> 14%) and 73% had negative MGMT protein expression. Both were associated with worse overall survival (OS; HR 2.31; P < 0.001 and HR 1.99, P = 0.012, respectively). In the MASTER cohort, patients with lower MGMT mRNA expression showed significantly poorer OS (median OS [mOS] 20.4 vs 31.7 months, unadjusted HR 1.89; P = 0.043). Our results suggest that MGMT inactivation is a frequent epigenetic alteration in BTC, with a significant prognostic impact, and provide the rationale to explore DNA-damaging agents in MGMT-inactivated BTCs. [ABSTRACT FROM AUTHOR]

Brain health is essential for physical and mental health, social well‐being, productivity, and creativity. Current neurological research focuses mainly on treating a diseased brain and preventing further deterioration rather than on developing and maintaining brain health. The pandemic has forced a shift toward virtual working environments that accelerated opportunities for transdisciplinary collaboration for fostering brain health among neurologists, psychiatrists, psychologists, neuro and socio‐behavioral scientists, scholars in arts and humanities, policymakers, and citizens. This could shed light on the interconnectedness of physical, mental, environmental, and socioeconomic determinants of brain disease and health. We advocate making brain health the top priority worldwide, developing common measures and definitions to enhance research and policy, and finding the cause of the decline of incidence of stroke and dementia in some countries and then applying comprehensive customized cost‐effective prevention solutions in actionable implementation units. Life cycle brain health offers the best single individual, communal, and global investment. [ABSTRACT FROM AUTHOR]

The objective of this study is to determine the bone mineral density (BMD) changes in adjacent vertebra following anterior cervical discectomy and fusion (ACDF). Consecutive patients undergoing ACDF with available preoperative and postoperative computed tomography (CT) imaging were included. Quantitative CT measurements of screw‐free cervical and first thoracic vertebra were performed. Comparisons between pre‐ and postoperative BMD in the vertebrae one or two levels above the upper instrumented vertebra (UIV + 1, UIV + 2) and one level below the lowest instrumented vertebra (LIV + 1) were assessed. Seventy‐two patients (men, 66.7%) met the inclusion criteria. The patient population was 91.7% Caucasian with a mean age of 55.0 years. The mean interval (±SD) between surgery and secondary CT was 157 ± 23 days. Preoperative BMD (±SD) in UIV + 1 was 300.6 ± 66.2 mg/cm3. There was a significant BMD loss of 1.5% at UIV + 1 after surgery, resulting in a postoperative BMD of 296.2 ± 64.8 mg/cm3 (p =.029). At UIV + 2 and LIV + 1, no significant differences between pre‐ and postoperative BMD (304.7 ± 75.7 mg/cm3 vs. 299.8 ± 74.3 mg/cm3, 197.3 ± 50.4 mg/cm3 vs. 200.8 ± 48.7 mg/cm3, p =.113 and p =.078, respectively) were observed. Clinical significance Our results demonstrate a small BMD decrease of 1.5% at UIV + 1. This suggests that the effect of ACDF surgery on the adjacent levels might be smaller compared to the previously described lumbar BMD loss of 10%–20% following posterior lumbar fusion procedures. [ABSTRACT FROM AUTHOR]

Background: The term "Cognitive Reserve" (CR) refers to the ability of the brain to cope with the damage in order to minimize symptomatology. Several studies have shown controversial data about functional and structural correlates of CR in normal and pathological aging, probably due to the use of different CR proxies (level of education, occupational complexity, participation in leisure activities, IQ, verbal abilities or intelligence, heterogeneous fMRI tasks). The aim of this study was to investigate imaging correlates of different aspects of CR in a sample of patients with Mild Cognitive Impairment (MCI). Method: Patients with a diagnosis of MCI and young onset of cognitive symptoms (< 65) answered the Cognitive Reserve Index questionnaire (CRIq) aimed at measuring cognitive reserve acquired during lifetime. Patients also underwent multimodal Magnetic Resonance Imaging (MRI) on a 3T scanner including high‐resolution T1 and functional MRI sequences acquired at rest (resting fMRI). CRIq‐Total score and single subscores (CRIq‐Education, ‐WorkingActivity and ‐LeisureTime) were related to regional grey matter (GM) volume, whole brain fractional anisotropy (FA) and functional connectivity of resting‐state networks (RSNs) using, respectively, Voxel Based Morphometry (VBM), Tract‐Based Spatial Statistics (TBSS), and independent component analysis of resting fMRI (MELODIC). Result: Thirty‐nine patients were recruited. The median CRIq‐Total, ‐Education, ‐WorkingActivity and ‐LeisureTime scores were respectively 102, 97, 105 and 105. VBM correlational analysis showed no significant results. TBSS revealed a negative correlation between CRIq‐LeisureTime and FA of the body of corpus callosum. Resting‐fMRI analyses revealed negative correlations between CRIq scores and functional connectivity, involving particularly frontal and temporal areas. Conclusion: In patients with MCI, cognitive reserve relates to functional connectivity of fronto‐temporal areas rather than to structural variability (grey matter atrophy or white matter microstructural integrity). The negative correlations found between functional connectivity and CRIq scores shows that patients with high cognitive reserve may not need to increase functional connectivity. [ABSTRACT FROM AUTHOR]

Background: We previously reported brain myelin (Dean et al, 2017) and gut microbial composition alterations (Vogt et al, 2017) in Alzheimer's disease (AD). Prior animal studies suggest that myelin is impacted by experimentally altered gut microbiota (Keogh et al, 2021), suggesting that gut microbiota may be linked to brain myelination. However, little is yet known about the human gut microbiome and myelin alterations in the context of AD. Here, we examined the gut‐brain association in humans using biomarker and neuroimaging data. Method: Amyloid positive (n=27) and negative (n=91) participants from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention were included based on completion of one MPnRAGE (Kecskemeti et al., 2018) scan and donation of one stool sample. Myelin was assessed using MPnRAGE‐derived quantitative R1 and myelin content in 9 white matter tracts were examined as primary outcomes (Table). Intestinal microbiota composition was characterized using 16S rRNA sequencing of fecal samples. QIIME2 was used to denoise and classify features. Phyloseq was used to filter rare taxa, compute relative abundances, and agglomerate at the family taxonomic rank, resulting in 35 microbial families used as primary predictors. Multiple regression was used to test associations between each microbial family and regional myelin content. Benjamini‐Hochberg false discovery rate (FDR) adjustment was applied post‐regression; results were considered significant at q<.05. Result: Microbial family Turicibacteraceae was positively associated with myelin indexed by R1 (Figure) in the forceps minor (b=.014, q=.037) and uncinate fasciculus (b=.011, q=.028). Across all white matter tracts, higher age was associated with lower R1. Interestingly, there was a significant Paraprevotellaceae‐by‐amyloid effect in the superior longitudinal fasciculus (b= ‐.017, p =.031) and Clostridiaceae‐by‐amyloid effect in the forceps major (b=.002, p=.037) though neither interaction survived FDR correction. Conclusion: In both the uncinate fasciculus and forceps minor, higher levels of Turicibacteraceae were associated with greater myelin content. Turicibacteraceae were previously identified as less abundant among individuals with AD; the current study's microbial associations with large white matter tracts that are altered in AD warrants further study. Future studies will test additional metrics of AD pathology to clarify gut microbe and brain relationships. [ABSTRACT FROM AUTHOR]

Background: Gut bacterial metabolites in circulation and postmortem brain tissue differ in abundance between cognitively unimpaired (CU) and Alzheimer's disease (AD) individuals. Furthermore, in mice chronic injection of bacterial components exacerbates AD pathology. In CSF, we found the microbially‐produced trimethylamine‐N‐oxide was linked to AD and neurodegeneration biomarkers. However, the broader extent to which microbe‐modulated metabolites relate to AD and neurodegeneration is unknown. We tested the hypothesis that in CSF of non‐demented adults, elevated metabolites would longitudinally associate with higher biomarkers. Method: CSF was collected biannually in the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention studies. Biomarkers of pTau181, Aβ42, tTau, axonal (NfL) and synaptic (neurogranin, α‐synuclein) degeneration were quantified using Elecsys assays (NeuroToolKit robust prototype, Roche Diagnostics). Metabolite relative abundances were quantified via untargeted metabolomics analysis (ultrahigh performance liquid chromatography‐tandem mass spectrometry, Metabolon). A priori literature and database review identified 76 detected microbe‐modulated metabolites. 200 CU participants with two or more analyzed CSF samples were included in statistical analysis (Table 1). For each metabolite‐biomarker pair, multilevel linear growth modeling tested person‐level mean metabolite effects on biomarker slope and intercept, and time‐varying metabolite effects on biomarker intercept (Figure 1). Covariates included age, sex, and APOE risk score; Benjamini‐Hochberg corrections adjusted for Type I error inflation. Result: Seven metabolites were positively associated with biomarker slope or intercept (Table 2). Mean gluconate, glycerate, and oxalate levels were correlated with increased tTau slope, and N‐acetylaspartate, N‐acetylglutamate and cholesterol were correlated with higher a‐synuclein or neurogranin intercepts. Phenol sulfate was linked to tTau and α‐synuclein trajectories. To our knowledge, this is the first study detecting phenol sulfate in human CSF. No metabolites significantly associated with NfL or pTau181/Aβ42. Conclusion: In CSF, participants with higher mean levels of bacteria‐utilized metabolites exhibited accelerated neurodegeneration (tTau). Gluconate is metabolized by Bifidobacterium and Lactobacillus, two genera reduced in AD. Furthermore, the microbially‐produced phenol sulfate predicted greater tTau development and synaptic degeneration. Uremic toxins related to phenol sulfate dysregulate endothelial barriers in the central nervous system and vascular tissues. Additional studies should evaluate microbial metabolites as mediators of gut microbiome‐neurodegeneration relationships, and should determine if they represent modifiable pathways. [ABSTRACT FROM AUTHOR]

To improve the success rate of current preclinical drug trials, there is a growing need for more complex and relevant models that can help predict clinical resistance to anticancer agents. Here, we present a three-dimensional (3D) technology, based on biomimetic collagen scaffolds, that enables the modeling of the tumor hypoxic state and the prediction of in vivo chemotherapy responses in terms of efficacy, molecular alterations, and emergence of resistance mechanisms. The human breast cancer cell lines MDA-MB-231 (triple negative) and MCF-7 (luminal A) were treated with scaling doses of doxorubicin in monolayer cultures, 3D collagen scaffolds, or orthotopically transplanted murine models. Lineage-specific resistance mechanisms were revealed by the 3D tumor model. Reduced drug uptake, increased drug efflux, and drug lysosomal confinement were observed in triple-negative MDA-MB-231 cells. In luminal A MCF-7 cells, the selection of a drug-resistant subline from parental cells with deregulation of p53 pathways occurred. These cells were demonstrated to be insensitive to DNA damage. Transcriptome analysis was carried out to identify differentially expressed genes (DEGs) in treated cells. DEG evaluation in breast cancer patients demonstrated their potential role as predictive biomarkers. High expression of the transporter associated with antigen processing 1 (TAP1) and the tumor protein p53-inducible protein 3 (TP53I3) was associated with shorter relapse in patients affected by ER+ breast tumor. Likewise, the same clinical outcome was associated with high expression of the lysosomal-associated membrane protein 1 LAMP1 in triple-negative breast cancer. Hypoxia inhibition by resveratrol treatment was found to partially re-sensitize cells to doxorubicin treatment. Our model might improve preclinical in vitro analysis for the translation of anticancer compounds as it provides: (a) more accurate data on drug efficacy and (b) enhanced understanding of resistance mechanisms and molecular drivers. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is the second most common form of presenile dementia. The differential diagnosis of FTD is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of diagnostic biomarkers. Here, we aimed to investigate the diagnostic potential of novel biomarkers in cerebrospinal fluid (CSF) and blood. Method: We included 137 patients from the Centre for Memory Disturbances in Perugia with a diagnosis of FTD (n=37), Alzheimer's disease (AD, n=47), Parkinson's Disease (PD, n=14), Dementia with Lewy bodies (DLB, n=8), and cognitively unimpaired patients with other neurological diseases as controls (OND, n=31). All had AD biomarker measurements available. Enzyme‐linked immunosorbent assay (ELISA) or single molecule array (Simoa) were used to quantify the biomarker levels of NPTX2, NPTXR, NfL and GFAP in CSF, as well as NfL and GFAP in serum. Statistical analyses were performed using age and sex corrected analysis of covariance (ANCOVA), generalized linear mixed models (GLMM), ROC analyses, and Spearman correlation coefficients (ρ). Result: Differences in protein levels across diagnostic groups were found for NPTX2, NPTXR, NfL (serum and CSF), and GFAP (serum and CSF, figure 1). GLMM predicted NPTX2 and total tau (t‐tau) to best distinguish FTD from OND (p<0.002), while serum GFAP and t‐tau best distinguished FTD from AD (p<0.05). A combined panel of NPTX2, serum GFAP and t‐tau differentiated FTD from the other groups with good accuracy (table 1). Serum GFAP and NPTX2 correlated negatively in FTD (ρ =‐0.40, p<0.05) and AD (ρ=‐0.31, p<0.05), but positively in DLB (ρ =0.87, p<0.01), while no significant correlation was found in OND and PD (figure 2). Conclusion: We show the potential use of a novel biomarker panel including CSF t‐tau, CSF NPTX2 and serum GFAP, for differential diagnosis of FTD from other dementias. The included biomarkers reflect different neurological pathways, i.e. neurodegeneration, synaptic and astrocytic function, respectively. This suggests a unique interplay of these pathways in FTD and demonstrates the added value of the novel biomarkers to the established classical AD biomarkers. To assess the diagnostic potential of this novel panel, validation in a larger cohort should be performed. [ABSTRACT FROM AUTHOR]

Background: Dietary patterns appear to impact cognitive trajectories in aging, and gut microbiota have been implicated in Alzheimer's disease (AD) pathogenesis, potentially as modulators of neuroinflammation early in the disease. Diets featuring low meat and dairy consumption have been linked to reduced AD risk, and recently, the gut microbial metabolite trimethylamine N‐oxide (TMAO) was found in cerebrospinal fluid (CSF) and linked to CSF biomarkers of AD. Because TMAO is largely derived from dietary sources of choline, carnitine, and betaine, we examined whether these precursors drive the association between TMAO and sTREM2, a marker for glial activation. Additionally, TMAO has been found to inhibit cholesterol metabolism, a strong risk factor for AD, which is further dysregulated by the APOE4 allele. Therefore, we aimed to determine whether TMAO‐glial activation relationships are moderated by APOE4 carrier status. Method: Participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center provided CSF samples (n=570, Table 1). sTREM2 and YKL‐40 biomarkers were measured with the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). TMAO, carnitine, choline, and betaine relative abundance were obtained using Metabolon's UHPLC‐MS/MS metabolomics platform. A subset of participants (n=159) completed the MIND diet questionnaire. Metabolite and biomarker levels were log‐transformed for analysis; models were adjusted for age, sex, and APOE4 carrier status. Linear regression tested associations between intake of TMAO precursor‐containing foods (red meat, butter, cheese, fish) and CSF levels of each TMAO precursor. Path analysis with Satorra‐Bentler adjustments tested whether TMAO mediated precursor‐biomarker relationships. Linear regression tested whether APOE4 carrier status moderated TMAO‐biomarker relationships. Result: Red meat and cheese consumption predicted levels of CSF carnitine (βs=0.009, ‐0.017; ps=0.0609, 0.0007; Figure 1 A, B; respectively). TMAO mediated the relationship between carnitine and sTREM2, although effects were marginal; several individual relationships throughout both path models showed strong associations (Tables 2, 3; Figures 2, 3). APOE4 carrier status did not significantly moderate TMAO‐glial activation relationships. Conclusion: This study suggests that CSF carnitine reflects dietary intake, and may drive the TMAO‐sTREM2 association previously identified. Future studies in animal models are required to confirm these results mechanistically. [ABSTRACT FROM AUTHOR]

The exact role of malignant ascites in the development of intraperitoneal metastases remains unclear, and the mechanisms by which extracellular vesicles (EVs) promote tumor progression in the pre‐metastatic niche have not been fully discovered. In this study, we characterized ascites from high‐grade epithelial ovarian cancer patients. Small‐EVs (30–150 nm) were isolated from two sources—the bulk ascites and the ascitic fluid‐derived tumor cell cultures—and assessed with a combination of imaging, proteomic profiling, and protein expression analyses. In addition, Gene Ontology and pathway analysis were performed using different databases and bioinformatic tools. The results proved that the small‐EVs derived from the two sources exhibited significantly different stiffness and size distributions. The bulk ascitic fluid‐derived small‐EVs were predominantly involved in the complement and coagulation cascade. Small‐EVs derived from ascites cell cultures contained a robust proteomic profile of extracellular matrix remodeling regulators, and we observed an increase in transforming growth factor‐β‐I (TGFβI), plasminogen activator inhibitor 1 (PAI‐1), and fibronectin expression after neoadjuvant chemotherapy. When measured in the two sources, we demonstrated that fibronectin exhibited opposite expression patterns in small‐EVs in response to chemotherapy. These findings highlight the importance of an ascites cell isolation workflow in investigating the treatment‐induced cancer adaption processes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common cause of dementia. Although it presents a long preclinical period, treatment has yet to be found, and individuals at risk, like first‐degree relatives, are being studied to identify early detection markers to maximise the effectiveness of treatments. Functional connectivity changes have been observed even at this early stage (Ramirez‐Toraño et al., 2021), but most disregard its temporal dimension. This study investigates the value of a simple estimation of dynamic functional connectivity (dFC) in a longitudinal follow‐up of individuals with varying risk of the disease, as this parameter is expected to decrease across the disease continuum (Grieder et al, 2018). Method: 95 cognitively unimpaired participants with a family history of AD (FH+) and 39 without it (FH‐) underwent two longitudinal 5‐minute resting‐state magnetoencephalography recordings, approximately 3 years apart. FC in the low alpha band (8‐10 Hz) was estimated in 4‐second segments using phase locking value in the source space, and the standard deviation (STD) across epochs was calculated. Then, a STD ratio was derived dividing the STD values of the follow‐up session by those of the baseline session, and then averaged over nodes belonging to the same regions of the automatic anatomical labelling atlas. Left‐tailed t‐tests between the STD ratio of both groups in each ROI link (n_comparisons = 3160) were calculated and corrected for multiple comparisons with a false discovery rate using q = 0.20. Result: 13 links show a significantly lower dFC in the FH+ group than in the FH‐ group (Figure 1). Interestingly, these links involve regions where amyloid‐beta deposits early in the AD continuum (Mattsson et al., 2019), and are strongly related to the default mode network (Palmqvist et al. 2017). Conclusion: This study suggests that a simple estimation of dFC like STD may be useful in early detection pathological patterns characteristic of AD, even in cognitively unimpaired individuals at risk. The fact that dFC decreases were detected in areas where amyloid deposits appear at an early stage might indicate that these changes are related to changes in the excitation/inhibition ratio, which will be further studied in upcoming investigations. [ABSTRACT FROM AUTHOR]

Background: Mild Cognitive Impairment (MCI) is a clinical condition that captures the stage between normal aging and dementia along the continuum of cognitive impairment. While it is usually thought to be precursor of Alzheimer's Disease, when occurring at young ages (i.e., before 65 years old) it may increase the risk of all forms of neurodegenerative dementing diseases. We studied which neuropsychological and biomarker characteristics are predictors of conversion to dementia in a sample of patients with young‐onset MCI. Method: Subjects with a diagnosis of MCI and early‐onset of cognitive symptoms (< 65 yo) were recruited in a prospective longitudinal study. They underwent extended neuropsychological assessment, Magnetic Resonance Imaging with measurement of hippocampal volume, and lumbar puncture with measurements of cerebrospinal fluid (CSF) light‐chain neurofilaments (NFL), beta‐amyloid 1‐42, total‐ and phosphorylated‐tau. They were followed‐up clinically and repeated the neuropsychological evaluation at 18 months from the baseline. Statistical analyses were performed with Stata15. Each biomarker and neuropsychological variable were added in multivariate Cox regression models with age, sex, and education. Result: 84 young‐onset MCI patients were recruited. After 18 months, 26 converted to dementia while 58 remained stable (i.e., MCI). Preliminary analyses showed that baseline smaller bilateral hippocampal volumes, lower baseline MMSE scores, baseline worst performances in tests of language, verbal long‐term memory, and executive functions, as well as baseline elevated levels of CSF NFLs increased the risk of conversion to dementia. Among them, the higher risk was given by the Free and Cued Selective Reminding Test (FCSRT), the Corsi Supraspan, the Frontal Assessment Battery, and the CSF NFLs levels, as shown by spline regression analyses (Figure 1). Of note, the FCSRT delayed recall showed a U‐shaped relationship with the risk of conversion (i.e., not only low/bad performance but also high/good performance were both related to a higher risk of conversion) suggesting that the types of predicted conversion may be different. Conclusion: Our results suggest that, in young‐onset MCI, a combination of CSF‐NFLs levels and baseline performance at long‐term memory tests may be predictive of conversion to dementia, either AD or FTD. [ABSTRACT FROM AUTHOR]

Background: Previous evidence showed that persons experiencing post‐COVID‐19 with "brain fog" were characterized by abnormal resting‐state electroencephalographic (rsEEG) rhythms reflecting vigilance dysfunctions. In the present exploratory study, we tested the hypothesis that in post‐COVID persons with normal cognitive status, abnormalities in those rhythms (and vigilance function) may be related to fatigue. Method: We enrolled post‐COVID participants about one year after their infection, which claimed "brain fog." They underwent clinical/neuropsychological assessment and 61‐channel‐EEG recordings. Matched controls (never COVID‐19 affected) were included. Using eLORETA freeware, regional neural current densities were estimated in the rsEEG cortical sources at individual delta, theta, and alpha bands and at beta and gamma fixed bands. Clinical and instrumental data were evaluated in the long COVID‐19 patients as a function of fatigue symptoms over the controls. Result: The post‐COVID patients had no cognitive deficits at the group level. Those patients showed lower posterior rsEEG alpha source activities than the controls. Notably, this effect was more significant with the long COVID‐19 patients experiencing fatigue symptoms than those without (Fig. 1). Conclusion: In post‐COVID patients with normal cognition, abnormal rsEEG alpha source activation may indicate a significant relationship between vigilance dysfunction and fatigue. [ABSTRACT FROM AUTHOR]

Background: Episodic memory deficits represent the typical manifestation of prodromal Alzheimer's disease (AD), namely amnestic Mild Cognitive Impairment (a‐MCI). Current neuropsychological criteria for MCI recommend the use of at least two measures for each cognitive domain. Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) are two widely used verbal episodic memory measures. Our aim was to investigate the value of these measures in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective fully characterized consecutive MCI cohort. Method: One‐hundred and six MCI patients were included. All of them underwent a comprehensive neuropsychological assessment including RAVLT (sub‐measures: RAVLT‐imm, RAVLT‐del, RAVLT‐false_recognitions) and LM. All patients underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, phospho‐tau, total tau). By applying the A/T/(N) classification model, patients were classified as AD (A+T+, MCI‐AD, n. 62) and non‐AD (A‐T*, MCI, n. 44). Pearson's r correlation coefficient was used to assess the relationship of RAVLT and LM sub‐scores with diagnosis. WALD logistic regression model was used to find which memory sub‐measures show the best predictive value on biomarkers positivity. To evaluate the discriminatory power of different sub‐measures for CSF AD profile, receiver‐operating characteristic (ROC) curves were generated. Result: With respect to non‐AD MCI, MCI‐AD patients showed worse scores on all RAVLT and LM sub‐measures. RAVLT‐del could predict both positivity of each biomarker (p<0.01) and CSF AD‐like profile (p<0.01). The combination of RAVLT‐del with other measures (RAVLT‐imm+RAVLT‐false_recognition+LM) discriminated these groups (AUC: 0.76, 95% CI: 0.67‐0‐85) with a sensitivity of 0.74 and a specificity of 0.66. Conclusion: Our study shows that the combination of all RAVLT memory sub‐measures and LM reaches the higher diagnostic accuracy in discriminating non‐AD MCI from MCI‐AD patients. Since RAVLT and LM measure different aspects of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tasks. Our findings support the use of different memory measures in the neuropsychological assessment of MCI patients. [ABSTRACT FROM AUTHOR]

Background: Episodic memory (EM) impairment is an important feature of early Alzheimer's Disease and is related to well accepted biomarkers of AD. Monitoring healthy individuals for EM impairment may allow for early detection of risk for AD or a better understanding of resilience to cognitive decline. The present study used a functional magnetic resonance imaging (fMRI) EM task to examine whether neural substrates of EM are associated with classic features of AD. Method: Healthy adults (n = 120, 84 females, 45‐85 years of age) completed a 5‐minute fMRI EM encoding task which presented photographs of unfamiliar faces and objects with instructions to remember the items for later recognition. Following fMRI preprocessing using FSL, first‐level statistical analysis (using Feat) included an explanatory variable that modeled Items that were correctly remembered in the recognition phase to reflect successful encoding. Group‐level voxel‐wise analysis then examined which of a number of different AD features independently moderated fMRI response during successful encoding, including amyloid deposition from PET, hippocampal volume from MRI, APOE e4 status, and performance on neuropsychological tests (Craft story recall, Multi‐Lingual Naming Test: MINT, global cognition: MOCA). Age, sex and education were included as covariates in all voxel‐wise analyses and activation maps were cluster‐corrected using Z > 3.1, p =.05. Result: The only AD marker that significantly moderated EM successful encoding was amyloid status. Amyloid+ individuals (n = 25) recruited an area of the left antero‐lateral temporal cortex (MNI coordinates: x = ‐68, y = ‐30, z = ‐14) more strongly than Amyloid‐ individuals (n = 94). A post‐hoc exploratory analysis (controlling for age, sex and education) revealed that in Amyloid+ individuals, activation in the dorsal aspect of this temporal region was associated with better delayed memory performance (partial r =.426, p =.048) and activation in the ventral aspect of this region was associated with greater left hippocampal volume (partial r =.489, p =.021). In contrast, in Amyloid‐ individuals, activation in the dorsal aspect of this temporal region was associated with better performance on the MINT (partial r =.288, p =.006). Conclusion: Recruitment of left lateral temporal cortex during successful encoding in Amyloid+ individuals was associated with better delayed memory recall performance and greater hippocampal volume, suggesting a potential profile of resilience to AD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that patients with Mild Cognitive Impairment due to Alzheimer's disease (ADMCI) were characterized by reduced posterior rsEEG alpha rhythms after a 12‐month follow‐up (Babiloni et al., 2013). However, none of them have found an alpha deterioration considering a shorter follow‐up. A promising neurophysiological biomarker of the quiet vigilance alteration is the measurement of the posterior rsEEG alpha rhythms reduction in amplitude (reactivity) in the transition from the eyes‐closed to the eyes‐open condition (Babiloni et al., 2022). Here we tested the exploratory hypothesis that ADMCI reactive patients may display a deterioration of rsEEG alpha rhythms at a 6‐month follow‐up as a sign of disease progression (a relevant feature for intervention clinical trials). Method: Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 matched healthy elderly (Healthy) seniors were available from an international archive (www.pdwaves.eu). The rsEEG frequency bands were individual delta, theta, and alpha (defined based on its posterior topography and "reactivity" to the eyes‐open condition) or background frequency (BGF), as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz). Cortical source estimation was performed by eLORETA freeware. Result: A substantial (> ‐10%) reduction in the posterior alpha source activities during the eyes‐open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI participants (mean age of 64.3±1.1) with "reactive" rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition predicted the global cognitive status at 6‐month follow‐up. In all younger ADMCI participants with "reactive" rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition reduced in magnitude at that follow‐up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. Conclusion: These results suggest that in ADMCI patients, the true ("reactive") posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. [ABSTRACT FROM AUTHOR]

Background: Patients with dementia due to Alzheimer's disease (ADD) and Parkinson's disease (PDD) suffer from vigilance dysregulation. We hypothesized that such dysregulation may be reflected by altered reactivity of posterior resting‐state electroencephalographic (rsEEG) alpha rhythms during the vigilance transition from eyes‐closed to ‐open condition. Method: A Eurasian database provided clinical, demographic, and rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions. Result: Results showed substantial (> ‐10%) reduction (reactivity) in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients (Figure 1). In these alpha‐reactive participants, there were lower reductions in the posterior alpha activities in the ADD and PDD groups than in the Healthy group. That reduction in the parietal region was lower in the PDD than in the ADD group (Figure 2). Conclusion: These results suggest that ADD and PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in the quiet wakefulness in ADD and PDD patients. Such biomarkers may provide endpoints targets for pharmacological intervention and brain electromagnetic stimulations to improve the ADD and PDD patients' general ability to regulate vigilance and visual primary consciousness in the activities of daily living. [ABSTRACT FROM AUTHOR]