Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer's Disease: Clues from [18F]FDG PET Voxel-Wise Analysis.

Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Metabolic and dopaminergic correlates of intellectual enrichment in de-novo Parkinson's disease patients.

BACKGROUND: Cognitive reserve (CR) is an expression of brain resilience in response to damage. Education, occupational experience and leisure activities are thought to increase CR and have beneficial effects on global cognition and cognitive decline in Parkinson's disease (PD). We aimed to disclose brain metabolic and dopaminergic correlates of CR in de-novo PD patients. METHODS: Sixty-two drug-naïve de-novo PD patients underwent [18F]FDG-PET and DAT-SPECT. CR was quantified through the Cognitive-Reserve-Index questionnaire including total-CR and 3 subscores (educational-CR, occupational-CR, leisure-CR). Specific binding ratios (SBRs) and Z-scores in basal ganglia were obtained with 'BasGan-V2'. Z-scores were used as dependent variables in general linear models to assess the interaction between dopaminergic function and CR. Voxel-based correlation between brain metabolism and CR-scores and between SBR and [18F]FDG-PET was evaluated using SPM12 (P<0.05 FWE-corrected at peak and cluster level considered significant). RESULTS: Dopaminergic deficit in the most affected hemisphere (MAH) putamen was significantly less marked in higher CR patients (Z-score -1.7±0.1 highly-educated versus -2.1±0.1 poorly-educated, P<0.02). Total and leisure-related-CR resulted correlated directly with z-scores of the MAH putamen (P<0.018 and P<0.003) and inversely with brain metabolism in both cerebellar hemispheres (P<0.001). MAH-putamen SBR correlated directly with metabolism in occipital and parietal cortex (P<0.003) and inversely in cerebellar hemispheres (P<0.02). CONCLUSIONS: CR proxies demonstrated to correlate directly with dopaminergic function and inversely with metabolism in cerebellar hemispheres in de-novo PD patients. The present multi-modal approach including both metabolic and dopaminergic correlates of CR allowed to identify possible compensation mechanisms, highlighting a potential role of the cerebellum that deserves further investigation.

Medical Information Extraction With NLP-Powered QABots: A Real-World Scenario.

The advent of computerized medical recording systems in healthcare facilities has made data retrieval tasks easier, compared to manual recording. Nevertheless, the potential of the information contained within medical records remains largely untapped, mostly due to the time and effort required to extract data from unstructured documents. Natural Language Processing (NLP) represents a promising solution to this challenge, as it enables the use of automated text-mining tools for clinical practitioners. In this work, we present the architecture of the Virtual Dementia Institute (IVD), a consortium of sixteen Italian hospitals, using the NLP Extraction and Management Tool (NEMT), a (semi-) automated end-to-end pipeline that extracts relevant information from clinical documents and stores it in a centralized REDCap database. After defining a common Case Report Form (CRF) across the IVD hospitals, we implemented NEMT, the core of which is a Question Answering Bot (QABot) based on a modern NLP model. This QABot is fine-tuned on thousands of examples from IVD centers. Detailed descriptions of the process to define a common minimum dataset, Inter-Annotator Agreement calculated on clinical documents, and NEMT results are provided. The best QABot performance show an Exact Match score (EM) of 78.1%, a F1-score of 84.7%, a Lenient Accuracy (LAcc) of 0.834, and a Mean Reciprocal Rank (MRR) of 0.810. EM and F1 scores outperform the same metrics obtained with ChatGPTv3.5 (68.9% and 52.5%, respectively). With NEMT the IVD has been able to populate a database that will contain data from thousands of Italian patients, all screened with the same procedure. NEMT represents an efficient tool that paves the way for medical information extraction and exploitation for new research studies.

Cognitive impairment assessment through handwriting (COGITAT) score: a novel tool that predicts cognitive state from handwriting for forensic and clinical applications.

Introduction: Handwriting deteriorates proportionally to the writer's cognitive state. Such knowledge is of special importance in the case of a contested will, where dementia of the testator is claimed, but medical records are often insufficient to decide what the testator's cognitive state really was. By contrast, if the will is handwritten, handwriting analysis allows us to gauge the testator's cognitive state at the precise moment when he/she was writing the will. However, quantitative methods are needed to precisely evaluate whether the writer's cognitive state was normal or not. We aim to provide a test that quantifies handwriting deterioration to gauge a writer's cognitive state. Methods: We consecutively enrolled patients who came for the evaluation of cognitive impairment at the Outpatient Clinic for Cognitive Impairment of the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Sciences (DINOGMI) of the University of Genoa, Italy. Additionally, we enrolled their caregivers. We asked them to write a short text by hand, and we administered the Mini Mental State Examination (MMSE). Then, we investigated which handwriting parameters correlated with cognitive state as gauged by the MMSE. Results: Our study found that a single score, which we called the COGnitive Impairment Through hAndwriTing (COGITAT) score, reliably allows us to predict the writer's cognitive state. Conclusion: The COGITAT score may be a valuable tool to gage the cognitive state of the author of a manuscript. This score may be especially useful in contested handwritten wills, where clinical examination of the writer is precluded.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease.

BACKGROUND: Neuronal pentraxin-2 (NPTX2), crucial for synaptic functioning, declines in cerebrospinal fluid (CSF) as cognition deteriorates. The variations of CSF NPTX2 across mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and its association with brain metabolism remain elusive, albeit relevant for patient stratification and pathophysiological insights. METHODS: We retrospectively analyzed 49 MCI-AD patients grouped by time until dementia (EMCI, n = 34 progressing within 2 years; LMCI, n = 15 progressing later/stable at follow-up). We analyzed demographic variables, cognitive status (MMSE score), and CSF NPTX2 levels using a commercial ELISA assay in EMCI, LMCI, and a control group of age-/sex-matched individuals with other non-dementing disorders (OND). Using [18F]FDG PET scans for voxel-based analysis, we explored correlations between regional brain metabolism metrics and CSF NPTX2 levels in MCI-AD patients, accounting for age. RESULTS: Baseline and follow-up MMSE scores were lower in LMCI than EMCI (p value = 0.006 and p < 0.001). EMCI exhibited significantly higher CSF NPTX2 values than both LMCI (p = 0.028) and OND (p = 0.006). We found a significant positive correlation between NPTX2 values and metabolism of bilateral precuneus in MCI-AD patients (p < 0.005 at voxel level, p < 0.05 with family-wise error correction at the cluster level). CONCLUSIONS: Higher CSF NPTX2 in EMCI compared to controls and LMCI suggests compensatory synaptic responses to initial AD pathology. Disease progression sees these mechanisms overwhelmed, lowering CSF NPTX2 approaching dementia. Positive CSF NPTX2 correlation with precuneus glucose metabolism links to AD-related metabolic changes across MCI course. These findings posit CSF NPTX2 as a promising biomarker for both AD staging and progression risk stratification.

Tracking the progression of Alzheimer's disease: Insights from metabolic patterns of SOMI stages.

BACKGROUND: SOMI (Stages of Objective Memory Impairment) is a novel classification that identifies six stages of memory decline in Alzheimer's Disease (AD) using the Free and Cued Selective Reminding Test (FCSRT). However, the relationship between SOMI stages and brain metabolism remains unexplored. This study aims to investigate the metabolic correlates of SOMI stages using FDG-PET in Mild Cognitive Impairment due to AD (MCI-AD) and early AD patients. METHODS: One hundred twenty-nine-patients (99 aMCI-AD and 30 AD), and 42 healthy controls (HCs) (MMSE = 29.2 ± .8; age:69.1 ± 8.6 years; education:10.7 ± 3.8 years) who underwent an extensive neuropsychological battery including FCSRT and brain FDG-PET were enrolled. According to their clinical relevance and available sample sizes, SOMI-4 (N = 24 subjects; MMSE score:26.6 ± 2.6: age:75.4 ± 3.2; education:9.9 ± 4.5) and SOMI-5 groups (N = 97; MMSE:25.3 ± 2.6; age:73.9 ± 5.8; education:9.4 ± 4.1) were investigated. RESULTS: Compared to HCs, SOMI-4 showed hypometabolism in the precuneus, medial temporal gyrus bilaterally, right pecuneus and angular gyrus. SOMI-5 exhibited broader hypometabolism, extending to the left posterior cingulate and medial frontal gyrus bilaterally. The conjunction analysis revealed overlapping areas in the precuneus, medial temporal gyrus bilaterally, and in the right angular gyrus and cuneus. The disjunction analysis identified SOMI-5 specific hypometabolism encompassing left inferior temporal gyrus, uncus and parahippocampal gyrus, and medial frontal gyrus bilaterally (p < .001, p-value (FWE) < .05). DISCUSSION: SOMI-4 relates to posterior hypometabolism, while SOMI-5 to more extensive hypometabolism further encompassing frontal cortices, suggesting SOMI as a biologically relevant classification system of memory decline. CONCLUSION: Memory decline staged with SOMI is associated with hypometabolism spreading in amnesic MCI-AD/AD, suggesting its usefulness as a clinical marker of increasing neurodegeneration.

Discrepancy Between Patient and Caregiver Estimate of Apathy Predicts Dementia in Patients with Amnestic Mild Cognitive Impairment.

BACKGROUND: Apathy is a frequent behavioral symptom of Alzheimer's disease (AD). The Apathy Evaluation Scale (AES) is a tool exploring the perception of apathy by both caregivers (CG-AES) and patients (PT-AES), and the discrepancy in their ratings is a proxy of patients' disease unawareness. OBJECTIVE: To assess in a cohort study of patients with amnesic mild cognitive impairment (aMCI) whether apathy and awareness of apathy predict progression to dementia and timing. METHODS: From the global AES scores of 110 patients with aMCI and their caregivers, we obtained two principal indices for analysis: 1) 'Apathy', the mean of PT-AES and CG-AES, and 2) 'Discrepancy', obtained by subtracting CG-AES from PT-AES. Patients were followed with visits every six months for three years or until dementia. AES indices and the principal demographical/neuropsychological variables were filtered from multicollinearity. The most robust variables entered a logistic regression model and survival analyses (Cox regression, log-rank test of Kaplan-Meier curves) to estimate which predicted the risk and timing of progression, respectively. RESULTS: Sixty patients (54.5%) developed dementia (57 AD) after 6.0-36.0 months, 22 (20%) remained in an MCI stage, and 28 (25.5%) dropped out. 'Discrepancy' was a robust and accurate predictor of the risk of progression (AUC = 0.73) and, after binarization according to a computed cutoff, of timing to dementia. CONCLUSION: A structured evaluation of apathy, both self-assessed and estimated by caregivers, can provide useful information on the risk and timing of progression from aMCI to dementia. The discrepancy between the two estimates is a fairly reliable index for prediction purposes as a proxy of disease unawareness.

Right posterior hypometabolism in Pisa syndrome of Parkinson's disease: A key to explain body schema perception deficit?

BACKGROUND: Pisa syndrome (PS) is a trunk postural abnormality in Parkinson's disease (PD). Its pathophysiology is still debated: peripheral and central mechanisms have been hypothesized. OBJECTIVE: To investigate the role of nigrostriatal dopaminergic deafferentation and of brain metabolism impairment in the onset PS in PD patients. METHODS: We retrospectively selected 34 PD patients who developed PS (PS+) and who had previously undergone dopamine transporter (DaT)-SPECT and/or brain F-18 fluorodeoxyglucose PET (FDG-PET). PS + patients were divided considering leaning body side in left ((l)PS+) or right ((r)PS+). DaT-SPECT specific-to-non-displaceable binding ratio (SBR) of striatal regions (BasGan V2 software) were compared between 30 PS+ and 60 PD patients without PS (PS-) as well as between 16 (l)PS+ and 14 (r)PS + patients. Voxel-based analysis (SPM12) was used to compare FDG-PET among 22 PS+, 22 PS- and 42 healthy controls (HC) and between 9 (r)PS+ and 13 (l)PS+. RESULTS: No significant DaT-SPECT SBR differences were found between PS+ and PS- groups or between (r)PD+ and (l)PS + subgroups. Compared to HC, significant hypometabolism in PS+ was found in bilateral temporal-parietal regions, mainly in the right hemisphere, whereas the right Brodmann area 39 (BA39) was relatively hypometabolic both in the (r)PS+ and in the (l)PS+. BA39 and bilateral posterior cingulate cortex were significantly hypometabolic in PS + than in PS- group. CONCLUSIONS: As a hub of the network supervising the body schema perception, the involvement of the right posterior hypometabolism supports the hypothesis PS is a result of a somatosensory perceptive deficit rather than a nigrostriatal dopaminergic unbalance.

Forgetting Rates of Prose Memory in Mild Cognitive Impairment.

BACKGROUND: Some authors report steeper slopes of forgetting in early Alzheimer's disease (AD), while others do not. Contrasting findings are thought to be due to methodological inconsistencies or variety of testing methods, yet they also emerge when people are assessed on the same testing procedure. OBJECTIVE: We aimed to assess if forgetting slopes of people with mild cognitive impairment due to AD (MCI-AD) are different from age-matched healthy controls (HC) by using a prose paradigm. METHODS: Twenty-nine people with MCI-AD and twenty-six HC listened to a short prose passage and were asked to freely recall it after delays of 1 h and 24 h. RESULTS: Generalized linear mixed modelling revealed that, compared to HC, people with MCI-AD showed poorer encoding at immediate recall and steeper forgetting up to 1 h in prose memory as assessed by free recall and with repeated testing of the same material. Forgetting rates between groups did not differ from 1 h to 24 h. CONCLUSION: The differences observed in MCI-AD could be due to a post-encoding deficit. These findings could be accounted either by a differential benefit from retrieval practice, whereby people with MCI-AD benefit less than HC, or by a working memory deficit in people with MCI-AD, which fails to support their memory performance from immediate recall to 1 h.

Cognitive and Brain Metabolism Profiles of Mild Cognitive Impairment in Prodromal Alpha-Synucleinopathy.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition. Idiopathic REM sleep behavior disorder (iRBD) can be associated with MCI (MCI-RBD). OBJECTIVE: To investigate neuropsychological and brain metabolism features of patients with MCI-RBD by comparison with matched MCI-AD patients. To explore their predictive value toward conversion to a full-blown neurodegenerative disease. METHODS: Seventeen MCI-RBD patients (73.6±6.5 years) were enrolled. Thirty-four patients with MCI-AD were matched for age (74.8±4.4 years), Mini-Mental State Exam score and education with a case-control criterion. All patients underwent a neuropsychological assessment and brain 18F-FDG-PET. Images were compared between groups to identify hypometabolic volumes of interest (MCI-RBD-VOI and MCI-AD-VOI). The dependency of whole-brain scaled metabolism levels in MCI-RBD-VOI and MCI-AD-VOI on neuropsychological test scores was explored with linear regression analyses in both groups, adjusting for age and education. Survival analysis was performed to investigate VOIs phenoconversion prediction power. RESULTS: MCI-RBD group scored lower in executive functions and higher in verbal memory compared to MCI-AD group. Also, compared with MCI-AD, MCI-RBD group showed relative hypometabolism in a posterior brain area including cuneus, precuneus, and occipital regions while the inverse comparison revealed relative hypometabolism in the hippocampus/parahippocampal areas in MCI-AD group. MCI-RBD-VOI metabolism directly correlated with executive functions in MCI-RBD (p = 0.04). MCI-AD-VOI metabolism directly correlated with verbal memory in MCI-AD (p = 0.001). MCI-RBD-VOI metabolism predicted (p = 0.03) phenoconversion to an alpha-synucleinopathy. MCI-AD-VOI metabolism showed a trend (p = 0.07) in predicting phenoconversion to dementia. CONCLUSION: MCI-RBD and MCI-AD showed distinct neuropsychological and brain metabolism profiles, that may be helpful for both diagnosis and prognosis purposes.

The Role of Monoaminergic Tones and Brain Metabolism in Cognition in De Novo Parkinson's Disease.

BACKGROUND: Cognitive impairment is frequent in Parkinson's disease (PD) and several neurotransmitter changes have been reported since the time of diagnosis, although seldom investigated altogether in the same patient cohort. OBJECTIVE: Our aim was to evaluate the association between neurotransmitter impairment, brain metabolism, and cognition in a cohort of de novo, drug-naïve PD patients. METHODS: We retrospectively selected 95 consecutive drug-naïve PD patients (mean age 71.89±7.53) undergoing at the time of diagnosis a brain [18F]FDG-PET as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT as a marker and dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological battery. RESULTS: Positive correlations were observed between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic tone and working memory (r = 0.304, p = 0.003), (iii) qEEG slowing in the posterior leads and both memory (r = 0.299, p = 0.004) and visuo-spatial functions (r = 0.357, p < 0.001). CONCLUSIONS: In subjects with PD, the impact of regional metabolism and diffuse projection systems degeneration differs across cognitive domains. These findings suggest possible tailored approaches to the treatment of cognitive deficits in PD.

Neurological long-COVID in the outpatient clinic: Two subtypes, two courses.

INTRODUCTION: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID. METHODS: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19. RESULTS: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement. CONCLUSION: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.

The Free and Cued Selective Reminding Test: Discriminative Values in a Naturalistic Cohort.

BACKGROUND: Neuropsychological assessment is still the basis for the first evaluation of patients with cognitive complaints. The Free and Cued Selective Reminding Test (FCSRT) generates several indices that could have different accuracy in the differential diagnosis between Alzheimer's disease (AD) and other disorders. OBJECTIVE: In a consecutive series of naturalistic patients, the accuracy of the FCSRT indices in differentiating patients with either mild cognitive impairment (MCI) due to AD or AD dementia from other competing conditions was evaluated. METHODS: We evaluated the accuracy of the seven FCSRT indices in differentiating patients with AD from other competing conditions in 434 consecutive outpatients, either at the MCI or at the early dementia stage. We analyzed these data through the receiver operating characteristics curve, and we then generated the odds-ratio map of the two indices with the best discriminative value between pairs of disorders. RESULTS: The immediate and the delayed free total recall, the immediate total recall, and the index of sensitivity of cueing were the most useful indices and allowed to distinguish AD from dementia with Lewy bodies and psychiatric conditions with very high accuracy. Accuracy was instead moderate in distinguishing AD from behavioral variant frontotemporal dementia, vascular cognitive impairment, and other conditions. CONCLUSION: By using odd-ratio maps and comparison-customized cut-off scores, we confirmed that the FCSRT represents a useful tool to characterize the memory performance of patients with MCI and thus to assist the clinician in the diagnosis process, though with different accuracy values depending on the clinical hypothesis.

The Role of Hub and Spoke Regions in Theory of Mind in Early Alzheimer's Disease and Frontotemporal Dementia.

Theory of mind (ToM, the ability to attribute mental states to others) deficit is a frequent finding in neurodegenerative conditions, mediated by a diffuse brain network confirmed by 18F-FDG-PET and MR imaging, involving frontal, temporal and parietal areas. However, the role of hubs and spokes network regions in ToM performance, and their respective damage, is still unclear. To study this mechanism, we combined ToM testing with brain 18F-FDG-PET imaging in 25 subjects with mild cognitive impairment due to Alzheimer's disease (MCI−AD), 24 subjects with the behavioral variant of frontotemporal dementia (bvFTD) and 40 controls. Regions included in the ToM network were divided into hubs and spokes based on their structural connectivity and distribution of hypometabolism. The hubs of the ToM network were identified in frontal regions in both bvFTD and MCI−AD patients. A mediation analysis revealed that the impact of spokes damage on ToM performance was mediated by the integrity of hubs (p < 0.001), while the impact of hubs damage on ToM performance was independent from the integrity of spokes (p < 0.001). Our findings support the theory that a key role is played by the hubs in ToM deficits, suggesting that hubs could represent a final common pathway leading from the damage of spoke regions to clinical deficits.

Phase and amplitude electroencephalography correlations change with disease progression in people with idiopathic rapid eye-movement sleep behavior disorder.

STUDY OBJECTIVES: Increased phase synchronization in electroencephalography (EEG) bands might reflect the activation of compensatory mechanisms of cognitive decline in people with neurodegenerative diseases. Here, we investigated whether altered large-scale couplings of brain oscillations could be linked to the balancing of cognitive decline in a longitudinal cohort of people with idiopathic rapid eye-movement sleep behavior disorder (iRBD). METHODS: We analyzed 18 patients (17 males, 69.7 ± 7.5 years) with iRBD undergoing high-density EEG (HD-EEG), presynaptic dopaminergic imaging, and clinical and neuropsychological (NPS) assessments at two time points (time interval 24.2 ± 5.9 months). We thus quantified the HD-EEG power distribution, orthogonalized amplitude correlation, and weighted phase-lag index at both time points and correlated them with clinical, NPS, and imaging data. RESULTS: Four patients phenoconverted at follow-up (three cases of parkinsonism and one of dementia). At the group level, NPS scores decreased over time, without reaching statistical significance. However, alpha phase synchronization increased and delta amplitude correlations decreased significantly at follow-up compared to baseline. Both large-scale network connectivity metrics were significantly correlated with NPS scores but not with sleep quality indices or presynaptic dopaminergic imaging data. CONCLUSIONS: These results suggest that increased alpha phase synchronization and reduced delta amplitude correlation may be considered electrophysiological signs of an active compensatory mechanism of cognitive impairment in people with iRBD. Large-scale functional modifications may be helpful biomarkers in the characterization of prodromal stages of alpha-synucleinopathies.

Polysomnographic correlates of sleep disturbances in de novo, drug naïve Parkinson's Disease.

BACKGROUND: Sleep disturbances are common non-motor symptoms of Parkinson's Disease (PD). METHODS: The aim of this study was to investigate the polysomnographic correlates of sleep changes, as investigated by the Parkinson's Disease Sleep Scale-2 (PDSS-2), in a cohort of sixty-two consecutive de novo, drug naïve PD patients (71.40 ± 7.84 y/o). RESULTS: PDSS-2 total score showed a direct correlation with stage shifts (p = 0.008). Fragmented sleep showed an inverse correlation with sleep efficiency (p = 0.012). Insomnia symptoms showed an inverse correlation with wake after sleep onset (p = 0.005) and direct correlation with periodic leg movements (p = 0.006) and stage shift indices (p = 0.003). Motor Symptoms showed a direct correlation with Apnoea-Hypopnoea (AHI; p = 0.02) and awakenings indices (p = 0.003). Dream distressing showed a direct correlation with REM without atonia (RWA, p = 0.042) and an inverse correlation with AHI (p = 0.012). Sleep quality showed an inverse correlation with RWA (p = 0.008). CONCLUSION: PDSS-2 features are significantly correlated with polysomnography objective findings, thus further supporting its reliability to investigate sleep disturbances in PD patients.

Added value of semiquantitative analysis of brain FDG-PET for the differentiation between MCI-Lewy bodies and MCI due to Alzheimer's disease.

PURPOSE: FDG-PET is an established supportive biomarker in dementia with Lewy bodies (DLB), but its diagnostic accuracy is unknown at the mild cognitive impairment (MCI-LB) stage when the typical metabolic pattern may be difficultly recognized at the individual level. Semiquantitative analysis of scans could enhance accuracy especially in less skilled readers, but its added role with respect to visual assessment in MCI-LB is still unknown. METHODS: We assessed the diagnostic accuracy of visual assessment of FDG-PET by six expert readers, blind to diagnosis, in discriminating two matched groups of patients (40 with prodromal AD (MCI-AD) and 39 with MCI-LB), both confirmed by in vivo biomarkers. Readers were provided in a stepwise fashion with (i) maps obtained by the univariate single-subject voxel-based analysis (VBA) with respect to a control group of 40 age- and sex-matched healthy subjects, and (ii) individual odds ratio (OR) plots obtained by the volumetric regions of interest (VROI) semiquantitative analysis of the two main hypometabolic clusters deriving from the comparison of MCI-AD and MCI-LB groups in the two directions, respectively. RESULTS: Mean diagnostic accuracy of visual assessment was 76.8 ± 5.0% and did not significantly benefit from adding the univariate VBA map reading (77.4 ± 8.3%) whereas VROI-derived OR plot reading significantly increased both accuracy (89.7 ± 2.3%) and inter-rater reliability (ICC 0.97 [0.96-0.98]), regardless of the readers' expertise. CONCLUSION: Conventional visual reading of FDG-PET is moderately accurate in distinguishing between MCI-LB and MCI-AD, and is not significantly improved by univariate single-subject VBA but by a VROI analysis built on macro-regions, allowing for high accuracy independent of reader skills.

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

INTRODUCTION: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. METHODS: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. RESULTS: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. DISCUSSION: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy.

BACKGROUND: Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)-sleep behavior disorder (iRBD). However, it might be used as a second-line stratification tool in clinical trials, because it is expensive and mini-invasive. OBJECTIVE: Aim of the study is to investigate whether other cost-effective and non-invasive biomarkers may be proposed as first-line stratification tools. METHODS: Forty-seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT-SPECT. All patients underwent 6 month-based clinical follow-up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk. RESULTS: Seventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non-displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS-AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox-regression analysis, only putamen SBR and NPS-AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9-19.8). At post-hoc analysis, the trail-making test B (TMT-B) was the single most efficient first-line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT-B and DAT-SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47). CONCLUSION: The TMT-B seems to be a cost-effective and efficient first-line screening tool, to be used to select patients that deserve DAT-SPECT as second-line screening tool for disease-modifying clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.