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During its pre-motor stage, Parkinson's disease (PD) presents itself with a multitude of non-motor symptoms with different degrees of specificity and sensitivity. The most important among them are REM sleep behavior disorder (RBD) and olfactory dysfunction. RBD is a parasomnia characterized by the loss of REM sleep muscle atonia and dream-enacting behaviors. Olfactory dysfunction in individuals with prodromal PD is usually described as hyposmia (reduced sense of smell) or anosmia (complete loss of olfactory function). These symptoms can precede the full expression of motor symptoms by decades. A close comprehension of these symptoms and the underlying mechanisms may enable early screening as well as interventions to improve patients' quality of life. Therefore, these symptoms have unmatched potential for identifying PD patients in prodromal stages, not only allowing early diagnosis but potentially opening a window for early, possibly disease-modifying intervention. However, they come with certain challenges. This review addresses some of the key opportunities and pitfalls of both RBD and olfactory dysfunction as early markers of PD. [ABSTRACT FROM AUTHOR]

Background: Currently, no standard scale has been validated to assess overall severity of RBD symptoms in the home environment. We aimed to evaluate the psychometric properties of the International RBD Severity Scale (IRBD-SSS), a new tool designed by the International RBD Study Group. Methods: Two versions of the IRBD-SSS were created, one for the patient (IRBD-SSS-PT) and another for the bedpartner (IRBD-SSS-BP), both consisting of 3 components, namely vocalizations, body movements and injury, with a fourth component (patient version only) evaluating dream content. To score each dimension, the frequency and severity/impact of behaviors during the previous month are multiplied. Psychometric properties of the IRBD-SSS were assessed, including reproducibility. Results: A total of 188 subjects including n = 132 RBD patients (n = 94 isolated RBD and n = 38 symptomatic RBD) and n = 52 bedpartners were enrolled from eight Sleep centers across France and Italy. Participants completed the scale at baseline and after one week. Acceptability of the scale was excellent in patients (97%) and bedpartners (98%). Internal consistency was acceptable for IRBD-SSS-PT (Cronbach α = 0.75) while slightly low for IRBD-SSS-BP (Cronbach α = 0.49). Concurrent validity was good for both patient (r = 0.70;p < 0.001, see Figure) and bedpartner (r = 0.69;p < 0.001) IRBD-SSS. Reproducibility was high for IRBD-SSS-PT (Lin's coefficient of agreement = 0.85 [0.81;0.90]) and good for the IRBD-SSS-BP (0.79 [0.68;0.90] (p < 0.001). Conclusions: Both the patient and bedpartner versions of the IRBD-SSS showed excellent acceptability, acceptable internal consistency, good external validity and high reproducibility. IRBD-SSS is a useful tool to test the severity of RBD symptoms in clinical settings and clinical trials. Trial registration: NCT04071899. [ABSTRACT FROM AUTHOR]

Background: REM Sleep Behavior Disorder (RBD) is characterized by absence of physiological muscle atonia during REM sleep (REM sleep without atonia, RWA). Nigro-striatal dopaminergic impairment is a feature of Parkinson disease (PD) and can be identified in prodromal stages as well, such as idiopathic RBD (iRBD). Aims of this study are to explore the efficacy of an automatic RWA quantification in identifying RBD patients and the correlation between RWA and nigro-striatal dopaminergic function. Methods: Forty-five iRBD, 46 PD with RBD, 24 PD without RBD patients and 11 healthy controls were enrolled in the Genoa Center (group A) and 25 patients with iRBD (group B) were enrolled in the Danish Center. Group A underwent brain [123I]FP-CIT-SPECT and group B underwent brain [18F]PE2I-PET as measures of nigro-striatal dopaminergic function. Chin muscle activity was recorded in all subjects and analyzed by applying a published automatic algorithm. Correlations between RWA and nigro-striatal dopaminergic function were explored. Results: The automatic quantification of RWA significantly differentiated RBD from non-RBD subjects (AUC = 0.86), although with lower accuracy compared with conventional visual scoring (AUC = 0.99). No significant correlation was found between RWA and nigro-striatal dopaminergic function. Conclusion: The automatic quantification of RWA is a reliable tool to identify subjects with RBD and may be used as a first-line screening tool, but without correlations with nigro-striatal dopaminergic functioning. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). Method s : In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography‐confirmed RBD who eventually phenoconverted to overt alpha‐synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non‐phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. Results: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD‐converters from DLB‐converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z‐score cutoff of −1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of −1.0 at the most affected hemisphere putamen/caudate ratio characterized PD‐converters. Interpretation: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease‐modifying trials. ANN NEUROL 2024;95:1178–1192 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: There are few comparative data on the third‐generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. Methods: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add‐on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan–Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. Results: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)‐naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17–3.29) and PER groups (HR = 1.64, 95% CI = 1.06–2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71–16.61), as well as PER‐treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05–2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] =.08, 95% CI =.01–.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV‐naïve (OR = 10.32, 95% CI = 1.55–68.78) versus men. PER (OR = 6.93, 95% CI = 3.32–14.44) and BRV in LEV‐naïve patients (OR = 6.80, 95% CI = 2.64–17.52) had a higher chance of AEs than LCM. Significance: Comparative evidence from real‐world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics. [ABSTRACT FROM AUTHOR]

This article discusses the diagnostic and prognostic value of dual-point amyloid PET in Alzheimer's disease (AD) mimickers. The case study focuses on a 74-year-old man who was referred to a neurologist for memory complaints. The patient underwent various tests, including cerebrospinal fluid biomarker evaluation and [18F]FDG-PET, which showed bilateral hypometabolism in certain brain regions. The article highlights the use of amyloid-PET with a dual-point protocol, which confirmed the absence of brain amyloidosis and provided valuable information for identifying AD mimickers. The authors emphasize the potential of dual-point amyloid-PET for replacing [18F]FDG-PET and providing prognostic stratification based on the severity of neurodegeneration. [Extracted from the article]

This article discusses a case study of a 72-year-old man who presented with memory and cognitive impairments, as well as motor symptoms. The patient underwent various imaging scans, including MRI, [123I]meta-iodobenzylguanidine (MIBG) scan, [18F]-FDG-PET, and [18F]-florbetaben-PET, to differentiate between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The results indicated posterior-cortical atrophy (PCA) with comorbid AD, and later confirmed DLB with comorbid AD. The case highlights the importance of biomarkers in diagnosing dementia and raises questions about the sequence of biomarker use. The article also mentions the potential use of co-pathology indicators in clinical trials. [Extracted from the article]

Introduction: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha‐synucleinopathies. Thus, iRBD patients are the ideal target for disease‐modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well‐characterized subjects. Methods: Polysomnography‐confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter‐single‐photon emission computed tomography (DaT‐SPECT) and categorized with visual semi‐quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios. Results: 365 patients were enrolled, and 289 patients with follow‐up (age 67.7 ± 7.3 years, 237 males, mean follow‐up 40 ± 37 months) were included in this study. At follow‐up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi‐quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow‐up within the FARPRESTO project. Conclusions: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi‐quantification of DaT‐SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non‐converted and newly diagnosed iRBD patients, who represent a trial‐ready cohort for upcoming disease‐modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to assess the role of cognitive evaluation in the prediction of phenoconversion in polysomnography‐confirmed idiopathic or isolated rapid eye movement sleep behaviour disorder, through a scoping review focussing on a longitudinal comprehensive neuropsychological assessment of patients with idiopathic REM sleep behaviour disorder. A literature search (2006–2022) yielded 1034 records, and 20 were selected for analysis. The sample included 899 patients from eight different cohorts and five countries. We extracted data on clinical evolution, mild cognitive impairment diagnosis, neuropsychological tests used, and classification of cognitive domains. Tests, cognitive domains, and mild cognitive impairment definitions were heterogeneous across the studies, precluding a meta‐analysis. Ten studies (50%) evaluated the presence of mild cognitive impairment; 14 studies (70%) grouped neuropsychological tests into between three (6 studies, 21.4%) and seven (1 study, 7.1%) cognitive domains. The most frequently used tests were semantic fluency, Stroop colour word test, trail making test A and B, digit span, Rey auditory verbal learning test, and Rey‐Osterrieth figure. All except digit span showed a role in predicting phenoconversion. The authors did not consistently assign tests to specific cognitive domains. In conclusion, we discuss methodological differences between the studies and highlight the need for a standardised framework for neuropsychological data acquisition and presentation, based on a multilevel approach covering test selection, domain assignment, and mild cognitive impairment diagnostic criteria. [ABSTRACT FROM AUTHOR]

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials. [ABSTRACT FROM AUTHOR]

Purpose: A cut-off of -2 z-score for striatal or putaminal SBR has been to date arbitrarily used to define an abnormal DaT SPECT in patients with suspected neurodegenerative parkinsonism. We aimed to experimentally identify the most accurate z-score cut-offs for SBR of striatal and substriatal regions to independently discriminate PD and DLB, with respect to essential tremor (ET) and Alzheimer's disease (AD) respectively. Methods: Two-hundred twenty-five patients undergoing DaT SPECT were enrolled (seventy-five de novo PD, eighty ET, fifty DLB, and twenty AD). Semiquantification was computed by means of Datquant® software which returns measures of striatal SBR and z-scores with respect to 118 healthy volunteers belonging to the Parkinson's Progression Markers Initiative (PPMI). ROC analysis was used to identify most accurate cut-offs for z-score for striatum and substriatal regions (clinical diagnosis at follow-up as gold standard). Results: Posterior putamen of the most affected hemisphere (MAH) with a z-score cut-off of − 1.27 demonstrated the highest accuracy to differentiate between PD and ET (sensitivity 0.97, specificity 0.94). The whole putamen (z-score cut-off − 0.96) was the most accurate parameter to support the diagnosis of DLB (sensitivity 0.74, specificity 0.95). Putamen to caudate ratio was accurate to detect PD (especially in early stages) while not DLB patients. Conclusion: We experimentally demonstrated that different substriatal regions and cut-offs for z-score of SBR should be considered to support the diagnosis of either PD or DLB. The identified less conservative cut-offs showed higher sensitivity without a measurable reduction in specificity with respect to the arbitrary − 2 z-score. [ABSTRACT FROM AUTHOR]

Introduction: Graph theory models a network by its nodes (the fundamental unit by which graphs are formed) and connections. 'Degree' hubs reflect node centrality (the connection rate), while 'connector' hubs are those linked to several clusters of nodes (mainly long-range connections). Methods: Here, we compared hubs modeled from measures of interdependencies of between-electrode resting-state eyes-closed electroencephalography (rsEEG) rhythms in normal elderly (Nold) and Alzheimer's disease dementia (ADD) participants. At least 5 min of rsEEG was recorded and analyzed. As ADD is considered a 'network disease' and is typically associated with abnormal rsEEG delta (<4 Hz) and alpha rhythms (8-12 Hz) over associative posterior areas, we tested the hypothesis of abnormal posterior hubs from measures of interdependencies of rsEEG rhythms from delta to gamma bands (2-40 Hz) using eLORETA bivariate and multivariate-directional techniques in ADD participants versus Nold participants. Three different definitions of 'connector' hub were used. Results: Convergent results showed that in both the Nold and ADD groups there were significant parietal 'degree' and 'connector' hubs derived from alpha rhythms. These hubs had a prominent outward 'directionality' in the two groups, but that 'directionality' was lower in ADD participants than in Nold participants. Discussion: In conclusion, independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward 'directionality' of partially preserved parietal 'degree' and 'connector' hubs derived from rsEEG alpha rhythms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Most patients with idiopathic REM sleep behavior disorder (iRBD) will develop an overt α-synucleinopathy over time, with a rate of phenoconversion of 73.5% after 12 years from diagnosis. Several markers of phenoconversion were identified; however, most studies investigated biomarkers separately, with retrospective study designs, in small cohorts or without standardized data collection methods. The risk FActoRs PREdictive of phenoconversion in idiopathic REM sleep behavior disorder: the Italian STudy (FARPRESTO) is a multicentric longitudinal retrospective and prospective study with a cohort of incident (prospective recruitment) and prevalent (retrospective recruitment) iRBD patients, whose primary aim is to stratify the risk of phenoconversion, through the systematic collection by means of electronic case report forms of different biomarkers. Secondary aims are to (1) describe the sociodemographic and clinical characteristics of patients with iRBD; (2) collect longitudinal data about the development of α-synucleinopathies; (3) monitor the impact of iRBD on quality of life and sleep quality; (4) assess the correlation between phenoconversion, cognitive performance, and loss of normal muscle atony during REM sleep; (5) identify RBD phenotypes through evaluating clinical, biological, neurophysiological, neuropsychological, and imaging biomarkers; and (6) validate vPSG criteria for RBD diagnosis. The FARPRESTO study will collect a large and harmonized dataset, assessing the role of different biomarkers providing a unique opportunity for a holistic, multidimensional, and personalized approach to iRBD, with several possible application and impact at different levels, from basic to clinical research, and from prevention to management. The FARPRESTO has been registered at clinicaltrials.gov (NCT05262543). [ABSTRACT FROM AUTHOR]

A classic approach to estimate individual theta‐to‐alpha transition frequency (TF) requires two electroencephalographic (EEG) recordings, one acquired in a resting state condition and one showing alpha desynchronisation due, for example, to task execution. This translates into long recording sessions that may be cumbersome in studies involving patients. Moreover, an incomplete desynchronisation of the alpha rhythm may compromise TF estimates. Here we present transfreq, a publicly available Python library that allows TF computation from resting state data by clustering the spectral profiles associated to the EEG channels based on their content in alpha and theta bands. A detailed overview of transfreq core algorithm and software architecture is provided. Its effectiveness and robustness across different experimental setups are demonstrated on a publicly available EEG data set and on in‐house recordings, including scenarios where the classic approach fails to estimate TF. We conclude with a proof of concept of the predictive power of transfreq TF as a clinical marker. Specifically, we present a scenario where transfreq TF shows a stronger correlation with the mini mental state examination score than other widely used EEG features, including individual alpha peak and median/mean frequency. The documentation of transfreq and the codes for reproducing the analysis of the article with the open‐source data set are available online at https://elisabettavallarino.github.io/transfreq/. Motivated by the results showed in this article, we believe our method will provide a robust tool for discovering markers of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Insomnia affects one-third of the adult population and is associated with multiple medical conditions. We conducted an observational epidemiological survey to assess (1) the prevalence of insomnia in an Italian group of patients aged over 50 years, presenting directly to the general physician (GP); (2) the association of insomnia with sleepiness and comorbidities; and (3) the pharmacological treatment. The study was carried out by GPs. Each GP was asked to enroll the first patient over 50 years old spontaneously presenting for any medical problems for 5 consecutive days. The Italian version of the Sleep Condition Indicator (SCI) was administered; daytime sleepiness was evaluated by a visual analogic scale (VAS). For every patient, GPs collected information regarding comorbidities and pharmacological treatment for insomnia and evaluated the severity of insomnia using the Clinical Global Impression Severity (CGI-S) scale. A total of 748 patients (mean age 65.12 ± 9.45 years) were enrolled by 149 GPs. Prevalence of insomnia was 55.3%. SCI, VAS, and CGI-S scores were highly correlated between each other (p < 0.0001). At general linear model analysis, the comorbidities more associated with the presence of insomnia were anxiety-depressive disorder (p < 0.001), other psychiatric disorders (p = 0.017), cardiovascular disorders (p = 0.006), and dementia (p = 0.027). A statistically significant correlation was found between SCI score and the use of benzodiazepines (p < 0.001), z-drugs (p = 0.012), antidepressants (p < 0.001), and melatonin-prolonged release (p < 0.001). Insomnia affects half of Italian primary care patients over 50 years and is frequently associated with different medical conditions, sleepiness, and use of multiple—often off-label—drugs. [ABSTRACT FROM AUTHOR]

Electric source imaging (ESI) estimates the cortical generator of the electroencephalography (EEG) signals recorded with scalp electrodes. ESI has gained increasing interest for the presurgical evaluation of patients with drug-resistant focal epilepsy. In spite of a standardised analysis pipeline, several aspects tailored to the individual patient involve subjective decisions of the expert performing the analysis, such as the selection of the analysed signals (interictal epileptiform discharges and seizures, identification of the onset epoch and time-point of the analysis). Our goal was to investigate the inter-analyser agreement of ESI in presurgical evaluations of epilepsy, using the same software and analysis pipeline. Six experts, of whom five had no previous experience in ESI, independently performed interictal and ictal ESI of 25 consecutive patients (17 temporal, 8 extratemporal) who underwent presurgical evaluation. The overall agreement among experts for the ESI methods was substantial (AC1 = 0.65; 95% CI: 0.59–0.71), and there was no significant difference between the methods. Our results suggest that using a standardised analysis pipeline, newly trained experts reach similar ESI solutions, calling for more standardisation in this emerging clinical application in neuroimaging. [ABSTRACT FROM AUTHOR]

Background: Patients with amnesic mild cognitive impairment due to Alzheimer's disease (ADMCI) typically show a "slowing" of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that "slowing."Objective: Here we tested the hypothesis that the "slowing" of rsEEG rhythms is related to EEA in ADMCI patients.Methods: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals.Results: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (<4 Hz) rsEEG source activities as compared to the ADMCI-noEEA and Nold groups. Those source activities showed moderate accuracy (AUROCC = 0.70-0.75) in the discrimination between ADMCI-noEEA versus ADMCI-EEA individuals.Conclusion: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Hyposmia is a common feature of COVID-19 and Parkinson's disease (PD). As parkinsonism has been reported after COVID-19, a link has been hypothesized between SARS-CoV2 infection and PD. We aimed to evaluate brain metabolic correlates of isolated persistent hyposmia after mild-to-moderate COVID-19 and to compare them with metabolic signature of hyposmia in drug-naïve PD patients. Methods: Forty-four patients who experienced hyposmia after SARS-COV2 infection underwent brain [18F]-FDG PET in the first 6 months after recovery. Olfaction was assessed by means of the 16-item "Sniffin' Sticks" test and patients were classified as with or without persistent hyposmia (COVID-hyposmia and COVID-no-hyposmia respectively). Brain [18F]-FDG PET of post-COVID subgroups were compared in SPM12. COVID-hyposmia patients were also compared with eighty-two drug-naïve PD patients with hyposmia. Multiple regression analysis was used to identify correlations between olfactory test scores and brain metabolism in patients' subgroups. Results: COVID-hyposmia patients (n = 21) exhibited significant hypometabolism in the bilateral gyrus rectus and orbitofrontal cortex with respect to COVID-non-hyposmia (n = 23) (p < 0.002) and in middle and superior temporal gyri, medial/middle frontal gyri, and right insula with respect to PD-hyposmia (p < 0.012). With respect to COVID-hyposmia, PD-hyposmia patients showed hypometabolism in inferior/middle occipital gyri and cuneus bilaterally. Olfactory test scores were directly correlated with metabolism in bilateral rectus and medial frontal gyri and in the right middle temporal and anterior cingulate gyri in COVID-hyposmia patients (p < 0.006) and with bilateral cuneus/precuneus and left lateral occipital cortex in PD-hyposmia patients (p < 0.004). Conclusion: Metabolic signature of persistent hyposmia after COVID-19 encompasses cortical regions involved in olfactory perception and does not overlap metabolic correlates of hyposmia in PD. [ABSTRACT FROM AUTHOR]

The role of MR Arterial-Spin-Labeling Cerebral Blood Flow maps (ASL-CBF) in the assessment of pediatric focal epilepsy is still debated. We aim to compare the Seizure Onset Zone (SOZ) detection rate of three methods of evaluation of ASL-CBF: 1) qualitative visual (qCBF), 2) z-score voxel-based quantitative analysis of index of asymmetry (AI-CBF), and 3) z-score voxel-based cluster analysis of the quantitative difference of patient's CBF from the normative data of an age-matched healthy population (cCBF). Interictal ASL-CBF were acquired in 65 pediatric patients with focal epilepsy: 26 with focal brain lesions and 39 with a normal MRI. All hypoperfusion areas visible in at least 3 contiguous images of qCBF analysis were identified. In the quantitative evaluations, clusters with a significant z-score AI-CBF ≤ −1.64 and areas with a z-score cCBF ≤ −1.64 were considered potentially related to the SOZ. These areas were compared with the SOZ defined by the anatomo-electro-clinical data. In patients with a positive MRI, SOZ was correctly identified in 27% of patients using qCBF, 73% using AI-CBF, and 77% using cCBF. In negative MRI patients, SOZ was identified in 18% of patients using qCBF, in 46% using AI-CBF, and in 64% using cCBF (p < 0.001). Quantitative analyses of ASL-CBF maps increase the detection rate of SOZ compared to the qualitative method, principally in negative MRI patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background: Degeneration of the nigrostriatal dopaminergic (DA) and the raphe‐thalamic serotonergic (SE) systems is among the earliest changes observed in Parkinson's disease (PD). The consequences of those changes on brain metabolism, especially regarding their impact on the cortex, are poorly understood. Objectives: Using multi‐tracer molecular imaging, we assessed in a cohort of drug‐naive PD patients the association between cortical metabolism and DA and SE system deafferentation of either striatum or thalamus, and we explored whether this association was mediated by either striatum or thalamus metabolism. Methods: We recruited 96 drug‐naive PD patients (aged 71.9 ± 7.5 years) who underwent [123I]ioflupane single‐photon emission computed tomography ([123I]FP‐CIT‐SPECT) and brain [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET). We used a voxel‐wise analysis of [18F]FDG‐PET images to correlate regional metabolism with striatal DA and thalamic SE innervation as assessed using [123I]FP‐CIT‐SPECT. Results: We found that [123I]FP‐CIT specific to nondisplaceable binding ratio (SBR) and glucose metabolism positively correlated with one another in the deep gray matter (thalamus: P = 0.001, r = 0.541; caudate P = 0.001, r = 0.331; putamen P = 0.001, r = 0.423). We then observed a direct correlation between temporoparietal metabolism and caudate DA innervation, as well as a direct correlation between prefrontal metabolism and thalamus SE innervation. The effect of caudate [123I]FP‐CIT SBR values on temporoparietal metabolism was mediated by caudate metabolic values (percentage mediated: 89%, P‐value = 0.008), and the effect of thalamus [123I]FP‐CIT SBR values on prefrontal metabolism was fully mediated by thalamus metabolic values (P < 0.001). Conclusions: These data suggest that the impact of deep gray matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in drug‐naive PD. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8-13 Hz).Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8-12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer's disease (ADMCI).Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. 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. Each group was stratified into three subgroups based on age ranges (i.e., tertiles).Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores.Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD. [ABSTRACT FROM AUTHOR]

Purpose: To investigate brain functional correlates of mild cognitive impairment (MCI) in idiopathic REM sleep behavior disorder (iRBD). Methods: Thirty-nine consecutive iRBD patients, 17 with (RBD-MCI, 73.6±6.5 years), and 22 without (RBD-NC, 69.6±6.1 years) MCI underwent neuropsychological assessment, 18F-FDG-PET, and 123I-FP-CIT-SPECT as a marker of nigro-striatal dopaminergic function. Forty-two healthy subjects (69.6±8.5 years) were used as control for 18F-FDG-PET analysis. Brain metabolism was compared between the three groups by univariate analysis of variance. Post hoc comparison between RBD-MCI and RBD-NC was performed to investigate the presence of an MCI-related volume of interest (MCI-VOI). Brain functional connectivity was explored by interregional correlation analysis (IRCA), using the whole-brain normalized MCI-VOI uptake as the independent variable. Moreover, the MCI-VOI uptake was correlated with 123I-FP-CIT-SPECT specific-to-non displaceable binding ratios (SBR) and neuropsychological variables. Finally, the MCI-VOI white matter structural connectivity was analyzed by using a MRI-derived human atlas. Results: The MCI-VOI was characterized by a relative hypometabolism involving precuneus and cuneus (height threshold p<0.0001). IRCA (height threshold p<0.0001) revealed a brain functional network involving regions in frontal, temporal, parietal, and occipital lobes, thalamus, caudate, and red nuclei in iRBD patients. In controls, the network was smaller and involved temporal, occipital, cingulate cortex, and cerebellum. Moreover, MCI-VOI metabolism was correlated with verbal memory (p=0.01), executive functions (p=0.0001), and nigro-putaminal SBR (p=0.005). Finally, MCI-VOI was involved in a white matter network including cingulate fasciculus and corpus callosum. Conclusion: Our data suggest that cuneus/precuneus is a hub of a large functional network subserving cognitive function in iRBD. [ABSTRACT FROM AUTHOR]

Background and purpose: To explore the feasibility of a neuroprotection trial in prodromal synucleinopathy, using idiopathic rapid eye movement sleep behavior disorder (iRBD) as the target population and 123I‐FP‐CIT‐SPECT as a biomarker of disease progression. Methods: Consecutive iRBD patients were randomly assigned to a treatment arm receiving selegiline and symptomatic rapid eye movement sleep behavior disorder treatment, or to a control arm receiving symptomatic treatment only. Selegiline was chosen because of a demonstrated neuroprotection effect in animal models. Patients underwent 123I‐FP‐CIT‐SPECT at baseline and after 30 months on average. The clinical outcome was the emergence of parkinsonism and/or dementia. A repeated‐measures general linear model (GLM) was applied using group (control and treatment) as "between" factor, and both time (baseline and follow‐up) and regions (123I‐FP‐CIT‐SPECT putamen and caudate uptake) as the "within" factors, adjusting for age. Results: Thirty iRBD patients completed the study (68.2 ± 6.9 years; 29 males; 21% dropout rate), 13 in the treatment arm, and 17 in the control arm. At follow‐up (29.8 ± 9.0 months), three patients in the control arm developed dementia and one parkinsonism, whereas two patients in the treatment arm developed parkinsonism. Both putamen and caudate uptake decreased over time in the control arm. In the treatment arm, only the putamen uptake decreased over time, whereas caudate uptake remained stable. GLM analysis demonstrated an effect of treatment on the 123I‐FP‐CIT‐SPECT uptake change, with a significant interaction between the effect of group, time, and regions (p = 0.004). Conclusions: A 30‐months neuroprotection study for prodromal synucleinopathy is feasible, using iRBD as the target population and 123I‐FP‐CIT‐SPECT as a biomarker of disease progression. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, the amy-PET is globally inspected to provide a binary outcome, but the role of a regional assessment has not been fully investigated yet.Objective: To deepen the role of regional amyloid burden and its implication on clinical-neuropsychological features.Materials: Amy-PET and a complete neuropsychological assessment (Trail Making Test, Rey Auditory Verbal Learning Test, semantic verbal fluency, Symbol Digit, Stroop, visuoconstruction) were available in 109 patients with clinical suspicion of Alzheimer's disease. By averaging the standardized uptake value ratio and ELBA, a regional quantification was calculated for each scan. Patients were grouped according to their overall amyloid load: correlation maps, based on regional quantification, were calculated and compared. A regression analysis between neuropsychological assessment and the regional amyloid-β (Aβ) load was carried out.Results: Significant differences were observed between the correlation maps of patients at increasing levels of Aβ and the overall dataset. The Aβ uptake of the subcortical gray matter resulted not related to other brain regions independently of the global Aβ level. A significant association of semantic verbal fluency was observed with ratios of cortical and subcortical distribution of Aβ which represent a coarse measure of differences in regional distribution of Aβ.Conclusion: Our observations confirmed the different susceptibility to Aβ accumulation among brain regions. The association between cognition and Aβ distribution deserves further investigations: it is possibly due to a direct local effect or it represents a proxy marker of a more aggressive disease subtype. Regional Aβ assessment represents an available resource on amy-PET scan with possibly clinical and prognostic implications. [ABSTRACT FROM AUTHOR]

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects. [ABSTRACT FROM AUTHOR]

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention.Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities.Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status.Results: Wake after sleep onset (WASO) was higher (p < 0.001) and sleep efficiency (SE) lower (p = 0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p = 0.004). SE was lower in male AD compared to female AD (p = 0.038) and SRI lower in male AD compared to male controls (p = 0.008), male MCI (p = 0.047), but also female AD subjects (p = 0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p = 0.009) in the overall population, controls (p = 0.005), and AD subjects (p = 0.034). The confusion-matrices showed good predictive power of actigraphic data.Conclusion: Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to compare a widely distributed commercial tool with an older free software (i) one another, (ii) with a clinical motor score, (iii) versus reading by experts. Procedures: We analyzed consecutive scans from one-hundred and fifty-one outpatients submitted to brain DAT SPECT for a suspected parkinsonism. Images were post-processed using a commercial (Datquant®) and a free (BasGanV2) software. Reading by expert was the gold standard. A subset of patients with pathological or borderline scan was evaluated with the clinical Unified Parkinson's Disease Rating Scale, motor part (MDS-UPDRS-III). Results: SBR, putamen-to-caudate (P/C) ratio, and both P and C asymmetries were highly correlated between the two software with Pearson's 'r' correlation coefficients ranging from.706 to.887. Correlation coefficients with the MDS-UPDRS III score were higher with caudate than with putamen SBR values with both software, and in general higher with BasGanV2 than with Datquant®. Datquant® correspondence with expert reading was 84.1% (94.0% by additionally considering the P/C ratio as a further index). BasGanV2 correspondence with expert reading was 80.8% (86.1% by additionally considering the P/C ratio). Conclusions: Both Datquant® and BasGanV2 work reasonably well and similarly one another in semi-quantification of DAT SPECT. Both tools have their own strength and pitfalls that must be known in detail by users in order to obtain the best help in visual reading and reporting of DAT SPECT. [ABSTRACT FROM AUTHOR]

Background: Assessment of nigrostriatal degeneration is a key element to discriminate between dementia with Lewy bodies (DLB) and Alzheimer disease (AD), and it is often evaluated using ioflupane (123I-FP-CIT) single-photon emission computed tomography (SPECT). Given the limited availability of 123I-FP-CIT SPECT, we evaluated if a mask-based approach to nigroputaminal magnetic resonance imaging (MRI) diffusion-weighted tractography could be able to capture microstructural changes reflecting nigroputaminal degeneration in DLB. Methods: A nigroputaminal bundle mask was delineated on 12 healthy volunteers (HV) and applied to MRI diffusion-weighted data of 18 subjects with DLB, 21 subjects with AD and another group of 12 HV. The correlation between nigroputaminal fractional anisotropy (FA) values and 123I-FP-CIT SPECT findings was investigated. Shapiro-Wilk, ANOVA, ANCOVA, and parametric correlation statistics as well as receiver operating characteristic (ROC) analysis were used. Results: DLB patients showed a higher nigroputaminal FA values compared with both AD and HV-controls groups (p = 0.001 for both comparisons), while no difference was observed between HV-controls and AD groups (p = 0.450); at ROC analysis, the area under the curve for the discriminating DLB and AD subjects was 0.820; FA values correlated with 123I-FP-CIT values (on the left, r = -0.670; on the right, r = -720). No significant differences were observed for the FA of the corticospinal tract across the three groups (p = 0.740). Conclusions: In DLB, nigroputaminal degeneration could be reliably assessed on MRI diffusion scans using a mask of nigroputaminal bundle trajectory. Nigroputaminal FA in DLB patients correlated with 123I-FP-CIT values data may allow to differentiate these patients from AD patients and HV-controls. [ABSTRACT FROM AUTHOR]

Background: An ideal imaging biomarker for a neurodegenerative disorder should be able to measure abnormalities in the earliest stages of the disease.Objective: We investigated metabolic network changes in two independent cohorts of drug-naïve Parkinson's disease (PD) patients who have not been exposed to dopaminergic medication.Methods: We scanned 85 de novo, drug-naïve PD patients and 85 age-matched healthy control subjects from Italy (n = 96) and the United States (n = 74) with [18 F]-fluorodeoxyglucose PET. All patients had clinical follow-ups to verify the diagnosis of idiopathic PD. Spatial covariance analysis was used to identify and validate de novo PD-related metabolic patterns in the Italian and U.S. cohorts. We compared the de novo PD-related metabolic patterns to the original PD-related pattern that was identified in more advanced patients who had been on chronic dopaminergic treatment.Results: De novo PD-related metabolic patterns were identified in each of the two independent cohorts of drug-naïve PD patients, and each differentiated PD patients from healthy control subjects. Expression values for these disease patterns were elevated in drug-naïve PD patients relative to healthy controls in the identification as well as in each of the validation subgroups. The two de novo PD-related metabolic patterns were topographically very similar to each other and to the original PD-related pattern.Conclusions: Reproducible PD-related patterns are expressed in de novo, drug-naïve PD patients. In PD, disease-related metabolic patterns have stereotyped topographies that develop independently of chronic levodopa treatment. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking.Objective: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR).Methods: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender.Results: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients.Conclusion: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients. [ABSTRACT FROM AUTHOR]