Bipolar disorder (BD) is a chronic and disabling psychiatric condition that is linked to significant disability and psychosocial impairment. Although current neuropsychological, molecular, and neuroimaging evidence support the existence of neuroprogression and its effects on the course and outcome of this condition, whether and to what extent neuroprogressive changes may impact the illness trajectory is still poorly understood. Thus, this selective review was aimed toward comprehensively and critically investigating the link between BD and neurodegeneration based on the currently available evidence. According to the most relevant findings of the present review, most of the existing neuropsychological, neuroimaging, and molecular evidence demonstrates the existence of neuroprogression, at least in a subgroup of BD patients. These studies mainly focused on the most relevant effects of neuroprogression on the course and outcome of BD. The main implications of this assumption are discussed in light of specific shortcomings/limitations, such as the inability to carry out a meta-analysis, the inclusion of studies with small sample sizes, retrospective study designs, and different longitudinal investigations at various time points.

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A BS TRACT: 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 AE 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 AE 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.

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 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, neuropsychological and imaging data. Results Four patients phenoconverted at follow-up (three cases of parkinsonism and one of dementia). At the group level, neuropsychological 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 neuropsychological 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.

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. KeywordsMCI with Lewy bodies • 18 F-FDG-PET • Semiquantitative tools • Volumetric regions of interest This article is part of the Topical Collection on Neurology * Federico Massa

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.