Derivation and Validation of a Phenoconversion-Related Pattern in Idiopathic Rapid Eye Movement Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of α-synucleinopathies. Reliable biomarkers are needed to predict phenoconversion. OBJECTIVE: The aim was to derive and validate a brain glucose metabolism pattern related to phenoconversion in iRBD (iRBDconvRP) using spatial covariance analysis (Scaled Subprofile Model and Principal Component Analysis [SSM-PCA]). METHODS: Seventy-six consecutive iRBD patients (70 ± 6 years, 15 women) were enrolled in two centers and prospectively evaluated to assess phenoconversion (30 converters, 73 ± 6 years, 14 Parkinson's disease and 16 dementia with Lewy bodies, follow-up time: 21 ± 14 months; 46 nonconverters, 69 ± 6 years, follow-up time: 33 ± 19 months). All patients underwent [18 F]FDG-PET (18 F-fluorodeoxyglucose positron emitting tomography) to investigate brain glucose metabolism at baseline. SSM-PCA was applied to obtain the iRBDconvRP; nonconverter patients were considered as the reference group. Survival analysis and Cox regression were applied to explore prediction power. RESULTS: First, we derived and validated two distinct center-specific iRBDconvRP that were comparable and significantly able to predict phenoconversion. Then, SSM-PCA was applied to the whole set, identifying the iRBDconvRP. The iRBDconvRP included positive voxel weights in cerebellum; brainstem; anterior cingulate cortex; lentiform nucleus; and middle, mesial temporal, and postcentral areas. Negative voxel weights were found in posterior cingulate, precuneus, middle frontal gyrus, and parietal areas. Receiver operating characteristic analysis showed an area under the curve of 0.85 (sensitivity: 87%, specificity: 72%), discriminating converters from nonconverters. The iRBDconvRP significantly predicted phenoconversion (hazard ratio: 7.42, 95% confidence interval: 2.6-21.4). CONCLUSIONS: We derived and validated an iRBDconvRP to efficiently discriminate converter from nonconverter iRBD patients. [18 F]FDG-PET pattern analysis has potential as a phenoconversion biomarker in iRBD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Metabolic correlates of olfactory dysfunction in COVID-19 and Parkinson's disease (PD) do not overlap.

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.

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.

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.

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.

Cuneus/precuneus as a central hub for brain functional connectivity of mild cognitive impairment in idiopathic REM sleep behavior patients.

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.

Dopaminergic and Serotonergic Degeneration and Cortical [18 F]Fluorodeoxyglucose Positron Emission Tomography in De Novo Parkinson's Disease.

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 [123 I]ioflupane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) and brain [18 F]fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET). We used a voxel-wise analysis of [18 F]FDG-PET images to correlate regional metabolism with striatal DA and thalamic SE innervation as assessed using [123 I]FP-CIT-SPECT. RESULTS: We found that [123 I]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 [123 I]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 [123 I]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.

Rapid eye movement sleep behavior disorder: A proof-of-concept neuroprotection study for prodromal synucleinopathies.

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 123 I-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 123 I-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 (123 I-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 123 I-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 123 I-FP-CIT-SPECT as a biomarker of disease progression.

Opportunities and Pitfalls of REM Sleep Behavior Disorder and Olfactory Dysfunction as Early Markers in Parkinson's Disease.

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.

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.

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.

Clinical validity of the Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB) in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. METHODS: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. RESULTS: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. CONCLUSIONS: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

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.

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.

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.

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.

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.

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.

Brain Resources: How Semantic Cueing Works in Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD).

Semantic cues in the Free and Cued Selective Reminding Test (FCRST) play a key role in the neuropsychological diagnosis of Amnesic Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD); however, the neural bases of their impact of recall abilities are only partially understood. Here, we thus decided to investigate the relationships between brain metabolism and the FCSRT Index of Sensitivity of Cueing (ISC) in patients with MCI-AD and in healthy controls (HC). Materials: Thirty MCI-AD patients (age: 74.7 ± 5.7 years; education: 9.6 ± 4.6 years, MMSE score: 24.8 ± 3.3, 23 females) and seventeen HC (age: 66.5 ± 11.1 years; education: 11.53 ± 4.2 years, MMSE score: 28.4 ± 1.14, 10 females) who underwent neuropsychological evaluation and brain F-18 fluorodeoxyglucose Positron Emission Tomography (FDG-PET) were included in the study. Results: ISC was able to differentiate HC from MCI-AD subjects as shown by a ROC analysis (AUC of 0.978, effect size Hedges's g = 2.89). MCI-AD subjects showed significant hypometabolism in posterior cortices, including bilateral inferior Parietal Lobule and Precuneus and Middle Temporal gyrus in the left hemisphere (VOI-1) compared to HC. ISC was positively correlated with brain metabolism in a single cluster (VOI-2) spanning the left prefrontal cortex (superior frontal gyrus) and anterior cingulate cortex (ACC) in the patient group (R2 = 0.526, p < 0.001), but not in HC. Mean uptake values of VOI-2 did not differ between HC and MCI-AD. The structural connectivity analysis showed that VOI-2 is connected with the temporal pole, the cingulate gyrus and the posterior temporal cortices in the left hemisphere. Conclusion: In MCI-AD, the relative preservation of frontal cortex metabolic levels and their correlation with the ISC suggest that the left frontal cortices play a significant role in maintaining a relatively good memory performance despite the presence of posterior hypometabolism in MCI-AD.