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.

Sporadic Creutzfeldt-Jakob disease is associated with reorganization of metabolic connectivity in a pathological brain network.

BACKGROUND AND PURPOSE: Although sporadic Creutzfeldt-Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored. METHODS: We explored 2-[18 F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods. RESULTS: The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005; receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90-0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization. CONCLUSIONS: The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.

Longitudinal changes in metabolic network activity in early Alzheimer's disease.

INTRODUCTION: The progression of Alzheimer's disease (AD) has been linked to two metabolic networks, the AD-related pattern (ADRP) and the default mode network (DMN). METHODS: Converting and clinically stable cognitively normal subjects (n = 47) and individuals with mild cognitive impairment (n = 96) underwent 2-[18 F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) three or more times over 6 years (nscans  = 705). Expression levels for ADRP and DMN were measured in each subject and time point, and the resulting changes were correlated with cognitive performance. The role of network expression in predicting conversion to dementia was also evaluated. RESULTS: Longitudinal increases in ADRP expression were observed in converters, while age-related DMN loss was seen in converters and nonconverters. Cognitive decline correlated with increases in ADRP and declines in DMN, but conversion to dementia was predicted only by baseline ADRP levels. DISCUSSION: The results point to the potential utility of ADRP as an imaging biomarker of AD progression.

Rapid Eye Movement Sleep Behavior Disorder: Abnormal Cardiac Image and Progressive Abnormal Metabolic Brain Pattern.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for α-synucleinopathies. OBJECTIVE: The aim of this study was to determine whether pathological cardiac [123 I]meta-iodobenzylguanidine scintigraphy ([123 I]MIBG) is associated with progression of [18 F]fluorodeoxyglucose-positron emission tomography-based Parkinson's disease (PD)-related brain pattern (PDRP) expression in iRBD. METHODS: Seventeen subjects with iRBD underwent [18 F]fluorodeoxyglucose-positron emission tomography brain imaging twice ~3.6 years apart. In addition, [123 I]MIBG and [123 I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) at baseline were performed. Olfactory, cognitive, and motor functions were tested annually. RESULTS: Twelve of 17 subjects had pathological [123 I]MIBG. At baseline, 6 of 12 of these expressed the PDRP (suprathreshold PDRP z score). At follow-up, 12 of 17 subjects had suprathreshold PDRP z scores, associated with pathological [123 I]MIBG in 92% and with pathological [123 I]FP-CIT-SPECT in 75%. Subjects with pathological [123 I]MIBG had higher PDRP z score change per year (P = 0.027). Three subjects phenoconverted to PD; all had pathological [123 I]MIBG and [123 I]FP-CIT-SPECT, suprathreshold baseline PDRP z scores, and hyposmia. CONCLUSIONS: Pathological [123 I]MIBG was associated with progressive and suprathreshold PDRP z scores at follow-up. Abnormal [123 I]MIBG likely identifies iRBD as prodromal PD earlier than pathological [123 I]FP-CIT-SPECT. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Four-Year Follow-up of [18 F]Fluorodeoxyglucose Positron Emission Tomography-Based Parkinson's Disease-Related Pattern Expression in 20 Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18 F]fluorodeoxyglucose-positron emission tomography (PET)-based PD-related brain pattern can be used to monitor disease progression. OBJECTIVE: We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. METHODS: Subjects underwent two [18 F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. RESULTS: At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic-determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD. CONCLUSIONS: Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

FDG PET, dopamine transporter SPECT, and olfaction: Combining biomarkers in REM sleep behavior disorder.

BACKGROUND: Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinson's disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD-related pattern were each associated with increased risk of conversion to PD. The objective of this study was to study the relationship between the PD-related pattern, dopamine transporter binding, and olfaction in idiopathic REM sleep behavior disorder. METHODS: In this cross-sectional study, 21 idiopathic REM sleep behavior disorder subjects underwent 18 F-fluorodeoxyglucose PET, dopamine transporter imaging, and olfactory testing. For reference, we included 18 F-fluorodeoxyglucose PET data of 19 controls, 20 PD patients, and 22 patients with dementia with Lewy bodies. PD-related pattern expression z-scores were computed from all PET scans. RESULTS: PD-related pattern expression was higher in idiopathic REM sleep behavior disorder subjects compared with controls (P = 0.048), but lower compared with PD (P = 0.001) and dementia with Lewy bodies (P < 0.0001). PD-related pattern expression was higher in idiopathic REM sleep behavior disorder subjects with hyposmia and in subjects with an abnormal dopamine transporter scan (P < 0.05, uncorrected). CONCLUSION: PD-related pattern expression, dopamine transporter binding, and olfaction may provide complementary information for predicting phenoconversion. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET.

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use.

Parkinson's Disease-Related Brain Metabolic Pattern Is Expressed in Schizophrenia Patients during Neuroleptic Drug-Induced Parkinsonism.

Drug-induced parkinsonism (DIP) is a frequent parkinsonian syndrome that appears as a result of pharmacotherapy for the management of psychosis. It could substantially hamper treatment and therefore its diagnosis has a direct influence on treatment effectiveness. Although of such high importance, there is a lack of systematic research for developing neuroimaging-based criteria for DIP diagnostics for such patients. Therefore, the current study was aimed at applying a metabolic brain imaging approach using the 18F-FDG positron emission tomography and spatial covariance analysis to reveal possible candidates for DIP markers. As a result, we demonstrated, to our knowledge, the first attempt at the application of the Parkinson's Disease-Related Pattern (PDRP) as a metabolic signature of parkinsonism for the assessment of PDRP expression for schizophrenia patients with DIP. As a result, we observed significant differences in PDRP expression between the control group and the groups with PD and DIP patients. Similar differences in PDRP expression were also found when the non-DIP schizophrenia patients were compared with the PD group. Therefore, our findings made it possible to conclude that PDRP is a promising tool for the development of clinically relevant criteria for the estimation of the risk of developing DIP.

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern.

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and 18F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.

The Metabolic Pattern of Idiopathic REM Sleep Behavior Disorder Reflects Early-Stage Parkinson Disease.

Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson disease (PD) and other Lewy body disorders. Spatial covariance analysis of 18F-FDG PET data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it with the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we studied the expression of the iRBD pattern in de novo PD patients. Methods: The iRBD-related pattern was identified in 18F-FDG PET scans of 21 patients with polysomnographically confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in 18F-FDG PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable REM sleep behavior disorder (RBD) according to the Mayo Sleep Questionnaire. Neuropsychologic evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom 16 also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms. Results: The iRBD-related pattern was characterized by relative hypermetabolism in the cerebellum, brain stem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in the middle cingulate, temporal, occipital, and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared with controls (P < 0.0001). iRBD-related pattern expression was not significantly different between PD patients with and without probable RBD, or between PD patients with unilateral or bilateral parkinsonism. iRBD-related pattern (iRBDRP) expression was higher in PD-MCI patients than in PD patients with preserved cognition (P = 0.001). Subject scores on the iRBD-related pattern were highly correlated to subject scores on the PDRP (r = 0.94, P < 0.0001). Conclusion: Our results show that the iRBDRP is an early manifestation of the PDRP. Expression of both PDRP and iRBDRP was higher in patients with a more severe form of PD (PD-MCI), which indicates that expression of the 2 patterns increases with disease severity.