BACKGROUND: Synucleinopathies include a spectrum of disorders varying in features and severity, including idiopathic/isolated REM sleep behaviour disorder (iRBD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Distinct brain atrophy patterns may already be seen in iRBD; however, how brain atrophy begins and progresses remains unclear. METHODS: A multicentric cohort of 1276 participants (451 polysomnography-confirmed iRBD, 142 PD with probable RBD, 87 DLB, and 596 controls) underwent T1-weighted MRI and longitudinal clinical assessments. Brain atrophy was quantified using vertex-based cortical surface reconstruction and volumetric segmentation. The unsupervised machine learning algorithm, Subtype and Stage Inference (SuStaIn), was used to reconstruct spatiotemporal patterns of brain atrophy progression. FINDINGS: SuStaIn identified two distinct subtypes of brain atrophy progression: 1) a "cortical-first" subtype, with atrophy beginning in the frontal lobes and involving the subcortical structures at later stages; and 2) a "subcortical-first" subtype, with atrophy beginning in the limbic areas and involving cortical structures at later stages. Both cortical- and subcortical-first subtypes were associated with a higher rate of increase in MDS-UPDRS-III scores over time, but cognitive decline was subtype-specific, being associated with advancing stages in patients classified as cortical-first but not subcortical-first. Classified patients were more likely to phenoconvert over time compared to stage 0/non-classified patients. Among the 88 patients with iRBD who phenoconverted during follow-up, those classified within the cortical-first subtype had a significantly increased likelihood of developing DLB compared to PD, unlike those classified within the subcortical-first subtype. INTERPRETATION: There are two distinct atrophy progression subtypes in iRBD, with the cortical-first subtype linked to an increased likelihood of developing DLB, while both subtypes were associated with worsening parkinsonian motor features. This underscores the potential utility of subtype identification and staging for monitoring disease progression and patient selection for trials. FUNDING: This study was supported by grants to S.R. from Alzheimer Society Canada (0000000082) and by Parkinson Canada (PPG-2023-0000000122). The work performed in Montreal was supported by the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec - Santé (FRQS), and the W. Garfield Weston Foundation. The work performed in Oxford was funded by Parkinson's UK (J-2101) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The work performed in Prague was funded by the Czech Health Research Council (grant NU21-04-00535) and by The National Institute for Neurological Research (project number LX22NPO5107), financed by the European Union - Next Generation EU. The work performed in Newcastle was funded by the NIHR Newcastle BRC based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences - IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Électricité de France (Fondation d'Entreprise EDF), the EU Joint Programme-Neurodegenerative Disease Research (JPND) for the Control-PD Project (Cognitive Propagation in Prodromal Parkinson's disease), the Fondation Thérèse et René Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and the Société Française de Médecine Esthétique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the ALICE Study). The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (#1095127). The work performed in Cologne was funded by the Else Kröner-Fresenius-Stiftung (grant number 2019_EKES.02), the Köln Fortune Program, Faculty of Medicine, University of Cologne, and the "Netzwerke 2021 Program (Ministry of Culture and Science of Northrhine Westphalia State). The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation.

• Klíčová slova
• Dementia with Lewy bodies, MRI, Machine learning, Parkinson's disease, REM sleep behaviour disorder, Subtyping,
• MeSH
• atrofie MeSH
• demence s Lewyho tělísky patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek * patologie   diagnostické zobrazování   MeSH
• Parkinsonova nemoc patologie   MeSH
• porucha chování v REM spánku * patologie   etiologie   diagnóza   diagnostické zobrazování   MeSH
• progrese nemoci MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: Cognitive impairment in Parkinson's disease (PD) is a key non-motor complication during the disease course. OBJECTIVES: A review of detailed cognitive instruments to detect mild cognitive impairment (PD-MCI) or dementia (PDD) is needed to establish optimal tests that facilitate diagnostic accuracy. METHODS: We performed a systematic literature review of tests that assess memory, language including premorbid intelligence, and visuospatial domains (for tests of attention and executive functions see accompanying review) to determine suitability to assess cognition in PD. Based on in-depth scrutiny of psychometric and other relevant clinimetric properties, tests were rated as "recommended," "recommended with caveats," "suggested," or "listed" by the International Parkinson and Movement Disorder Society (IPMDS) panel of experts according to the IPMDS Clinical Outcome Assessment Scientific Evaluation Committee guidelines. RESULTS: We included 39 tests encompassing 48 outcome measures. Seven tests (different versions or subtests of the test counted once) were recommended, including four for memory, one for visuospatial domains, one for language (including three measures), and one for estimated premorbid intelligence. Furthermore, 10 tests (12 measures) were "recommended with caveats," 11 were "suggested," and 11 (15 measures) were "listed." CONCLUSIONS: Recommended neuropsychological tests in memory, visuospatial functions, and language are proposed to guide the assessment of cognitive impairment and its progression in PD-MCI and PDD, and for use in clinical trials to stratify participants or as outcome measures. Novel measures being developed will need extensive validation research to be "recommended." © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Klíčová slova
• Parkinson's disease, clinimetric, cognitive, dementia, neuropsychology, rating scales, test,
• MeSH
• jazyk (prostředek komunikace) * MeSH
• kognitivní dysfunkce * diagnóza   etiologie   MeSH
• lidé MeSH
• neuropsychologické testy * normy   MeSH
• paměť * fyziologie   MeSH
• Parkinsonova nemoc * komplikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH

Diffusion tensor image analysis along the perivascular space (DTI-ALPS) is a potential non-invasive marker of glymphatic function that typically relies on manual region of interest (ROI) placement. This study compared ALPS indices in treatment-naïve, de novo diagnosed patients with Parkinson's disease (PD), patients with isolated REM behavior disorder (iRBD), and healthy controls using both manual and automatic approaches to the ROI selection used in ALPS-index calculation. ALPS indices were analyzed bilaterally and correlated with clinical severity (MDS-UPDRS) and nigrostriatal denervation (DAT-SPECT). ANCOVA revealed significant inter-group differences using both manual (p = 0.018) and automatic (p = 0.002) ROI selection methods. The automatic ROI selection approach showed significantly lower ALPS indices in PD compared to controls (p = 0.001) and iRBD (p = 0.009). ALPS indices correlated with symptom severity and nigrostriatal denervation. These findings underscore the reliability of the automatic ROI placement approach for ALPS index calculation and may indicate early glymphatic alterations in Parkinson's disease.

• Publikační typ
• časopisecké články MeSH

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). METHODS: 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.

• MeSH
• demence s Lewyho tělísky * diagnostické zobrazování   MeSH
• dopamin * metabolismus   MeSH
• jednofotonová emisní výpočetní tomografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• Parkinsonova nemoc * diagnostické zobrazování   komplikace   MeSH
• porucha chování v REM spánku * diagnostické zobrazování   MeSH
• presynaptická zakončení metabolismus   MeSH
• senioři MeSH
• strojové učení * MeSH
• synukleinopatie * diagnostické zobrazování   MeSH
• zobrazení dopaminergního systému MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.

• Klíčová slova
• Parkinson disease, QSM, REM sleep behavioral disorder, iron, whole brain,
• MeSH
• lidé MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• Parkinsonova nemoc * komplikace   MeSH
• porucha chování v REM spánku * diagnostické zobrazování   MeSH
• substantia nigra diagnostické zobrazování   patologie   MeSH
• synukleinopatie * komplikace   patologie   MeSH
• železo MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• železo MeSH

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

• MeSH
• demence s Lewyho tělísky * genetika   MeSH
• HLA antigeny MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé MeSH
• porucha chování v REM spánku * genetika   komplikace   MeSH
• synukleinopatie * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• HLA antigeny MeSH
• HLA-DRB1 řetězec MeSH

REM sleep without atonia (RWA) is the hallmark of isolated REM sleep behavior disorder (iRBD) and is caused by neurodegeneration of brainstem structures. Previously, quantitative susceptibility mapping (QSM) was shown to detect microstructural tissue changes in neurodegenerative diseases. The goal of the study was to compare brainstem magnetic susceptibility (MS) in iRBD and controls using the voxel-based QSM approach and to examine the association between brainstem MS and severity of RWA in iRBD. Sixty iRBD patients and 41 healthy controls were included in the study. Phasic, tonic, mixed RWA and SINBAR score was quantified. QSM maps were reconstructed with QSMbox software from a multi-gradient-echo sequence acquired at 3T MRI system and normalized using a custom T1 template. Voxel-based analysis with age and gender as covariates was performed using a two-sample t-test model for between-group comparison and using a linear regression model for association with the RWA parameters. Statistical maps were generated using threshold free cluster enhancement with p-value p < 0.05, corrected for family wise error. Compared to controls, the iRBD group had higher MS in bilateral substantia nigra (SN), red nucleus and the ventral tegmental area. MS positively correlated with iRBD duration in the right pedunculotegmental nucleus and white matter of caudal mesencephalic and pontine tegmentum and with phasic RWA in bilateral SN. QSM was able to detect MS abnormalities in several brainstem structures in iRBD. Association of MS levels in the brainstem with the intensity of RWA suggests that increased iron content in SN is related to RWA severity.

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: Isolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen ( HLA ) were suggested to be associated with a protective effect. This study examined whether the HLA locus plays a similar role in iRBD, LBD and PD. METHODS: We performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance. RESULTS: In iRBD, HLA-DRB1 *11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93, p =2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR=1.26, 95%CI=1.12-1.41, p =8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91, p =3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35, p =1.35e-03). In HLA-DRB1 , position 71 ( p omnibus =0.00102) and 70 ( p omnibus =0.00125) were associated with iRBD. We found no association in LBD. DISCUSSION: This study identified an association between HLA-DRB1 11:01 and iRBD, distinct from the previously reported association in PD. Therefore, the HLA locus may play different roles across synucleinopathies. Additional studies are required better to understand HLA's role in iRBD and LBD.

• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.

• MeSH
• celogenomová asociační studie MeSH
• lidé MeSH
• mozek MeSH
• Parkinsonova nemoc * genetika   MeSH
• porucha chování v REM spánku * genetika   MeSH
• synukleinopatie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Imprecise vowels represent a common deficit associated with hypokinetic dysarthria resulting from a reduced articulatory range of motion in Parkinson's disease (PD). It is not yet unknown whether the vowel articulation impairment is already evident in the prodromal stages of synucleinopathy. We aimed to assess whether vowel articulation abnormalities are present in isolated rapid eye movement sleep behaviour disorder (iRBD) and early-stage PD. A total of 180 male participants, including 60 iRBD, 60 de-novo PD and 60 age-matched healthy controls performed reading of a standardized passage. The first and second formant frequencies of the corner vowels /a/, /i/, and /u/ extracted from predefined words, were utilized to construct articulatory-acoustic measures of Vowel Space Area (VSA) and Vowel Articulation Index (VAI). Compared to controls, VSA was smaller in both iRBD (p = 0.01) and PD (p = 0.001) while VAI was lower only in PD (p = 0.002). iRBD subgroup with abnormal olfactory function had smaller VSA compared to iRBD subgroup with preserved olfactory function (p = 0.02). In PD patients, the extent of bradykinesia and rigidity correlated with VSA (r = -0.33, p = 0.01), while no correlation between axial gait symptoms or tremor and vowel articulation was detected. Vowel articulation impairment represents an early prodromal symptom in the disease process of synucleinopathy. Acoustic assessment of vowel articulation may provide a surrogate marker of synucleinopathy in scenarios where a single robust feature to monitor the dysarthria progression is needed.

• Publikační typ
• časopisecké články MeSH