Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

Reduced Gastric Contraction in Rapid-Eye-Movement Sleep Behavior Disorder and De Novo Parkinson's Disease.

BACKGROUND: Reduced gastric motility in Parkinson's disease (PD) has been reported, but hardly any study exists in subjects with isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD), a specific prodrome of α-synucleinopathies. OBJECTIVES: We compared the gastric motility of 17 iRBD subjects with that of 18 PD subjects (15 drug naive, 3 early treated in defined off) and 15 healthy controls (HC) with real-time magnetic resonance imaging (rtMRI). METHODS: After overnight fasting, participants consumed a standardized breakfast and underwent a 3-T rtMRI of the stomach. Amplitude and velocity of the peristaltic waves were analyzed under blinded conditions. Gastric motility index (GMI) was calculated. The procedure was repeated in 12 of 17 iRBD subjects ~2.5 years later. Nine of these 12 iRBD subjects were hyposmic. RESULTS: In iRBD and PD subjects the amplitude of the peristaltic waves was significantly reduced compared with HCs (iRBD vs. HC: 8.7 ± 3.7 vs. 11.9 ± 4.1 mm, P = 0.0097; PD vs. HC: 6.8 ± 2.2 vs. 11.9 ± 4.1 mm, P = 0.0001). The amplitude in iRBD and PD subjects was decreased to the same extent. The GMI was reduced in only PD subjects (PD vs. HC: P = 0.0027; PD vs. iRBD: P = 0.0203). After ~2.5 years the amplitude in iRBD subjects did not significantly decrease further. CONCLUSION: The amplitude of the peristaltic waves was markedly reduced in iRBD, a prodrome of α-synucleinopathies. This reduction was similar to the extent observed already in manifest early PD. This finding implies that the α-synuclein pathology affects the innervation of the stomach already in the prodromal stage. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

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.

Risk Factors for Phenoconversion in Rapid Eye Movement Sleep Behavior Disorder.

OBJECTIVE: This study was undertaken to follow up predictive factors for α-synuclein-related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center. RESULTS: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21-0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia. INTERPRETATION: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022;91:404-416.

Occipital hypometabolism is a risk factor for conversion to Parkinson's disease in isolated REM sleep behaviour disorder.

PURPOSE: Isolated REM sleep behaviour disorder (iRBD) patients are at high risk of developing clinical syndromes of the α-synuclein spectrum. Progression markers are needed to determine the neurodegenerative changes and to predict their conversion. Brain imaging with 18F-FDG PET in iRBD is promising, but longitudinal studies are scarce. We investigated the regional brain changes in iRBD over time, related to phenoconversion. METHODS: Twenty iRBD patients underwent two consecutive 18F-FDG PET brain scans and clinical assessments (3.7 ± 0.6 years apart). Seventeen patients also underwent 123I-MIBG and 123I-FP-CIT SPECT scans at baseline. Four subjects phenoconverted to Parkinson's disease (PD) during follow-up. 18F-FDG PET scans were compared to controls with a voxel-wise single-subject procedure. The relationship between regional brain changes in metabolism and PD-related pattern scores (PDRP) was investigated. RESULTS: Individual hypometabolism t-maps revealed three scenarios: (1) normal 18F-FDG PET scans at baseline and follow-up (N = 10); (2) normal scans at baseline but occipital or occipito-parietal hypometabolism at follow-up (N = 4); (3) occipital hypometabolism at baseline and follow-up (N = 6). All patients in the last group had pathological 123I-MIBG and 123I-FP-CIT SPECT. iRBD converters (N = 4) showed occipital hypometabolism at baseline (third scenario). At the group level, hypometabolism in the frontal and occipito-parietal regions and hypermetabolism in the cerebellum and limbic regions were progressive over time. PDRP z-scores increased over time (0.54 ± 0.36 per year). PDRP expression was driven by occipital hypometabolism and cerebellar hypermetabolism. CONCLUSIONS: Our results suggest that occipital hypometabolism at baseline in iRBD implies a short-term conversion to PD. This might help in stratification strategies for disease-modifying trials.

Evaluation of a Structured Screening Assessment to Detect Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) cohorts have provided insights into the earliest neurodegenerative processes in α-synucleinopathies. Even though polysomnography (PSG) remains the gold standard for diagnosis, an accurate questionnaire-based algorithm to identify eligible subjects could facilitate efficient recruitment in research. OBJECTIVE: This study aimed to optimize the identification of subjects with iRBD from the general population. METHODS: Between June 2020 and July 2021, we placed newspaper advertisements, including the single-question screen for RBD (RBD1Q). Participants' evaluations included a structured telephone screening consisting of the RBD screening questionnaire (RBDSQ) and additional sleep-related questionnaires. We examined anamnestic information predicting PSG-proven iRBD using logistic regressions and receiver operating characteristic curves. RESULTS: Five hundred forty-three participants answered the advertisements, and 185 subjects fulfilling inclusion and exclusion criteria were screened. Of these, 124 received PSG after expert selection, and 78 (62.9%) were diagnosed with iRBD. Selected items of the RBDSQ, the Pittsburgh Sleep Quality Index, the STOP-Bang questionnaire, and age predicted iRBD with high accuracy in a multiple logistic regression model (area under the curve >80%). When comparing the algorithm to the sleep expert decision, 77 instead of 124 polysomnographies (62.1%) would have been carried out, and 63 (80.8%) iRBD patients would have been identified; 32 of 46 (69.6%) unnecessary PSG examinations could have been avoided. CONCLUSIONS: Our proposed algorithm displayed high diagnostic accuracy for PSG-proven iRBD cost-effectively and may be a convenient tool for research and clinical settings. External validation sets are warranted to prove reliability. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The roles of connectivity and neuronal phenotype in determining the pattern of α-synuclein pathology in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and motor dysfunction has been attributed to loss of dopaminergic neurons. However, motor dysfunction is only one of many symptoms experienced by patients. A neuropathological hallmark of PD is intraneuronal protein aggregates called Lewy pathology (LP). Neuropathological staging studies have shown that dopaminergic neurons are only one of the many cell types prone to manifest LP. Progressive appearance of LP in multiple brain regions, as well as peripheral nerves, has led to the popular hypothesis that LP and misfolded forms of one of its major components - α-synuclein (aSYN) - can spread through synaptically connected circuits. However, not all brain regions or neurons within connected circuits develop LP, suggesting that cell autonomous factors modulate the development of pathology. Here, we review studies about how LP develops and progressively engages additional brain regions. We focus on how connectivity constrains progression and discuss cell autonomous factors that drive pathology development. We propose a mixed model of cell autonomous factors and trans-synaptic spread as mediators of pathology progression and put forward this model as a framework for future experiments exploring PD pathophysiology.

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Dysprosody in Isolated REM Sleep Behavior Disorder with Impaired Olfaction but Intact Nigrostriatal Pathway.

BACKGROUND: Impairments of olfactory and speech function are likely early prodromal symptoms of α-synucleinopathy. OBJECTIVE: The aim of this study is to assess whether dysprosody is present in isolated rapid eye movement sleep behavior disorder (iRBD) with hyposmia/anosmia and a normal nigrostriatal system. METHODS: Pitch variability during speech was investigated in 17 iRBD subjects with normal olfactory function (iRBD-NOF), 30 iRBD subjects with abnormal olfactory function (iRBD-AOF), and 50 healthy controls. iRBD subjects were evaluated using the University of Pennsylvania Smell Identification Test and [123I]-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane dopamine transporter single-photon emission computed tomography (DAT-SPECT). All iRBD subjects completed the 24-month follow-up with DAT-SPECT, speech, and olfactory testing. RESULTS: At baseline, only iRBD-AOF showed monopitch when compared to iRBD-NOF (P = 0.04) and controls (P = 0.03), with no difference between iRBD-NOF and controls (P = 1). At follow-up, dysprosody progressed only in iRBD-AOF with abnormal DAT-SPECT (P = 0.03). CONCLUSION: Prosody is impaired in hyposmic but not in normosmic iRBD subjects before the nigrostriatal dopaminergic transmission is affected (Braak stage 2). © 2021 International Parkinson and Movement Disorder Society.

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.

Circuit imaging biomarkers in preclinical and prodromal Parkinson's disease.

Parkinson's disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD.

Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.

Saccade, Pupil, and Blink Responses in Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Parkinson's disease (PD) patients exhibit deficits in saccade performance, pupil function, and blink rate. Isolated REM (rapid eye movement) Sleep Behavior Disorder (RBD) is a harbinger to PD making them candidates to investigate for early oculomotor abnormalities as PD biomarkers. OBJECTIVES: We tested whether saccade, pupillary, and blink responses in RBD were similar to PD. METHODS: RBD (n = 22), PD (n = 22) patients, and healthy controls (CTRL) (n = 74) were studied with video-based eye-tracking. RESULTS: RBD patients did not have significantly different saccadic behavior compared to CTRL, but PD patients differed from CTRL and RBD. Both patient groups had significantly lower blink rates, dampened pupil constriction, and dilation responses compared to CTRL. CONCLUSION: RBD and PD patients had altered pupil and blink behavior compared to CTRL. Because RBD saccade parameters were comparable to CTRL, pupil and blink brain areas may be impacted before saccadic control areas, making them potential prodromal PD biomarkers. © 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.

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

BACKGROUND: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). OBJECTIVE: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. METHODS: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. RESULTS: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. CONCLUSION: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

[Neuroprotective treatment of idiopathic, genetic and atypical Parkinson's disease with alpha-synuclein-Pathology]. / Neuroprotektive Therapien bei idiopathischen, genetischen und atypischen Parkinson-Syndromen mit α-Synuklein ­ Pathologie.

The key aspect of the classification of neurodegenerative diseases is the histopathological detection of certain proteins in the brain. The various disease entities are distinguished with respect to the type of detected protein and with respect to the configuration and localization of the corresponding protein aggregates. Aggregates of alpha-synuclein (ASYN) are the defining hallmark of several neurodegenerative disorders termed synucleinopathies. The most well-known diseases in this spectrum are Parkinson's disease (PD) with neuronal detection of Lewy bodies, dementia with Lewy bodies (DLB), with additional detection of beta-amyloid and multiple system atrophy (MSA), where ASYN aggregates are found in glia cells in the form of Papp-Lantos inclusions. ASYN has been identified as a key target for the development of therapeutic approaches to synucleinopathies given its central role in the pathophysiology of these diseases. Current treatment strategies can be roughly classified into six groups: 1) lowering ASYN expression (antisense therapy), 2) inhibition of formation of toxic ASYN aggregates (aggregation inhibitors, chelators), 3) dissolving or removal of intracellular or extracellular toxic AYSN aggregates (active and passive immunotherapy, aggregation inhibitors), 4) enhancement of cellular clearance mechanisms (autophagy, lysosomal microphagy) for removal of toxic forms of alpha-synuclein, 5) modulation of neuroinflammatory processes and 6) neuroprotective strategies. This article summarizes the current therapeutic approaches and sheds light on promising future treatment approaches.

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

Widespread microglial activation in multiple system atrophy.

BACKGROUND: The pattern and role of microglial activation in multiple system atrophy is largely unclear. The objective of this study was to use [11 C](R)-PK11195 PET to determine the extent and correlation of activated microglia with clinical parameters in MSA patients. METHODS: Fourteen patients with the parkinsonian phenotype of MSA (MSA-P) with a mean disease duration of 2.9 years (range 2-5 years) were examined with [11 C](R)-PK11195 PET and compared with 10 healthy controls. RESULTS: Patients with the parkinsonian phenotype of MSA showed a significant (P ≤ 0.01) mean increase in binding potentials compared with healthy controls in the caudate nucleus, putamen, pallidum, precentral gyrus, orbitofrontal cortex, presubgenual anterior cingulate cortex, and the superior parietal gyrus. No correlations between binding potentials and clinical parameters were found. CONCLUSIONS: In early clinical stages of the parkinsonian phenotype of MSA, there is widespread microglial activation as a marker of neuroinflammatory changes without correlation to clinical parameters in our patient population. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.