Contribution of MRI for the Early Diagnosis of Parkinsonism in Patients with Diagnostic Uncertainty.

BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comparison of mean diffusivity, R2* relaxation rate and morphometric biomarkers for the clinical differentiation of parkinsonism.

INTRODUCTION: Quantitative biomarkers for clinical differentiation of parkinsonian syndromes are still lacking. Our aim was to evaluate the value of combining clinically feasible manual measurements of R2* relaxation rates and mean diffusivity (MD) in subcortical regions and brainstem morphometric measurements to improve the discrimination of parkinsonian syndromes. METHODS: Twenty-two healthy controls (HC), 25 patients with Parkinson's disease (PD), 19 with progressive supranuclear palsy (PSP) and 27 with multiple system atrophy (MSA, 21 with the parkinsonian variant -MSAp, 6 with the cerebellar variant -MSAc) were recruited. R2*, MD measurements and morphometric biomarkers including the midbrain to pons area ratio and the Magnetic Resonance Parkinsonism Index (MRPI) were compared between groups and their diagnostic performances were assessed. RESULTS: Morphometric biomarkers discriminated better patients with PSP (ratio: AUC 0.89, MRPI: AUC 0.89) and MSAc (ratio: AUC 0.82, MRPI: AUC 0.75) from other groups. R2* and MD measurements in the posterior putamen performed better in separating patients with MSAp from PD (R2*: AUC 0.89; MD: AUC 0.89). For the three-class classification "MSA vs PD vs PSP", the combination of MD and R2* measurements in the posterior putamen with morphometric biomarkers (AUC: 0.841) outperformed each marker separately. At the individual-level, there were seven discordances between imaging-based prediction and clinical diagnosis involving MSA. Using the new Movement Disorder Society criteria for the diagnosis of MSA, three of these seven patients were clinically reclassified as predicted by quantitative imaging. CONCLUSION: Combining R2* and MD measurements in the posterior putamen with morphometric biomarkers improves the discrimination of parkinsonism.

Regional Selectivity of Neuromelanin Changes in the Substantia Nigra in Atypical Parkinsonism.

BACKGROUND: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently. OBJECTIVE: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin-sensitive magnetic resonance imaging (MRI). METHODS: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal-to-noise ratio (SNR) values of the SNc were derived from neuromelanin-sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc. RESULTS: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast-to-noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD. CONCLUSIONS: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes. © 2022 International Parkinson and Movement Disorder Society.

Automated Categorization of Parkinsonian Syndromes Using Magnetic Resonance Imaging in a Clinical Setting.

BACKGROUND: Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing. OBJECTIVE: The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes. METHODS: Three hundred twenty-two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA-P), and 23 with MSA of the cerebellar variant (MSA-C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner-dependent effects, we tested two types of normalizations using patient data or healthy control data. RESULTS: In the replication cohort, high accuracies were achieved using volumetry in the classification of PD-PSP, PD-MSA-C, PSP-MSA-C, and PD-atypical parkinsonism (balanced accuracies: 0.840-0.983, area under the receiver operating characteristic curves: 0.907-0.995). Performances were lower for the classification of PD-MSA-P, MSA-C-MSA-P (balanced accuracies: 0.765-0.784, area under the receiver operating characteristic curve: 0.839-0.871) and PD-PSP-MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI. CONCLUSIONS: A machine learning approach based on volumetry enabled accurate classification of subjects with early-stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 International Parkinson and Movement Disorder Society.

Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations.

INTRODUCTION: A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their "red flags" according to current IPD criteria. METHODS: Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and "red flag" features from MDS criteria were analyzed for each case. RESULTS: Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. CONCLUSION: We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.

French validation of the questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS).

INTRODUCTION: The management of impulse control disorders (ICDs) in Parkinson's disease (PD) relies on their early identification, allowing adjustment of antiparkinsonian treatment before these manifestations lead to major social, financial or legal consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) is an English-developed and -validated PD-specific rating scale constructed to support the rating of ICDs and related disorders and the assessment of changes in symptom severity over time, but it has not to date been validated in French. METHODS: We conducted an observational, multicenter, cross-sectional study among a subset of patients (n = 280) from the Drug Interacting with Genes in PD (DIG-PD) cohort, aiming to assess psychometric properties of the French version of QUIP-RS: acceptability, internal consistency, factor analysis, reproductibility and hypotheses testing. In addition to this scale, the following measures were applied: MDS-Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, Frontal Assessment Behavior, and Ardouin Scale of Behavior in Parkinson's Disease (ASBPD). RESULTS: Cronbach's alpha coefficient was 0.72 and ranged from 0.25 to 0.55. Regarding test-retest reliability and inter-rater reliability, the Lin concordance coefficient for items was higher than 0.58. The correlations between QUIP-RS and ASBPD were moderate to high except for dopaminergic addiction and hobbyism (r = 0.41 and 0.40 respectively, p < 0.001). No clinically significant correlation was found between QUIP-RS total score (and items) and other scales. CONCLUSION: The French version of the QUIP-RS appears to be a valid, reliable, and precise instrument for the assessment of ICDs and related disorders in PD. REGISTRATION NUMBER: clinicaltrials.gov number NCT01564992.

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

BACKGROUND: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. METHODS: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. RESULTS: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. CONCLUSIONS: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.

A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood.

BACKGROUND: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. RESULTS: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. CONCLUSIONS: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.

Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS-UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross-sectional study, demographic data and MDS-UPDRS scores were collected, including HY stage. Subscores on MDS-UPDRS Parts I through IV were analyzed using 1-way analyses of variance for each HY stage and in 5-year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0-5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS-UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5-year increments of disease duration, MDS-UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS-UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5-year increments of disease duration in the first 15 years of the disease.

Inflammatory profile in LRRK2-associated prodromal and clinical PD.

BACKGROUND: There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients. METHODS: We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium. RESULTS: A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles. CONCLUSIONS: Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations.

Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson's disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates calcium (Ca2+) exchange between the two compartments and is essential for Parkin-dependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from PARK2 knockout (KO) mice and PD patients with PARK2 mutations than in controls. Ca2+ flux to the cytosol was also modified, due to enhanced ER-to-mitochondria Ca2+ transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with PARK2 mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ER-mitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in PARK2 KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca2+ transients in fibroblasts from patients with PARK2 mutations. In contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.

BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

Sleep aspects on video-polysomnography in LRRK2 mutation carriers.

BACKGROUND: Rapid eye movement sleep behavior disorder and sleepiness precede or accompany idiopathic Parkinson's disease (PD), but their presence in subjects with leucine-rich repeat kinase 2 mutations is unknown. METHODS: Ten patients with leucine-rich repeat kinase 2-associated PD, four healthy leucine-rich repeat kinase 2 mutation carriers, 20 patients with idiopathic PD, and 12 healthy controls underwent clinical assessments and a nighttime video-polysomnography. RESULTS: No sleep changes, no rapid eye movement sleep behavior disorder, or rapid eye movement sleep without atonia was found in the 14 subjects with leucine-rich repeat kinase 2mutations compared with controls, whereas 41% of patients with idiopathic PD had rapid eye movement sleep behavior disorder. Eventually, 20% of patients with leucine-rich repeat kinase 2-associated PD had abnormal periodic leg movements, a frequency similar to the idiopathic PD group frequency. CONCLUSIONS: The sleep phenotype in leucine-rich repeat kinase 2 mutations parallels that of idiopathic PD, except for absent rapid eye movement sleep behavior disorder here in the presymptomatic and symptomatic stages.

Genetics of impulse control disorders in Parkinson's disease.

Impulse control disorders (ICD) have been recognised in Parkinson's disease (PD) as adverse effects of dopamine replacement therapy, particularly with dopamine agonists. Although virtually all PD patients are treated with dopaminergic drugs, only a minority will develop hyperdopaminergic states, suggesting predisposing and/or protecting factors. The age at onset, the sex and the dose or type of dopaminergic drugs have been identified as clinical predictive factors. Recent genetic studies have investigated associations between ICD and polymorphisms of genes involved in the dopamine metabolism pathway (COMT, DAT), dopamine receptors (DRD1, DRD2, DRD3, DRD4), serotonin receptors and its transporter (HTR2A, 5HTT), and glutamate receptors (GRIN2B). Although validation in larger and independent cohorts is needed, the results from these studies give us some insights into the pathophysiology of hyperdopaminergic states and may be useful, at term, in personalising antiparkinsonian treatment in clinical practice.