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Objective: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS)., Methods: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication., Results: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05)., Interpretation: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024;96:234-246., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: De novo Parkinson's disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown., Objectives: To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis., Methods: Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [ 11 C]PE2I for dopamine transporter and [ 11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis., Results: After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy., Conclusion: Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background: Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far., Methods: To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([ 11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([ 11 C]PE2I) and serotonin ([ 11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([ 11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled., Results: The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas., Conclusions: Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS)., Methods: All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses., Results: In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome., Interpretation: Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597., (© 2020 American Neurological Association.)

Background: Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction., Methods: We compared the morphological and microstructural architecture in gray matter using voxel-based morphometry and diffusion tensor imaging coupled with white matter tract-based spatial statistics in a multimodal imaging case-control study enrolling 14 apathetic and 13 nonapathetic patients with de novo Parkinson's disease and 15 age-matched healthy controls, paired with PET imaging of the presynaptic dopaminergic and serotonergic systems., Results: De novo parkinsonian patients with apathy had bilateral microstructural alterations in the medial corticostriatal limbic system, exhibiting decreased fractional anisotropy and increased mean diffusivity in the anterior striatum and pregenual anterior cingulate cortex in conjunction with serotonergic dysfunction. Furthermore, microstructural alterations extended to the medial frontal cortex, the subgenual anterior cingulate cortex and subcallosal gyrus, the medial thalamus, and the caudal midbrain, suggesting disruption of long-range nondopaminergic projections originating in the brainstem, in addition to microstructural alterations in callosal interhemispheric connections and frontostriatal association tracts early in the disease course. In addition, microstructural abnormalities related to depressive symptoms in apathetic and nonapathetic patients revealed a distinct, mainly right-sided limbic subnetwork involving limbic and frontal association tracts., Conclusions: Early limbic microstructural alterations specifically related to apathy and depression emphasize the role of early disruption of ascending nondopaminergic projections and related corticocortical and corticosubcortical networks which underpin the variable expression of nonmotor and neuropsychiatric symptoms in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification., (© 2019 Wiley Periodicals, Inc.)

Background: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD., Methods: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset., Results: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105)., Conclusions: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Dopamine replacement therapy in PD has been associated with both behavioral addictions and dopamine addiction., Objectives: To investigate potential association between l-dopa induced neuropsychiatric fluctuations and addictions in PD., Methods: A cohort of 102 patients with PD suffering from motor complications of l-dopa treatment was prospectively analyzed. We evaluated dopamine addiction, behavioral addictions, and neuropsychiatric fluctuations using the Ardouin scale of behavior in PD., Results: Patients with (n = 51) or without (n = 51) neuropsychiatric fluctuations did not differ in age, disease duration, medication, or UPDRS III motor score during on and off drug condition. Patients with neuropsychiatric fluctuations had a higher H & Y stage in off-drug condition. A multivariate model showed that dopamine addiction (odds ratio: 8.9; P = 0.02) and behavioral addictions (odds ratio: 3.76; P = 0.033) were more frequent in the presence of neuropsychiatric fluctuations. Behavioral addictions and dopamine addiction were more frequent in the presence than in the absence of on-drug euphoria (46% vs. 13.9%; P < 0.001 and 27% vs 6.2 %; P = 0.003), while conversely, no association emerged between dopamine or behavioral addictions and presence of off-drug dysphoria. Patients with neuropsychiatric fluctuations had a poorer quality of life and a more frequent history of anxiety disorder., Conclusions: The psychostimulant effects of dopamine treatment during on-drug euphoria, rather than avoidance of off-drug dysphoria, appear to drive both behavioral addictions and abuse of medication. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: Subthalamic stimulation improves the motor and neuropsychiatric symptoms of Parkinson's disease. However, the impact of this treatment on impulse control and personality is the subject of heavy debate. The objective of this study was to investigate personality changes after subthalamic stimulation., Methods: Using Cloninger's biosocial model, we assessed personality in 73 Parkinson's disease patients before and 12 months after subthalamic stimulation accompanied by a drastic reduction in dopaminergic medication. Changes in psychobehavioral symptoms were measured using a battery of validated clinical scales (apathy, depression, anxiety, hyperemotionality, mania, psychosis, punding, and impulse control behaviors)., Results: One year after surgery, the harm avoidance personality domain total score increased compared with the baseline (+2.8; 34 patients; P < 0.001), as did 3 of its 4 subdomains: anticipatory worry (+0.7; 10 patients; P = 0.005), shyness (+0.6; 7 patients; P = 0.03), and fatigability (+1.1; 10 patients; P = 0.0014). Evolution of the shyness personality trait correlated with the decrease in dopaminergic medication. Total scores in the other personality domains remained unchanged, except for extravagance, a subdomain of novelty seeking, and persistence, a subdomain of reward dependence, which both decreased following surgery (-0.3; 7 patients; and -0.6; 9 patients; P = 0.03 and P = 0.0019, respectively). Although apathy increased, other psychobehavioral symptoms, including impulse control behaviors and neuropsychiatric nonmotor fluctuations, improved. Depression and anhedonia remained stable. Scores in hypodopaminergia and neuropsychiatric nonmotor OFF correlated with harm avoidance. Scores in hyperdopaminergia and neuropsychiatric nonmotor ON correlated with novelty seeking., Conclusions: When subthalamic stimulation is applied in Parkinson's disease, significant changes in personality traits are observed, which may be related to postoperative tapering of dopaminergic treatment. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Neuropsychiatric symptoms are common and disabling in PD. Their neurobiological bases are complex, partly because of the disease itself and partly because of the dopaminergic treatment. The aim of this review is to focus on the emotional manifestations stemming from the neurodegenerative process itself. We focus on depression, anxiety, apathy, and fatigue, which can all be part of the clinical spectrum of premotor disease and may be improved or masked by medications targeting parkinsonian motor signs or psychiatric symptoms as the disease progresses. Findings from clinical, neuroimaging, and animal studies are reviewed, showing a major contribution of the dopaminergic system to the pathophysiology of these disabling symptoms. Degeneration of noradrenergic and serotonergic projection systems also has an impact on psychiatric symptoms of PD. The available literature is reviewed, but at present there is a lack of studies that would allow disentangling the separate contribution of each of the monoaminergic systems. The use of a pragmatic classification of all these symptoms under the umbrella of hypodopaminergic behavioral syndrome seems clinically useful, as it emphasizes the crucial, although not exclusive, nature of their dopaminergic neurobiological basis, which has important implications in the clinical management of PD. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Postural abnormalities such as postural deviations affect nearly all patients with advanced Parkinson's disease and represent an important source of disability. Although their existence has long been known, their management remains a challenge as they respond poorly to medication, brain surgery, or physiotherapy. Improving management strategies will require better understanding of the mechanisms underlying such postural deformities. In this review on the pathophysiology of Pisa syndrome, we examine the data supporting the central and peripheral hypotheses that attempt to explain these lateral trunk deviations. Although the pathophysiology is very probably multifactorial, the bulk of the data supports central, rather than peripheral, hypotheses. The central hypotheses that are best supported by both animal studies and clinical data include asymmetry of basal ganglia output and abnormalities in the central integration of sensory information. Further studies are needed to elucidate the pathophysiology underlying Pisa syndrome., (© 2014 International Parkinson and Movement Disorder Society.)

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β-hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α-synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α-synuclein oligomers, with a higher oligomeric/total α-synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β-glucocerebrosidase activity, oligomeric/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD., (© 2014 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.)