Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System.

INTRODUCTION: Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. METHODS: To promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. RESULTS: As a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). DISCUSSION: We suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials

Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System

IntroductionTherapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders.MethodsTo promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies.ResultsAs a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression).DiscussionWe suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.</p

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Depression in Patients with Parkinson's Disease: Current Understanding of its Neurobiology and Implications for Treatment

Depression is one of the most frequent and burdensome non-motor symptoms in Parkinson's disease (PD), across all stages. Even when its severity is mild, PD depression has a great impact on quality of life for these patients and their caregivers. Accordingly, accurate diagnosis, supported by validated scales, identification of risk factors, and recognition of motor and non-motor symptoms comorbid to depression are critical to understanding the neurobiology of depression, which in turn determines the effectiveness of dopaminergic drugs, antidepressants and non-pharmacological interventions. Recent advances using in vivo functional and structural imaging demonstrate that PD depression is underpinned by dysfunction of limbic networks and monoaminergic systems, depending on the stage of PD and its associated symptoms, including apathy, anxiety, rapid eye movement sleep behavior disorder (RBD), cognitive impairment and dementia. In particular, the evolution of serotonergic, noradrenergic, and dopaminergic dysfunction and abnormalities of limbic circuits across time, involving the anterior cingulate and orbitofrontal cortices, amygdala, thalamus and ventral striatum, help to delineate the variable expression of depression in patients with prodromal, early and advanced PD. Evidence is accumulating to support the use of dual serotonin and noradrenaline reuptake inhibitors (desipramine, nortriptyline, venlafaxine) in patients with PD and moderate to severe depression, while selective serotonin reuptake inhibitors, repetitive transcranial magnetic stimulation and cognitive behavioral therapy may also be considered. In all patients, recent findings advocate that optimization of dopamine replacement therapy and evaluation of deep brain stimulation of the subthalamic nucleus to improve motor symptoms represents an important first step, in addition to physical activity. Overall, this review indicates that increasing understanding of neurobiological changes help to implement a roadmap of tailored interventions for patients with PD and depression, depending on the stage and comorbid symptoms underlying PD subtypes and their prognosis

Semi-quantitative analysis of visually normal 123I-FP-CIT across three large databases revealed no difference between control and patients

Abstract Background To show the equivalence between the specific binding ratios (SBR) of visually normal 123I-FP-CIT SPECT scans from patients to those from healthy volunteers (Hv) or patients without dopaminergic degeneration to allow their use as a reference database. Methods The SBR values of visually normal SPECT scans from 3 groups were studied: (1) suspected Parkinsonism and no diagnostic follow-up (ScanOnlyDB: n = 764, NM/CT 670 CZT, GE Healthcare), (2) no degenerative dopaminergic pathology after a 5-year follow-up (NoDG5YearsDB: n = 237, Symbia T2, Siemens Medical Solutions), and 3) Hv (HvDB: n = 118, commercial GE database). A general linear model (GLM) was constructed with caudate, putamen, and striatum SBR as the dependent variables, and age and gender as the independent variables. Following post-reconstruction harmonization of the data, DB were combined in pairs, ScanOnlyDB&NoDG5yearsDG and ScanOnlyDB&HvDB before performing GLM analysis. Additionally, ScanOnlyDB GLM estimates were compared to those published from Siemens commercial DB (SiemensDB) and ENC-DAT. Results The dispersion parameters, R 2 and the SBR coefficients of variation, did not differ between databases. For all volumes of interest and all databases, SBR decreased significantly with age (e.g., decrease per decade for the striatum: − 4.94% for ScanOnlyDB, − 4.65% for NoDG5YearsDB, − 5.69% for HvDB). There was a significant covariance between SBR and gender for ScanOnlyDB (P < 10–5) and NoDG5YearsDB (P < 10–2). The age-gender interaction was significant only for ScanOnlyDB (P < 10–2), and the p-value decreased to 10–6 after combining ScanOnlyDB with NoDG5YearsDB. ScanOnlyDB GLM estimates were not significantly different from those from SiemensDB or ENC-DAT except for age-gender interaction. Conclusion SBR values distribution from visually normal scans were not different from the existing reference database, enabling this method to create a reference database by expert nuclear physicians. In addition, it showed a rarely described age-gender interaction related to its size. The proposed post-reconstruction harmonization method can also facilitate the use of semi-quantitative analysis

Removing deep brain stimulation artifacts from the electroencephalogram: Issues, recommendations and an open-source toolbox

International audienceA major question for deep brain stimulation (DBS) research is understanding how DBS of one target area modulates activity in different parts of the brain. EEG gives privileged access to brain dynamics, but its use with implanted patients is limited since DBS adds significant high-amplitude electrical artifacts that can completely obscure neural activity measured using EEG. Here, we systematically review and discuss the methods available for removing DBS artifacts. These include simple techniques such as oversampling, antialiasing analog filtering and digital low-pass filtering, which are necessary but typically not sufficient to fully remove DBS artifacts when each is used in isolation. We also cover more advanced methods, including techniques tracking outliers in the frequency-domain, which can be effective, but are rarely used. The reason for that is twofold: First, it requires advanced skills in signal processing since no user friendly tool for removing DBS artifacts is currently available. Second, it involves fine-tuning to avoid over-aggressive filtering. We highlight an open-source toolbox incorporating most artifact removal methods , allowing users to combine different strategies

Contribution of Jules Froment to the study of parkinsonian rigidity

International audienceRigidity is commonly defined as a resistance to passive movement. In Parkinson's disease (PD), two types of rigidity are classically recognized which may coexist, "leadpipe " and "cogwheel". Charcot was the first to investigate parkinsonian rigidity during the second half of the nineteenth century, whereas Negro and Moyer described cogwheel rigidity at the beginning of the twentieth century. Jules Froment, a French neurologist from Lyon, contributed to the study of parkinsonian rigidity during the 1920s. He investigated rigidity of the wrist at rest in a sitting position as well as in stable and unstable standing postures, both clinically and with physiological recordings using a myograph. With Gardère, Froment described enhanced resistance to passive movements of a limb about a joint that can be detected specifically when there is a voluntary action of another contralateral body part. This has been designated in the literature as the "Froment's maneuver " and the activation or facilitation test. In addition, Froment showed that parkinsonian rigidity diminishes, vanishes, or enhances depending on the static posture of the body. He proposed that in PD "maintenance stabilization " of the body is impaired and that "reactive stabilization " becomes the operative mode of muscular tone control. He considered "rigidification " as compensatory against the forces of gravity. Froment also demonstrated that parkinsonian rigidity increases during the Romberg test, gaze deviation, and oriented attention. In their number, breadth, and originality, Froment's contributions to the study of parkinsonian rigidity remain currently relevant to clinical and neurophysiological issues of PD

Additional file 4 of Semi-quantitative analysis of visually normal 123I-FP-CIT across three large databases revealed no difference between control and patients

Additional file 4: Statistical analysis