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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.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.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 [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.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.

Background Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). Methods One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. Results Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. Conclusions Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. (c) 2019 International Parkinson and Movement Disorder Society

BACKGROUND: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes. OBJECTIVE: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates. METHODS: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with mu parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold. RESULTS: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (mu) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower mu in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower mu in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022). CONCLUSION: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. (c) 2019 International Parkinson and Movement Disorder Society.

Background Non-motor fluctuations represent a main source of disability in Parkinson's disease (PD). Among them, neuropsychiatric fluctuations are the most frequent and are often under-recognized by patients and physicians, partly because specific tools for assessment of neuropsychiatric fluctuations are lacking. Objective To develop a scale for detecting and evaluating the presence and the severity of neuropsychological symptoms during the ON and OFF phases of non-motor fluctuations. Methods Neuropsychiatric symptoms reported by PD patients in the OFF- and the ON-medication conditions were collected using different neuropsychiatric scales (BDI-II, BAI, Young, VAS, etc.). Subsequently, tree phases of a pilot study was performed for cognitive pretesting, identification of ambiguous or redundant items (item reduction), and to obtain preliminary data of acceptability of the new scale. In all the three phases, the scale was applied in both the OFF and ON condition during a levodopa challenge. Results Twenty items were selected for the final version of the neuropsychiatric fluctuation scale (NFS): ten items measured the ON neuropsychological symptoms and ten items the OFF neuropsychological manifestations. Each item rated from 0-3, providing respective subscores from 0 to 30. Conclusions Once validated, our NFS can be used to identify and quantify neuropsychiatric fluctuations during motor fluctuations. The main novelty is that it could be used in acute settings. As such, the NFS can assess the neuropsychiatric state of the patient at the time of examination. The next step will be to validate the NFS to be used in current practice.

BACKGROUND Diffusion tensor imaging has received major interest to highlight markers of neurodegeneration in Parkinson's disease. Whether the alteration of diffusion parameters mostly depicts dopaminergic lesions or can also reveal serotonergic denervation remains a question. OBJECTIVES The aim of this study was to determine the best diffusion tensor imaging markers of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylene-dioxy-methamphetamine (MDMA; also known as ecstasy) lesions in the nonhuman primate. METHODS We acquired measures of mean diffusivity and fractional anisotropy longitudinally (before and after MPTP and MDMA) and correlated them with severity of parkinsonism, PET imaging, and postmortem fiber quantification. RESULTS MPTP-induced lesions were associated with increases of mean diffusivity within both the caudate nucleus and the anterior cingulate cortex, whereas MDMA-induced lesions caused an increase of fractional anisotropy within the caudate nucleus. These variations of diffusion tensor imaging correlated with the motor score. CONCLUSION Taken together, these results demonstrate that diffusion measures within specific brain regions can mark severity of dopaminergic and serotonergic induced lesions in a neurotoxic nonhuman primate model of Parkinson's disease. © 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

Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting new tracer developments hold the potential for in vivo markers of underlying pathology. Herein, we provide an overview of molecular imaging advances and how these approaches help us to understand PD and atypical parkinsonisms. © 2016 International Parkinson and Movement Disorder Society.

International audience

Historically, Parkinson's disease (PD) was defined as a pure movement disorder. Currently, it is widely accepted that this disease is also characterized by nonmotor signs, such as depression, apathy, and anxiety. On the other hand, the consideration of Gilles de la Tourette syndrome (GTS) as a neuropsychiatric disorder has also been debated. In this review, we will focus on these two disorders, which combine both motor and behavioral features and in which dysfunction of cortical and subcortical regions was suggested. Anatomical, experimental, and clinical data are reported to support the involvement of basal ganglia (BG) in cognitive and motivational functions in addition to motor control. In PD, the nonmotor signs could result from the heterogeneity of dopaminergic lesions and excessive activation of the dopamine receptors, particularly within the limbic neuronal networks. Experimental results obtained on nonhuman primates using local disinhibition within functional territories of BG allowed the precise mapping of their motor and nonmotor functions. Thus, impairment of inhibitory control inside specific striatal territories induced behavioral disorders and abnormal movements, which had striking similarities to clinical expressions of GTS. Establishing such a relationship between BG subterritories and motor and behavioral disorders could potentially be helpful for future target choices for DBS in many neuropsychiatric disorders. Furthermore, it is also of great interest for therapeutic research and for the efficient targeting of symptom relief to determine the precise pharmacological effects of the two main modulators of BG function, which are dopamine and serotonin.

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery.

The aim of this work was to study cerebral vasoreactivity to hypercapnia in Parkinson's disease (PD) before and after levodopa administration. The prospective study was conducted in 20 patients presenting with PD, using 3T blood oxygenation level-dependent (BOLD) functional MRI (fMRI) covering the whole brain. The hypercapnic stimulus was block-designed using carbogen inhalation, a gas mixture of 7% CO2 and 93% O2, before (OFF) and 60 minutes after administration of a suprathreshold (120%) therapeutic L-dopa dose (ON). Ten age-matched controls were enrolled for between-group comparisons. Analyses were conducted with a random effects model and corrected for multiple comparisons. No adverse reaction to the hypercapnic stimulus was reported. However, 10 patients and 2 controls were excluded because of incomplete protocol realization, inappropriate hypercapnic stimulus, or excessive movements, leaving 10 patients and 8 controls for further analyses. The hypercapnic stimulus increased whole-brain BOLD signal of 1.48% ± 0.06% (mean ± standard error) in controls, 1.59% ± 0.05% in patients OFF, and 1.62% ± 0.09% in patients ON. Regions of interest analyses showed a signal increase in gray matter of 2.60% ± 0.16% in controls, 2.89% ± 0.21% in patients OFF, and 2.87% ± 0.12% in patients ON. No global or regional significant difference was detected, when comparing patients OFF and ON L-dopa, or between patients and controls. Contrary to Alzheimer's disease, the vasoreactivity to hypercapnia was normal in PD before and after L-dopa administration, compared to controls. This negative result is an important finding, especially for neuroscientists using fMRI to investigate motricity and cognition, discarding a significant confounding effect.

Malformations of cortical development (MCD) with polymicrogyria and schizencephaly are due to abnormal cortical organization and usually manifest by intractable epilepsy and mental retardation. Epileptical activity is often hard to register and focal dystonia associated with such MCD has previously been described but without any metabolic imaging. We report here a 46-year-old man presenting with late-onset atypical abnormal movements of his left hand associated with right central region MCD. To demonstrate the involvement of an epileptical focus, we performed [(18)F]FDG-PET and fMRI both before and after a single dose of clobazam and diazepam, respectively. Characteristics of the abnormal hand movements, clinical response to the medication, and the result of the [(18)F]FDG-PET and fMRI investigations all favor the diagnosis of epilepsia partialis continua. We conclude that the dystonic movement is part of the partial seizure.

International audience; Although slowness of movement is a typical feature of Parkinson's disease (PD), it has been suggested that severely disabled patients remained able to produce normal motor responses in the context of urgent or externally driven situations. To investigate this phenomenon (often designated “paradoxical kinesis”), we required PD patients and healthy subjects to press a large switch under three main conditions: Self Generated, produce the fastest possible movement; External Cue, same as Self Generated but in response to an acoustic cue; Urgent External Cue, same as External Cue with the switch controlling an electromagnet that prevented a ball falling at the bottom of a tilted ramp. Task difficulty was equalized for the two experimental groups. Results showed that external cues and urgent conditions decreased movement duration (Urgent External Cue < External Cue < Self Generated) and reaction time (Urgent External Cue < External Cue). The amount of reduction was identical in PD patients and healthy subjects. These observations show that paradoxical kineses are not a hallmark of PD or a byproduct of basal ganglia dysfunctions, but a general property of the motor system.

Subthalamic nucleus stimulation dramatically improves parkinsonian symptoms, notably the tremor. The occurrence of a tremor in the first 6 months after the surgical procedure in patients without tremor preoperatively is much less common. We report on the cases of 3 patients who developed such modification of their parkinsonian symptomatology. Physiopathological hypotheses are discussed.

Autosomal dominant cerebellar ataxias constitute one of the most clinically, neuropathologically, and genetically heterogeneous groups of neurodegenerative disorders. Approximately 50 to 80% of the families carry mutations in genes known to be implicated in spinocerebellar ataxias (SCAs). Numerous loci (SCAn) also have been mapped, often in single families, but the responsible genes have not yet been identified. This suggests further genetic heterogeneity. We have ascertained 18 subjects from a large French family in which cerebellar ataxia and prominent sensory neuropathy segregated as a dominant trait. Intrafamilial variability was high regarding age at onset (17 months to 39 years), severity, and the clinical picture that ranged from pure sensory neuropathy with little cerebellar involvement to a Friedreich's ataxia-like phenotype. After excluding known genes/loci responsible for SCA and hereditary sensory neuropathies, we detected linkage with chromosome 2p markers in a genomewide screen. We designated this new locus SCA25 after testing of 16 additional markers. Maximum two-point logarithm of odds scores of 3.15 and 3.10 were obtained at D2S2378 and D2S2734, respectively. Haplotype analysis defined a critical 12.6cM region of 15Mb between D2S2174 and D2S2736. No linkage to this locus was found in four other families. This interval contains several genes that could be responsible for the disease. One of these genes, CRIPT, encodes a postsynaptic protein, but no mutations were found by direct sequencing, excluding its responsibility in the disease. CAG repeat expansions often are involved in SCA pathogenesis, but no pathological expansions were found at the protein or at the DNA level using the 1C2 antibody and the repeat expansion detection method, respectively. The gene responsible for SCA25 remains to be identified.

Background: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a recently recognized neurovascular disease due to mutations of the Notch3 gene, manifesting with strokes or stroke-like episodes, major psychiatric symptoms and dementia. The diagnosis can be confirmed either by molecular analysis or by ultrastructural examination of the brain or more simply the skin. Methods: The skin of a patient with a suspected diagnosis of CADASIL was studied by electron microscopy. Results: Characteristic granular osmiophilic material within the basement membrane surrounding pericytes and smooth muscle cells of small and medium-sized vessels of the skin were found, confirming the diagnosis of CADASIL. Conclusions: CADASIL is an additional example of a neurologic disease that can be diagnosed thanks to electron microscopic examination of the skin. Dermatopathologists should be aware of these ultrastructural findings, all the more so since the disease could be more common than originally thought. Kanitakis J, Thobois S, Claudy A, Broussolle E. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): a neurovascular disease diagnosed by ultrastructural examination of the skin.

Bilateral high-frequency stimulation of the internal part of the pallidum has proven its efficacy in improving motor symptoms of dystonia. In Parkinson's disease, the stimulation of the external pallidum (GPe) can induce dyskinesias. This has never been described in dystonia. We report here a case of abnormal movements induced by the stimulation of GPe in a dystonic patient and discuss the pathophysiological mechanisms.