SB-258585 reduces food motivation while blocking 5-HT6 receptors in the non-human primate striatum.

The interest in new 5-HT6 agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT6 receptors, few studies have focused on it. We thus hypothesized that 5-HT6 receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT6 receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT6 receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT6 targets using PET imaging to measure 5-HT6 receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT6 receptor occupancy with the specific PET imaging [18F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT6 transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT6 receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential.

Volumetric changes and clinical trajectories in Parkinson's disease: a prospective multicentric study.

BACKGROUND: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. OBJECTIVE: We aimed to identify brain volumetric changes characterizing PD patients, and determine whether regional brain volumetric characteristics at baseline can predict motor, psycho-behavioral and cognitive evolution at one year in a prospective cohort of PD patients. METHODS: In this multicentric 1 year longitudinal study, PD patients and healthy controls from the MPI-R2* cohort were assessed for demographical, clinical and brain volumetric characteristics. Distinct subgroups of PD patients according to motor, cognitive and psycho-behavioral evolution were identified at the end of follow-up. RESULTS: One hundred and fifty PD patients and 73 control subjects were included in our analysis. Over one year, there was no significant difference in volume variations between PD and control subjects, regardless of the brain region considered. However, we observed a reduction in posterior cingulate cortex volume at baseline in PD patients with motor deterioration at one year (p = 0.017). We also observed a bilateral reduction of the volume of the amygdala (p = 0.015 and p = 0.041) and hippocampus (p = 0.015 and p = 0.053) at baseline in patients with psycho-behavioral deterioration, regardless of age, dopaminergic treatment and center. CONCLUSION: Brain volumetric characteristics at baseline may predict clinical trajectories at 1 year in PD as posterior cingulate cortex atrophy was associated with motor decline, while amygdala and hippocampus atrophy were associated with psycho-behavioral decline.

Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease.

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson's disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson's disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson's disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality. The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody. As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference. R2∗ values significantly increased in Parkinson's disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND < 0.0001). After stratification into four subgroups according to the disease duration, no significant R2∗ difference was found in all regions of interest when comparing Parkinson's disease subgroups. By applying our ISQR strategy, R2(ISQR)∗ values significantly increased in the substantia nigra (PSN_D and PSN_ND < 0.0001) when comparing all Parkinson's disease patients to controls. R2(ISQR)∗ values in the substantia nigra significantly increased with the disease duration (PSN_D = 0.01; PSN_ND = 0.03) as well as the severity of the disease (Hoehn & Yahr scale <2 and ≥ 2, PSN_D = 0.02). Additionally, correlations between R2(ISQR)∗ and clinical features, mainly related to the severity of the disease, were found. Our results support the use of ISQR to reduce variations not directly related to Parkinson's disease, supporting the concept that ISQR strategy is useful for the evaluation of Parkinson's disease.

Noradrenaline and Movement Initiation Disorders in Parkinson's Disease: A Pharmacological Functional MRI Study with Clonidine.

Slowness of movement initiation is a cardinal motor feature of Parkinson's disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 µg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson's disease.

Limbic Stimulation Drives Mania in STN-DBS in Parkinson Disease: A Prospective Study.

In this one-year prospective study, Parkinson's disease (PD) patients with or without mania following STN-DBS were compared to investigate risk and etiological factors, clinical management and consequences. Eighteen (16.2%) out of 111 consecutive PD patients developed mania, of whom 17 were males. No preoperative risk factor was identified. Postoperative mania was related to ventral limbic subthalamic stimulation in 15 (83%) patients, and resolved as stimulation was relocated to the sensorimotor STN, besides discontinuation or reduction of dopamine agonists and use of low-dose clozapine in 12 patients, while motor and nonmotor outcomes were similar. These findings underpin the prominent role of limbic subthalamic stimulation in postoperative mania. ANN NEUROL 2022;92:411-417.

Limbic Serotonergic Plasticity Contributes to the Compensation of Apathy in Early Parkinson's Disease.

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.

Serotonergic and Dopaminergic Lesions Underlying Parkinsonian Neuropsychiatric Signs.

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.

The Human Basal Ganglia Mediate the Interplay between Reactive and Proactive Control of Response through Both Motor Inhibition and Sensory Modulation.

The basal ganglia (BG) have long been known for contributing to the regulation of motor behaviour by means of a complex interplay between tonic and phasic inhibitory mechanisms. However, after having focused for a long time on phasic reactive mechanisms, it is only recently that psychological research in healthy humans has modelled tonic proactive mechanisms of control. Mutual calibration between anatomo-functional and psychological models is still needed to better understand the unclear role of the BG in the interplay between proactive and reactive mechanisms of control. Here, we implemented an event-related fMRI design allowing proper analysis of both the brain activity preceding the target-stimulus and the brain activity induced by the target-stimulus during a simple go/nogo task, with a particular interest in the ambiguous role of the basal ganglia. Post-stimulus activity was evoked in the left dorsal striatum, the subthalamus nucleus and internal globus pallidus by any stimulus when the situation was unpredictable, pinpointing its involvement in reactive, non-selective inhibitory mechanisms when action restraint is required. Pre-stimulus activity was detected in the ventral, not the dorsal, striatum, when the situation was unpredictable, and was associated with changes in functional connectivity with the early visual, not the motor, cortex. This suggests that the ventral striatum supports modulatory influence over sensory processing during proactive control.

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

Endogenous testosterone is associated with increased striatal response to audience effects during prosocial choices.

The role of testosterone on cognitive functions in humans remains controversial. One recent hypothesis suggests that this steroid hormone advances social status. As being observed by others is known to modulate a range of behaviors because of image concerns, we hypothesized that such an audience effect might be an important component of status seeking that is under the control of testosterone. Thus, we investigated to which extent testosterone levels are associated with the effect of being observed during prosocial choices and the neural mechanisms underlying this effect. We enrolled twenty-four male participants, aged 22.47 ± 2.62 years, in an fMRI experiment to examine the relationship between testosterone levels and brain activity engaged in deciding whether to accept or reject monetary transfers to two types of organizations (a positively evaluated organization and a negatively evaluated organization) in presence or absence of an audience. When comparing the public to the private condition, the rate of acceptance increased for the positively evaluated organization, while the rate of rejection increased for the negatively evaluated one. Higher testosterone levels were linked to greater activation in the striatum in the public compared to the private condition, regardless of the organization type. These results indicate a relationship between testosterone levels and striatal activity induced by the audience effect. These findings provide new insights on the role of testosterone in human social behavior.

Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task.

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals' impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.

Prior MDMA administration aggravates MPTP-induced Parkinsonism in macaque monkeys.

The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.

The anterior caudate nucleus supports impulsive choices triggered by pramipexole.

BACKGROUND: Pramipexole is a dopamine agonist used as a treatment in PD and restless legs syndrome to reduce motor symptoms, but it often induces impulse control disorders. In particular, patients with impulse control disorders tend to make more impulsive choices in the delay discounting task, that is, they choose small immediate rewards over larger delayed ones more often than patients without impulse control disorders and healthy subjects do. Yet the site of action of pramipexole that produces these impulsive choices remains unknown. Based on the heterogeneity of corticostriatal projections and the massive dopamine innervation of the striatum, we hypothesized that impulsive choices triggered by dopamine treatments may be supported by a specific striatal territory. OBJECTIVES: This study aims to determine by which anteriorstriatum territory the Pramipexole trigger impulsive choices; the caudate nucleus, the ventral striatum or the putamen. METHODS: We compared pramipexole intramuscular injections to intracerebral microinjections within the three striatal territories in healthy monkeys trained to execute the delay discounting task, a behavioral paradigm typically used to evaluate impulsive choices. RESULTS: We found that pramipexole intramuscular injections induced impulsive choices in all monkeys. Local microinjections were performed inside the anterior caudate nucleus, ventral striatum, and anterior putamen and reproduced those impulsive choices when pramipexole was directly injected into the caudate nucleus, whereas injections into the ventral striatum or putamen had no effect on monkeys' choices. CONCLUSIONS: These results, consistent with clinical studies, suggest that impulsive choices triggered by pramipexole are supported by the caudate nucleus, allowing us to emphasize the importance of dopamine modulation inside this striatal territory in decision processes underlying impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Early limbic microstructural alterations in apathy and depression in de novo Parkinson's disease.

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.

Neurocomputational mechanisms at play when weighing concerns for extrinsic rewards, moral values, and social image.

Humans not only value extrinsic monetary rewards but also their own morality and their image in the eyes of others. Yet violating moral norms is frequent, especially when people know that they are not under scrutiny. When moral values and monetary payoffs are at odds, how does the brain weigh the benefits and costs of moral and monetary payoffs? Here, using a neurocomputational model of decision value (DV) and functional (f)MRI, we investigated whether different brain systems are engaged when deciding whether to earn money by contributing to a "bad cause" and when deciding whether to sacrifice money to contribute to a "good cause," both when such choices were made privately or in public. Although similar principles of DV computations were used to solve these dilemmas, they engaged 2 distinct valuation systems. When weighing monetary benefits and moral costs, people were willing to trade their moral values in exchange for money, an effect accompanied by DV computation engaging the anterior insula and the lateral prefrontal cortex (PFC). In contrast, weighing monetary costs against compliance with one's moral values engaged the ventral putamen. Moreover, regardless of the type of dilemma, a brain network including the anterior cingulate cortex (ACC), anterior insula, and the right temporoparietal junction (TJP) was more engaged in public than in private settings. Together, these findings identify how the brain processes three sources of motivation: extrinsic rewards, moral values, and concerns for image.

Structural Imaging in Parkinson's Disease: New Developments.

PURPOSE OF REVIEW: To review the advances in structural imaging for the diagnosis, prognosis, and treatment of Parkinson's disease (PD) during the last 5 years. RECENT FINDINGS: Structural imaging using high-field MRI (≥ 3 T) and new MR sequences sensitive to iron and nigral pigments have achieved to assess in vivo pathological surrogates useful for PD diagnosis (notably decreased nigral neuromelanin and loss of dorsal nigral hyperintensity, increased nigral iron content, diffusivity, and free-water), prodromal diagnosis (decreased neuromelanin signal in the locus coeruleus), and PD progression (with increasing nigral iron content (increasing R2* rate) and nigral damage (increasing free-water)). Additionally, evaluation of atrophy in small monoaminergic nuclei is useful for prognosis, including cholinergic basal forebrain nuclei atrophy for cognitive impairment. New advances in multimodal structural imaging improve diagnosis, prognosis, and prediction of invasive treatment outcome in PD, and may further benefit from machine learning and large scale longitudinal studies to better identify prognostic subtypes.

Age and time course of long-term motor and nonmotor complications in Parkinson disease.

OBJECTIVE: To determine the time course of hazard for motor and nonmotor milestones of Parkinson disease (PD) in the long term and to investigate whether risk scales nonlinearly with time is instrumental in identifying changes in pathological processes and evaluating disease-modifying therapies in PD. METHODS: Outpatients with PD at the Lyon University Movement Disorders Center were evaluated for 7 clinical milestones in this retrospective cohort study, encompassing 4 domains of PD progression: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations); and (4) cognitive (dementia) complications. For each complication, we estimated the outcome-specific hazard using parsimonious smooth parametric Poisson regression models allowing for nonlinear scaling over disease duration, age at diagnosis, current age, and their interaction. RESULTS: A total of 1,232 patients with PD experienced 1,527 disease-related complications in up to 12 years of follow-up. Specific to each complication, hazard rates increased dramatically starting from diagnosis and were highest for motor fluctuations and lowest for dementia up to 6 years after diagnosis in patients aged 65 years at diagnosis. Nonlinear patterns indicated dramatic changes in the course of PD after 5 years and predicted more severe axial prognosis after 70 years and for motor fluctuations, dyskinesias, and impulse control disorders before 60 years at diagnosis. CONCLUSION: Time course of motor and nonmotor milestones in PD is determined by disease duration and age at diagnosis in nonlinear patterns and their interaction. This indicates disease- and age-specific thresholds across the multiple neurodegenerative processes accumulating in PD at different paces.

Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates.

BACKGROUND: Dopaminergic and serotonergic degenerations alter pharmacological neurotransmission and structural markers in Parkinson's disease (PD). Alteration of diffusion measures in key brain regions depict MPTP/MDMA lesions in the monkey model of PD. Whether dopatherapy impacts such diffusion measures remains an open question. OBJECTIVES: The aim of this study was to investigate the consequences of l-DOPA treatment on diffusion alterations, PET imaging and immunohistochemical markers in MPTP/MDMA-intoxicated monkeys. METHODS: We acquired PET imaging and measures of mean diffusivity and fractional anisotropy longitudinally and correlated them with behavior and post-mortem fiber quantification. RESULTS: Severity of l-DOPA-induced dyskinesia was correlated to serotonin transporter radioligand binding increases in the ventral striatum and the anterior cingulate cortex and decreases of mean diffusivity in the ventral striatum. After lesion of serotonergic fibers by MDMA and the second l-DOPA period, diffusion measures were no more altered while the serotonergic binding still increased in all regions of interest, despite abolition of dyskinesia. Interestingly, in the anterior cingulate cortex, the SERT radioligand binding was negatively correlated to the number of SERT fibers. CONCLUSION: These results show that the increase of SERT radioligand binding is not systematically paralleled by an increase of SERT fibers and does not always reflect the presence of LID. More specifically, our study suggest that SERT increase may be underpinned by an increased density of serotonergic fibers after MPTP and the first l-DOPA period, and by an elevation of SERT itself after MDMA and the second l-DOPA period. This highlights that DTI is complementary to PET imaging to decipher pathophysiological mechanisms underlying l-DOPA-induced dyskinesia in a non-human primate model of PD.

Diffusion tensor imaging marks dopaminergic and serotonergic lesions in the Parkinsonian monkey.

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.

Characterization and Reliability of [18F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT6 Receptors.

Brain serotonin-6 receptor (5-HT6R) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [18F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HT6R neuroimaging in primates. [18F]2FNQ1P was characterized by in vitro autoradiography and in vivo PET imaging in cynomolgus monkeys. Following in vivo PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test-retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HT6R antagonist, SB258585. In vitro, results showed wide cerebral distribution of the tracer with specificity toward 5-HT6Rs as binding was effectively displaced by SB258585. In vivo brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HT6R antagonist pre-injection significantly decreased [18F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [18F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies.