Striatal Dopamine Depletion Research Articles

Dysautonomia Is Linked to Striatal Dopamine Deficits and Regional Cerebral Perfusion in Early Parkinson Disease.

The aim of this study was to investigate the association between autonomic dysfunction and striatal dopamine depletion or metabolic changes in de novo Parkinson disease (PD). Based on the Composite Autonomic Severity Score (CASS), patients with de novo PD were classified into PD with (PD-AUT+) and without autonomic dysfunction (PD-AUT-) groups. We compared the dopamine transporter (DAT) availability in the striatum by quantitatively measuring F-FP-CIT PET between both groups. We also assessed the association between DAT availability and the CASS. In addition, we compared regional uptake in early-phase images of F-FP-CIT PET as well as cortical thickness between the PD-AUT+ and PD-AUT- groups. The PD-AUT+ group had significantly lower DAT availability in all striatal subregions than did the PD-AUT- group. The total CASS was significantly correlated with DAT availability in all striatal subregions. In addition, the subscores of the adrenergic component were correlated with DAT availability in all striatal subregions. The subscores of the cardiovagal component were negatively correlated with DAT availability in the caudate and ventral striatum. In early-phase F-FP-CIT PET, the PD-AUT+ group exhibited decreased regional perfusion in the parieto-occipital areas and increased regional perfusion in the pallidothalamic, pontocerebellar, inferior frontal, and primary motor areas compared with the PD-AUT- group. There were no regions of different cortical thickness between the PD groups. The present study revealed that autonomic dysfunction is closely linked to striatal dopamine depletion and prominent PD-related perfusion patterns in de novo PD, suggesting a greater pathological burden in patients with dysautonomia.

The effect of ascorbic acid pretreatment on amphetamine-induced dopamine depletion in male and female mice

The repeated administration of high doses of amphetamine has been shown to cause long-lasting depletions of striatal dopamine which, when substantial enough, have been shown to result in cognitive and motor impairment. These amphetamine-induced lesions are slightly larger in males than that in females and can be partially ameliorated by pretreatment with antioxidants. The objective of the present study was to replicate these two latter observations using an amphetamine dosing regimen that yields only minor depletions of dopamine. It was found that a low-dose treatment of amphetamine using only two subcutaneous injections caused a 57% depletion of striatal dopamine with males slightly more affected than females. Furthermore, pretreatment with ascorbic acid reduced the magnitude of this dopamine depletion with males exhibiting a slightly enhanced protection as compared to females. Compared to the traditionally used high-dose regimens, these effects were mild but in the same direction. The advantage of this regimen is that it better reflects amphetamine-induced depletions of dopamine in humans.

Striatal Nurr1, but not FosB expression links a levodopa-induced dyskinesia phenotype to genotype in Fisher 344 vs. Lewis hemiparkinsonian rats

Numerous genes, and alterations in their expression, have been identified as risk factors for developing levodopa-induced dyskinesia (LID). However, our understanding of the complexities of molecular changes remains insufficient for development of clinical treatment. In the current study we used gene array, in situ hybridization, immunohistochemistry, and microdialysis to provide a unique compare and contrast assessment of the relationship of four candidate genes to LID, employing three genetically distinct rat strains (Sprague-Dawley (SD), Fischer-344 (F344) and Lewis-RT.1) showing differences in dyskinesia susceptibility and ‘first-ever LID’ versus ‘chronic LID’ expression in subjects displaying equal dyskinesia severity. In these studies, rat strains were easily distinguishable for their LID propensity with: 1) a majority of SD rats expressing LID (LID+) and a subset being resistant (LID-); 2) all F344 rats readily developing (LID+); and 3) all Lewis rats being LID-resistant (LID-). Following chronic levodopa, LID+ SD rats showed significant increases in candidate gene expression: Nr4a2/(Nurr1) > > Trh > Inhba = Fosb. However, SD rats with long-standing striatal dopamine (DA) depletion treated with first-ever versus chronic high-dose levodopa revealed that despite identical levels of LID severity: 1) Fosb and Nurr1 transcripts but not protein were elevated with acute LID expression; 2) FOSB/ΔFOSB and NURR1 proteins were elevated only with chronic LID; and 3) Trh transcript and protein were elevated only with chronic LID. Strikingly, despite similar levodopa-induced striatal DA release in both LID-expressing F344 and LID-resistant Lewis rats, Fosb, Trh, Inhba transcripts were significantly elevated in both strains; however, Nurr1 mRNA was significantly increased only in LID+ F344 rats. These findings suggest a need to reevaluate currently accepted genotype-to-phenotype relationships in the expression of LID, specifically that of Fosb, a transcription factor generally assumed to play a causal role, and Nurr1, a transcription factor that has received significant attention in PD research linked to its critical role in the survival and function of midbrain DA neurons but who's striatal expression, generally below levels of detection, has remained largely unexplored as a regulator of LID. Finally these studies introduce a novel ‘model’ (inbred F344 vs inbred Lewis) that may provide a powerful tool for investigating the role for ‘dyskinesia-resistance’ genes downstream of ‘dyskinesia-susceptibility’ genes in modulating LID expression, a concept that has received considerably less attention and offers a new ways of thinking about antidyskinetic therapies.

Serial Dopamine Transporter Imaging of Nigrostriatal Function in Parkinson's Disease With Probable REM Sleep Behavior Disorder.

The current study aimed to confirm whether probable rapid eye movement sleep behavior disorder (pRBD) is associated with a specific pattern of striatal dopamine depletion in an international, multicenter, prospective cohort of patients with Parkinson’s disease (PD). Two hundred and seventy de novo, drug-naïve patients with PD underwent dopamine transporter (DAT) single photon emission computed tomography with 123I-FP-CIT at baseline and 1, 2, and 4 years after the initial scan. The diagnosis of pRBD was based on the 10-item RBD Screening Questionnaire. Striatal DAT binding levels and their rates of decline were compared between patients with pRBD and those without. At baseline, patients in the PD-pRBD+ group showed lower striatal DAT binding in the caudate (which was more pronounced in the less-affected hemisphere) and in the putamen. During the 4-year follow-up, patients in the PD-pRBD+ group consistently exhibited greater DAT loss than patients in the PD-pRBD− group with comparable disease duration in all four striatal subregions. These patients also exhibited a more rapid decrease in DAT binding in the caudate and a less prominent interhemispheric asymmetry in the putamen. The distinct pattern of striatal DAT depletion may contribute to a more malignant phenotype of PD associated with RBD, specifically faster progression of motor symptoms.

Increased GABAergic transmission in neuropeptide Y-expressing neurons in the dopamine-depleted murine striatum.

As the main input nucleus of the basal ganglia, the striatum plays a central role in planning, control, and execution of movement and motor skill learning. More than 90% of striatal neurons, so-called medium spiny neurons (MSN), are GABAergic projection neurons, innervating primarily the substantia nigra pars reticulata or the globus pallidus internus. The remaining neurons are GABAergic and cholinergic interneurons, synchronizing and controlling striatal output by reciprocal connections with MSN. Besides prominent local cholinergic influence, striatal function is globally regulated by dopamine (DA) from the nigrostriatal pathway. Little is known about whether DA depletion, as occurs in Parkinson's disease, affects the activity of striatal interneurons. Here we focused on neuropeptide Y (NPY)-expressing interneurons, which are among the major subgroups of GABAergic interneurons in the striatum. We investigated the effects of striatal DA depletion on GABAergic transmission in NPY interneurons by electrophysiologically recording GABAergic spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) in identified NPY interneurons in slices from 6-hydroxydopamine (6-OHDA)- and vehicle-injected transgenic NPY-humanized Renilla green fluorescent protein (hrGFP) mice with the whole cell patch-clamp technique. We report a significant increase in sIPSC and mIPSC frequency as well as the occurrence of giant synaptic and burst sIPSCs in the 6-OHDA group, suggesting changes in GABAergic circuit activity and synaptic transmission. IPSC kinetics remained unchanged, pointing to mainly presynaptic changes in GABAergic transmission. These results show that chronic DA depletion following 6-OHDA injection causes activity-dependent and -independent increase of synaptic GABAergic inhibition onto striatal NPY interneurons, confirming their involvement in the functional impairments of the DA-depleted striatum.NEW & NOTEWORTHY Neuropeptide Y (NPY) interneurons regulate the function of striatal projection neurons and are upregulated upon dopamine depletion in the striatum. Here we investigated how dopamine depletion affects NPY circuits and show electrophysiologically that it leads to the occurrence of giant synaptic and burst GABAergic spontaneous inhibitory postsynaptic currents (IPSCs) and to an activity-independent increase in GABAergic miniature IPSC frequency in NPY neurons. We suggest that degeneration of dopaminergic terminals in the striatum causes functional changes in striatal GABAergic function.

Initial motor reserve and long-term prognosis in Parkinson's disease

There are individual differences in motor deficits, despite a similar degree of dopamine neuronal loss in Parkinson's disease (PD), called motor reserve (MR). Factors enhancing MR have been documented previously, but the influence of initial MR on the long-term prognosis remains unclear. In this longitudinal study, we enrolled 205 patients with de novo PD to estimate individual MR based on initial motor deficits and striatal dopamine depletion using the residual-based approach. We assessed the risk of developing levodopa-induced dyskinesia (LID) or freezing of gait (FOG) and longitudinal increases in levodopa-equivalent dose (LED) according to MR estimates using the Cox regression model and linear mixed model, respectively. Throughout the follow-up period (≥3 years), greater MR estimates were associated with a lower risk for LID and FOG. In addition, patients with high MR received lower LED than those with low MR. These findings suggest that the initial MR, that is, individual's capacity to cope with PD-related pathologies, can be maintained with disease progression and can modulate the risk for LID or FOG.

Identifying the Functional Brain Network of Motor Reserve in Early Parkinson's Disease.

The severity of motor symptoms in Parkinson's disease (PD) does not always correlate with the degree of nigral dopaminergic neuronal loss. Individuals with greater motor reserve may have milder motor signs than their striatal dopamine loss. In this study, we explored the functional brain network associated with motor reserve in early-stage PD. We analyzed 134 patients with de novo PD who underwent dopamine transporter scans and resting-state functional magnetic resonance imaging. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We applied network-based statistic analysis to identify the functional brain network associated with the measure of motor reserve (ie, motor reserve network). We also assessed the effect of motor reserve network connectivity strength on the longitudinal increase in levodopa-equivalent dose during the 2-year follow-up period. Network-based statistic analysis identified the motor reserve network composed of the basal ganglia, inferior frontal cortex, insula, and cerebellar vermis at a primary threshold of P value 0.001. Patients with an increased degree of functional connectivity within the motor reserve network had greater motor reserve. There was a significant interaction between the motor reserve network strength and time in the linear mixed model, indicating that higher motor reserve network strength was associated with slower longitudinal increase in levodopa-equivalent dose. The present study revealed the functional brain network associated with motor reserve in patients with early-stage PD. Functional connections within the motor reserve network are associated with the individual's capacity to cope with PD-related pathologies. © 2020 International Parkinson and Movement Disorder Society.

Clinical and striatal dopamine transporter predictors of β-amyloid in dementia with Lewy bodies

To investigate the relationship between β-amyloid (Aβ) deposition and striatal dopamine depletion, cognitive functions, and neuropsychiatric symptoms in dementia with Lewy bodies (DLB). We consecutively recruited 51 patients with DLB who had undergone a neuropsychological test, Neuropsychiatric Inventory assessment, brain MRI, N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) PET, and 18F-florbetaben PET within 6 months. The patients were divided into Aβ-negative (DLB-Aβ-, n = 20) and Aβ-positive (DLB-Aβ+, n = 31) groups according to the brain amyloid plaque load score. We performed comparative analyses of dopamine transporter (DAT) activity, neuropsychological profile, and neuropsychiatric symptoms between the 2 groups. Compared to the DLB-Aβ- group, the DLB-Aβ+ group had a younger age at diagnosis (p = 0.017), poorer performance in attention (p = 0.028) and visuospatial (p = 0.006) functions, and higher proportion of anxiety (p = 0.006) and total neuropsychiatric burden (p = 0.013). Those in the DLB-Aβ+ group also had lower DAT activity in the anterior putamen (p = 0.015) and ventral striatum (p = 0.006) regardless of age, sex, and years of education. In addition, lower DAT activity in the ventral striatum was significantly associated with anxiety and total neuropsychiatric burden in DLB. This study demonstrated that Aβ deposition in DLB is associated with diagnosis at a younger age, higher cognitive and neuropsychiatric burden, and decreased DAT activity, suggesting that evaluation of clinical features and DAT activity can predict the presence of Aβ in DLB.

Sex-dependent association of urate on the patterns of striatal dopamine depletion in Parkinson's disease.

The aim was to investigate the relationship between the serum urate (UA) levels and patterns of striatal dopamine depletion in patients with de novo Parkinson's disease (PD). In all, 167 de novo PD patients who underwent 18 F-fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane positron emission tomography scans were enrolled. After quantifying dopamine transporter (DAT) availability in each striatal subregion, sex-dependent patterns of striatal dopamine depletion were analysed by measuring (i) dopamine depletion in the other striatal subregions and posterior putamen (intersubregional ratio, ISR) and (ii) the interhemispheric asymmetry of dopamine depletion in the posterior putamen (asymmetric ratio, AR). The interaction analysis revealed a significant interaction effect of sex and serum UA levels on the ISR but not on the AR. The ISR was negatively correlated with the serum UA levels in all patients with PD (r=-0.156, P=0.045), and this association was more prominent in male PD patients (r=-0.422, P<0.001). However, no significant association between the AR and serum UA levels was found in any of the patients. In addition, serum UA levels were significantly associated with DAT availability in the posterior putamen on both the more affected side (r=0.312, P=0.005) and the less affected side (r=0.312, P=0.005) only in male PD patients. The present study demonstrated the potentially close sex-specific relationship between the serum UA levels and the anterior-posterior gradient of DAT patterns, suggesting a sex-specific protective effect of UA on nigrostriatal dopaminergic neurons in de novo PD.

White matter hyperintensities and risk of levodopa-induced dyskinesia in Parkinson's disease.

ObjectiveTo investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa‐induced dyskinesia (LID) in Parkinson’s disease (PD).MethodsAccording to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug‐naïve early stage PD (follow‐up >3 years) were divided into two groups of PD with minimal WMHs (PD‐WMH–; n = 227) and moderate‐to‐severe WMHs (PD‐WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD‐WMH + group compared with the PD‐WMH– group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID.ResultsPatients in the PD‐WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD‐WMH– group. Patients in the PD‐WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P < 0.001) than those in the PD‐WMH– group after adjustment for other confounding factors. A greater WMH burden was associated with earlier occurrence of LID (hazard ratio, 1.04; P = 0.001), although the effects of WMHs on LID development did not exhibit region‐specific patterns.InterpretationThe present study demonstrates that the burden of WMHs is associated with occurrence of LID in patients with PD, suggesting comorbid WMHs as a risk factor for LID.

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Striatal dopamine deficits play a key role in the pathogenesis of Parkinson's disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

Depressive symptoms precede cognitive impairment in de novo Parkinson's disease patients: Analysis of the PPMI cohort.

Nonmotor symptoms, including depression, anxiety, apathy, and cognitive dysfunction, are common in Parkinson's disease (PD). Although a link between mood symptoms and cognitive impairment in PD has been theorized vis-à-vis striatal dopamine depletion, studies have been inconsistent regarding the relationship between mood symptoms and cognitive function. Inconsistencies may reflect the cross-sectional nature of previous studies. The current study examined the bidirectional longitudinal relationship between mood and cognition. Data were obtained from 310 individuals newly diagnosed with PD, who were followed up to 4 years (baseline, 1st, 2nd, 3rd, and 4th annual follow-ups). Apathy, anxiety, depressive symptoms, motor severity, and neurocognitive functioning were assessed at each annual assessment. The longitudinal relationship between apathy, anxiety, depressive symptoms, and cognition was analyzed with multilevel models. Over the 4-year period, more severe depressive symptoms were related to worse performance on tasks of processing speed, verbal learning, and verbal delayed recall. Additionally, there was a significant Depression × Time interaction, suggesting that individuals with more severe depressive symptoms experience more rapid declines in global cognitive functioning and verbal learning. Apathy and anxiety were not significantly related to performance in any cognitive test. Lagged models revealed that changes in depression precede declines in working memory, verbal learning, delayed verbal recall, and global cognition. Findings suggest depressive symptoms may be a harbinger for future cognitive decline among individuals with PD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Characteristic response of striatal astrocytes to dopamine depletion.

Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function, and also regulate pathological processes in brain diseases and injury. However, the role of astrocytes in the dopamine-depleted striatum remains unclear. A rat model of Parkinson's disease was therefore established by injecting 10 μL 6-hydroxydopamine (2.5 μg/μL) into the right medial forebrain bundle. Immunohistochemical staining was used to detect the immunoreactivity of glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), and signal transducer and activator of transcription 3 (STAT3) in the striatum, and to investigate the co-expression of GFAP with S100B and STAT3. Western blot assay was used to measure the protein expression of GFAP, S100B, and STAT3 in the striatum. Results demonstrated that striatal GFAP-immunoreactive cells had an astrocytic appearance under normal conditions, but that dopamine depletion induced a reactive phenotype with obvious morphological changes. The normal striatum also contained S100B and STAT3 expression. S100B-immunoreactive cells were uniform in the striatum, with round bodies and sparse, thin processes. STAT3-immunoreactive cells presented round cell bodies with sparse processes, or were darkly stained with a large cell body. Dopamine deprivation induced by 6-hydroxydopamine significantly enhanced the immunohistochemical positive reaction of S100B and STAT3. Normal striatal astrocytes expressed both S100B and STAT3. Striatal dopamine deprivation increased the number of GFAP/S100B and GFAP/STAT3 double-labeled cells, and increased the protein levels of GFAP, S100B, and STAT3. The present results suggest that morphological changes in astrocytes and changes in expression levels of astrocyte-related proteins are involved in the pathological process of striatal dopamine depletion. The study was approved by Animal Care and Use Committee of Sun Yat-sen University, China (Zhongshan Medical Ethics 2014 No. 23) on September 22, 2014.

Levodopa Modulates Functional Connectivity in the Upper Beta Band Between Subthalamic Nucleus and Muscle Activity in Tonic and Phasic Motor Activity Patterns in Parkinson's Disease.

Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson’s disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons.Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI).Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50–150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300–500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF.Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus’ functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.

Heterogeneous Patterns of Striatal Dopamine Loss in Patients with Young- versus Old-Onset Parkinson's Disease: Impact on Clinical Features.

ObjectiveAmple evidence has suggested that age at onset of Parkinson’s disease (PD) is associated with heterogeneous clinical features in individuals. We hypothesized that this may be attributed to different patterns of nigrostriatal dopamine loss.MethodsA total of 205 consecutive patients with de novo PD who underwent 18F-FP-CIT PET scans (mean follow-up duration, 6.31 years) were divided into three tertile groups according to their age at onset of parkinsonian motor symptoms. Striatal dopamine transporter (DAT) availability was compared between the old- (n = 73) and young-onset (n = 66) groups. In addition, the risk of developing freezing of gait (FOG) and longitudinal requirements for dopaminergic medications were examined.ResultsThe old-onset PD group (mean age at onset, 72.66 years) exhibited more severe parkinsonian motor signs than the young-onset group (52.58 years), despite comparable DAT availability in the posterior putamen; moreover, the old-onset group exhibited more severely decreased DAT availability in the caudate than the young-onset group. A Cox regression model revealed that the old-onset PD group had a higher risk for developing FOG than the young-onset group [hazard ratio 2.523, 95% confidence interval (1.239–5.140)]. The old-onset group required higher doses of dopaminergic medications for symptom control than the young-onset group over time.ConclusionThe present study demonstrated that the old-onset PD group exhibited more severe dopamine loss in the caudate and were more likely to develop gait freezing, suggesting that age at onset may be one of the major determinants of the pattern of striatal dopamine depletion and progression of gait disturbance in PD.

Dysfunction of serotonergic neurons in Parkinson's disease and dyskinesia.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra, the depletion of striatal dopamine and the presence of Lewy aggregates containing alpha-synuclein. Clinically, there are motor impairments involving cardinal movement symptoms, bradykinesia, resting tremor, muscle rigidity, and postural abnormalities, along with non-motor symptoms such as sleep, behavior and mood disorders. The current treatment for PD focuses on restoring dopaminergic neurotransmission by l-3,4-dihydroxyphenylalanine (levodopa), which loses therapeutic efficacy and induces disabling abnormal involuntary movements known as levodopa-induced dyskinesia (LID) after several years. Evidence indicates that the pathophysiology of both PD and LID disorders is also associated with the dysfunctional activity of the serotonergic (5-HT) neurons that may be responsible for motor and non-motor disturbances. The main population of 5-HT neurons is located in the dorsal raphe nuclei (DRN), which provides extensive innervation to almost the entire neuroaxis and controls multiple functions in the brain. The degeneration of DRN 5-HT neurons occurs in early PD. These neurons can also take exogenous levodopa to transform it into dopamine, which may disturb neuron activity. This review will provide an overview of the underlying mechanisms responsible for 5-HT dysfunction and its clinical relevance in PD and dyskinesia.

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease.

Parkinson’s disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to striatal dopamine depletion. A partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion causes 40–60% dopamine depletion in the lesioned rat striatum, modeling the early stage of PD. In this study, we explored the connectivity between the brain regions in partially 6-OHDA lesioned male Wistar rats under urethane anesthesia using functional magnetic resonance imaging (fMRI) at 5 weeks after the 6-OHDA infusion. Under urethane anesthesia, the brain fluctuates between the two states, resembling rapid eye movement (REM) and non-REM sleep states. We observed clear urethane-induced sleep-like states in 8/19 lesioned animals and 8/18 control animals. 6-OHDA lesioned animals exhibited significantly lower functional connectivity between the brain regions. However, we observed these differences only during the REM-like sleep state, suggesting the involvement of the nigrostriatal dopaminergic pathway in REM sleep regulation. Corticocortical and corticostriatal connections were decreased in both hemispheres, reflecting the global effect of the lesion. Overall, this study describes a promising model to study PD-related sleep disorders in rats using fMRI.

Mechanistic comparison between MPTP and rotenone neurotoxicity in mice

Animal models for Parkinson’s disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. These results suggest that MPTP-induced dopaminergic neurotoxicity is more acute and specific in comparison to rotenone toxicity, and compensatory brain-derived neurotrophic factor (BDNF) induction and AMPK activation in the rotenone-treated brain might suppress the neuronal injury.

The monoamine oxidase inhibition properties of C6-mono- and N3/C6-disubstituted derivatives of 4(3H)-quinazolinone

Parkinson’s disease is characterised by the death of the nigrostriatal neurons and depletion of striatal dopamine. The standard symptomatic therapy consists of dopamine replacement with l-dopa, the metabolic precursor of dopamine, which represents the most effective treatment. Since monoamine oxidase (MAO) B is a key dopamine metabolising enzyme in the brain, MAO-B inhibitors are often used as adjuvants to l-dopa. In addition to the symptomatic benefits offered by MAO-B inhibitors, these drugs may also possess neuroprotective properties and possibly delay the progression of Parkinson’s disease. Based on the therapeutic use of MAO-B inhibitors, the present study evaluates a series of mono- and disubstituted derivatives of 4(3H)-quinazolinone as potential inhibitors of recombinant human MAO-A and MAO-B. Twelve C6-monosubstituted and nine N3/C6-disubstituted 4(3H)-quinazolinone derivatives were synthesised, which led to the discovery of novel quinazolinone derivatives with micromolar and submicromolar activities as inhibitors of MAO-B. The most potent mono- and disubstituted derivatives exhibited IC50 values of 6.35 μM (7f) and 0.685 μM (8b), respectively. This study identifies suitable substitution patterns for the design of 4(3H)-quinazolinone derivatives as MAO-B inhibitors.

The Pattern of Striatal Dopamine Depletion as a Prognostic Marker in De Novo Parkinson Disease

To investigate whether the patterns of striatal dopamine depletion could provide prognostic information on the clinical profiles of early-stage Parkinson disease (PD). Approximately 634 patients with drug-naive PD who underwent F-FP-CIT PET scans were followed up for at least 2 years. After quantifying dopamine transporter (DAT) availability in each striatal subregion, the patterns of striatal dopamine depletion of each patient were assessed based on (1) the degree of dopamine loss in the other striatal subregions compared to the posterior putamen (inter-subregional ratio [ISR]) and (2) the interhemispheric asymmetry of dopamine loss in the posterior putamen (asymmetry index [AI]). According to their patterns, we assessed the longitudinal changes in L-dopa-equivalent doses and L-dopa-induced dyskinesia (LID)-free times using the linear mixed model and Cox regression model, respectively. There was no significant correlation between the ISR and AI values (Pearson correlation coefficient, 0.150). The linear mixed model showed that higher AI values were associated with slower longitudinal increases in L-dopa-equivalent dose across time (P = 0.003), whereas ISR values were not (P = 0.154). The Cox regression model demonstrated that higher ISR values were associated with early development of LID (hazard ratio, 1.693; P = 0.010), whereas AI values were not (P = 0.269). The present study demonstrated that the pattern of anterior-to-posterior gradient and right-to-left asymmetry of striatal DAT availability predicted the development of LID and increasing doses of dopaminergic medications.