Young-onset Parkinson's Disease Research Articles

Emotion-Specific Affective Theory of Mind Impairment in Parkinson\u2019s Disease

The neuropathology of Parkinson’s disease (PD) involves the frontal-subcortical circuit, an area responsible for processing affective theory of mind (ToM). Patients with PD are expected to experience deficits in the affective ToM. This study aims to investigate whether the ability to infer emotion in others is affected in either young-onset Parkinson’s disease (YOPD) or middle-onset PD (MOPD) patients and to test whether the impairments in affective ToM are associated with the motor symptoms. The affective ToM, global mental abilities, and clinical symptoms were assessed in a total of 107 MOPD, 30 YOPD, and 30 normal controls (NCs). The MOPD patients exhibited deficits in affective ToM to the negative and neutral valences, when compared to the participants in the NCs and YOPD group. By conducting gender-stratified analysis, the deficits in affective ToM was only found in female participants. After adjusting for demographic variables, the multiple linear regression model revealed that affective ToM predicted motor symptoms, especially in female MOPD patients. The present study may aid in the development of medical care programs by advocating for a more comprehensive therapeutic plan that includes continuous disease progression monitoring and social skills training for female MOPD patients or their caregivers.

Non-motor Symptoms in Patients with Parkinson's Disease: A Cross-sectional Survey.

BackgroundIn multiple studies around the globe, non-motor symptoms (NMS) have been identified as a source of immense disability in patients with Parkinson’s disease (PD). However, there is a scarcity of data from Asia. This is the first study of the Pakistani population to assess the impact of NMS in PD on patients.ObjectivesTo determine the frequency of NMS of PD in the Pakistani population and compare it with existing data.MethodsIn this cross-sectional survey, patient demographics were retrospectively collected from a tertiary care hospital neurology database. This study population comprised 97 patients at different stages of PD who presented to the neurology outpatient department. Disease severity was assessed using the Hoehn and Yahr scale. The NMS questionnaire was employed to identify the presence of NMS. Medical records were reviewed for demographic data and recent treatment history.ResultsThe mean age was 67 years (76.3% of patients had adult onset PD and 23.7% had young onset PD). The NMS with the highest frequencies were nocturia (77.3%), urinary urgency (61.9%), constipation (59.8%), dementia (58.8%), insomnia (52.6%), and orthostatic hypotension (52.6%). The earliest manifestations of NMS were nocturia, forgetfulness, low mood, and orthostatic hypotension. Sleep abnormalities, falling episodes, and hallucinations are prevalent among patients with advanced disease.ConclusionThere is a higher frequency of NMS present in the Pakistani population as compared to existing data in other populations.

Identification of mutations in the PARK2 gene in Serbian patients with Parkinson's disease

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations.Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method.We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers.In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene.

Human tyrosine hydroxylase in Parkinson's disease and in related disorders.

Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline). PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD. However, this decrease in TH is thought to be secondary due to neurodegeneration of DA neurons caused by some as yet unidentified genetic and environmental factors, and thus, TH deficiency may not play a direct role in PD. This manuscript provides an overview of the role of human TH in the pathophysiology of PD, covering the following aspects: (1) structures of the gene and protein of human TH in relation to PD; (2) similarity and dissimilarity between the phenotypes of aging-related sPD and those of young-onset fPD or DOPA-responsive dystonia due to DA deficiency in the striatum with decreased TH activity caused by mutations in either the TH gene or GTP cyclohydrolase I (GCH1) gene; and (3) genetic variants of the TH gene (polymorphisms, rare variants, and mutations) in PD, as discovered recently by advanced genome analysis.

Young-onset multiple system atrophy: Clinical and pathological features.

The onset of multiple system atrophy (MSA) before age 40 years is referred to as "young-onset MSA." We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young-onset Parkinson's disease and late-onset MSA. We reviewed the available clinical and pathological features in cases that fulfilled consensus criteria for diagnosis of probable MSA or had autopsy confirmed MSA with an onset before age 40 years and compared the clinical features with 16 autopsy confirmed cases with young-onset Parkinson's disease and a large published series of late-onset MSA from the European MSA Study Group. We identified 22 patients with young-onset MSA, 8 of whom had available pathology. The mean age of onset was 36.7 years (standard deviation 2.3). Levodopa-induced dyskinesia was more common, whereas myoclonus and pyramidal signs were less common in young-onset Parkinson's disease when compared with young-onset MSA. Dystonia, levodopa responsiveness, levodopa-induced dyskinesia, and pyramidal signs were more common (P < .05) when compared with the data in late-onset MSA. On postmortem analysis, the minimal-change pathological variant was more common in young-onset MSA (n = 2) than late-onset MSA (P = .045), with a mean survival of 11.1 ± 3.2 years (range 5.5-14.6) in pathologically confirmed cases of young-onset MSA. This study has identified useful differences that may improve diagnostic accuracy, help us understand the pathological basis, and assist clinicians with the early diagnosis of young-onset MSA. © 2018 International Parkinson and Movement Disorder Society.

Characterization of Dopaminergic System in the Striatum of Young Adult Park2\u2212/\u2212 Knockout Rats

Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our findings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.

Characteristic Motor and Nonmotor Symptoms Related to Quality of Life in Drug-Naïve Patients with Late-Onset Parkinson Disease

Background/Aims: Unlike young-onset Parkinson disease (YOPD), characteristics of late-onset PD (LOPD) have not yet been clearly elucidated. We investigated characteristic features and symptoms related to quality of life (QoL) in LOPD patients. Methods: We recruited drug-naïve, early PD patients. The patient cohort was divided into 3 subgroups based on patient age at onset (AAO): the YOPD group (AAO <50 years), the middle-onset PD (MOPD) group, and the LOPD group (AAO ≥70 years). Using various scales for motor symptoms (MS) and non-MS (NMS) and QoL, we compared the clinical features and impact on QoL. Results: Of the 132 enrolled patients, 26 were in the YOPD group, 74 in the MOPD group, and 32 in the LOPD group. Among parkinsonian symptoms, patients in the LOPD group had a lower score on the Korean version of the Montreal Cognitive Assessment than the other groups. Logistic regression analysis showed genitourinary symptoms were related to the LOPD group. Linear regression analysis showed both MS and NMS were correlated with QoL in the MOPD group, but only NMS were correlated with QoL in the LOPD group. Particularly, anxiety and fatigue affected QoL in the LOPD group. Conclusion: LOPD patients showed different characteristic clinical features, and different symptoms were related with QoL for LOPD than YOPD and MOPD patients.

Reduced saccadic velocity and pupillary width in young onset Parkinson’s disease

BackgroundPatients with Young onset Parkinson disease patients (YODP) are individuals with motor complications identical to late onset Parkinson’s disease (PD) but onset in early age. YOPD is a specific subgroup of PD and their performance on saccadic eye movements is not well established. This study evaluated saccadic eye movements in patients with YOPD (< 40 years at onset of illness). MethodsEye movements were recorded during saccadic eye movement tasks, induced by presentation of a visual target and reflexive saccadic task was administered. ResultsYOPD patients showed reduced saccadic velocity on reflexive saccadic task (Gap task) as compared to their age matched healthy controls. Additionally, pupil width in gap period and at saccade onset was measured. Pupil width was significantly smaller in patients with YOPD as compared to control subjects. ConclusionsReduced saccadic velocity implies that Parkinson’s disease affects saccadic circuitry in patients with YOPD reflecting impaired circuitry at the brainstem level. The reduced pupillary response in gap condition is attributed to deficits in motor preparedness in patients compared to controls.

Depression and associated factors in nondemented Chinese patients with Parkinson’s disease

ObjectivesDepression is more common in Parkinson’s disease (PD) than other chronic and disabling disorders. This study aimed to estimate the prevalence and identify potential risk factors influencing depression in 519 consecutive nondemented Chinese PD patients. Patients and methodsDepression was assessed using the Hamilton Rating Scale for Depression (HAMD), PD severity was assessed using Hoehn and Yahr (H&Y) staging, motor symptoms were measured with the Unified PD Rating Scale (UPDRS) part III, and the Non-Motor Symptoms Questionnaire (NMS-Quest) was used to evaluate the global non-motor symptoms (NMS). The PD Sleep Scale (PDSS), and Mini-Mental State Examination (MMSE) were also administered. ResultsThe mean total HAMD score was 12.60±9.29, and the most prevalent depressive domain was retardation (84.4%). There were significant correlations between the total HAMD score and sex, PD-duration, UPDRS-III, H&Y stage, PD-NMS, PDSS, and MMSE. Non-motor symptoms, poor sleep quality, younger age, and cognitive dysfunction are independent predictors of depression. Among these, non-motor symptoms or sleep disturbances are the most powerful predictors of each depressive domain. We observed a significantly higher total HAMD score and domains of anxiety/somatization, mental disorder, and hopelessness in female patients. However, there was no difference in HAMD total scores and HAMD sub-items between young-onset PD and late-onset PD patients when adjusted by potential confounding factors. ConclusionsThe prevalence rate of depression among nondemented Chinese PD patients is high and similar to those reported in previous studies. The presence of depression in PD patients should be routinely assessed in clinical practice.

Non-motor symptom in young onset parkinson disease as a cause of pharmacoresistence in epilepsy: Case report

Background: Female with history of refractory depression, was reviewed after third seizure in three years, age 45. Lithium was withdrawn and lamotrigine commenced. Her MRI, EEG, SDEEG were normal.

Screening for TMEM230 mutations in young-onset Parkinson's disease

TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD.

Twenty years since the discovery of the parkin gene.

Nearly 20years have passed since we identified the causative gene for a familial Parkinson's disease, parkin (now known as PARK2), in 1998. PARK2 is the most common gene responsible for young-onset Parkinson's disease. It codes for the protein Parkin RBR E3 ubiquitin-protein ligase (PARK2), which directly links to the ubiquitin-proteasome as a ubiquitin ligase. PARK2 is involved in mitophagy, which is a type of autophagy, in collaboration with PTEN-induced putative kinase 1 (PINK1). The PINK1 gene (previously known as PARK6) is also a causative gene for young-onset Parkinson's disease. Both gene products may be involved in regulating quality control within the mitochondria. The discovery of PARK2 as a cause of young-onset Parkinson's disease has had a major impact on other neurodegenerative diseases. The involvement of protein degradation systems has been implicated as a common mechanism for neurodegenerative diseases in which inclusion body formation is observed. The discovery of the involvement of PARK2 in Parkinson's disease focused attention on the involvement of protein degradation systems in neurodegenerative diseases. In this review, we focus on the history of the discovery of PARK2, the clinical phenotypes of patients with PARK2 mutations, and its functional roles.

Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease.

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon ΔΨm reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

Longitudinal Decline of Striatal Subregional [18F]FP-CIT Uptake in Parkinson's Disease.

Dopamine transporter imaging is suggested to be a useful imaging biomarker for Parkinson's disease (PD) progression and monitoring drug effects. We investigated the longitudinal decline characteristics of striatal [18F]FP-CIT uptake in PD. We retrospectively reviewed 35 PD patients and 9 non-PD patients. All patients underwent [18F]FP-CIT PET at the initial diagnosis and follow-up. PET images were spatially normalized and analyzed with eight striatal and one occipital VOI templates. We measured the specific to non-specific binding ratio (SNBR) of the striatal subregions and calculated the absolute annual reduction (AAR) and relative annual reduction (%RAR) of the SNBRs. Total striatal SNBRs in PD patients were significantly lower than those in non-PD patients, with the most significant difference in the posterior putamen. Both AAR (0.26±0.14 vs. 0.09±0.19, p<0.05) and %RAR (6.9±3.5 vs. 1.2±2.7, p<0.001) of total striatal SNBRs were significantly greater in PD than non-PD patients. There were no significant differences in the AAR and %RAR of total striatal SNBRs between elderly and young onset PD. The AARs of the posterior putamen were higher in early PD than in advanced PD. Conversely, the %RARs were not significantly different between early and more advanced PD. The disease duration was significantly negatively correlated with the AAR but not with the %RAR of the posterior putamen. The longitudinal decline of striatal [18F]FP-CIT uptake in PD was nonlinear and significantly faster than that in non-PD, with a different rate of decline among the striatal subregions.

Understanding uncertainty in young-onset Parkinson disease.

Objectives Individuals living with young-onset Parkinson's disease compose a rare subtype of a disease typically associated with older age. Situated within a large grounded theory study exploring information behavior, this paper describes the core category of the theory, i.e. uncertainty. Methods Data were collected with 39 individuals living with young-onset Parkinson's disease who took part in in-depth interviews, focus groups and/or an online discussion board. Fourteen autobiographies written by individuals living with young-onset Parkinson's disease were also used as data sources. Results Through experiencing young-onset Parkinson's disease, participants were confronted with uncertainty along two main lines. First, they experienced uncertainty with respect to their identities as young- and middle-aged adults, deviating from the idealized age-graded life path marked out within their socio-cultural context. Second, they experienced uncertainty with respect to their functioning, as the heterogeneous nature of Parkinson's progression meant that it would not be possible to chart how their disease would change over time. This uncertainty was associated with feelings of lost control over their lives and increased grief. Discussion With a deeper appreciation for how uncertainty is experienced in the lives of those with young-onset Parkinson's disease, health professionals may be better prepared to discuss these issues with patients and provide support and resources.

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: thePR EDIGT score.

Fifty‐five years after the concept of dopamine replacement therapy was introduced, Parkinson disease (PD) remains an incurable neurological disorder. To date, no disease‐modifying therapeutic has been approved. The inability to predict PD incidence risk in healthy adults is seen as a limitation in drug development, because by the time of clinical diagnosis ≥ 60% of dopamine neurons have been lost. We have designed an incidence prediction model founded on the concept that the pathogenesis of PD is similar to that of many disorders observed in ageing humans, i.e. a complex, multifactorial disease. Our model considers five factors to determine cumulative incidence rates for PD in healthy adults: (i) DNA variants that alter susceptibility (D), e.g. carrying a LRRK2 or GBA risk allele; (ii) Exposure history to select environmental factors including xenobiotics (E); (iii) Gene–environment interactions that initiate pathological tissue responses (I), e.g. a rise in ROS levels, misprocessing of amyloidogenic proteins (foremost, α‐synuclein) and dysregulated inflammation; (iv) sex (or gender; G); and importantly, (v) time (T) encompassing ageing‐related changes, latency of illness and propagation of disease. We propose that cumulative incidence rates for PD (P R) can be calculated in healthy adults, using the formula: P R (%) = (E + D + I) × G × T. Here, we demonstrate six case scenarios leading to young‐onset parkinsonism (n = 3) and late‐onset PD (n = 3). Further development and validation of this prediction model and its scoring system promise to improve subject recruitment in future intervention trials. Such efforts will be aimed at disease prevention through targeted selection of healthy individuals with a higher prediction score for developing PD in the future and at disease modification in subjects that already manifest prodromal signs.

Impulse control disorders in patients with young-onset Parkinson’s disease: A cross-sectional study seeking associated factors

IntroductionThe aim of this cross-sectional study was to investigate the frequency and factors associated with impulse control disorder (ICD) symptoms, including personality characteristics, in Czech young-onset Parkinson’s disease (PD) patients. Subjects and methodsWe examined 49 young-onset PD patients and 38 age-matched control subjects. ICD symptoms were identified using the South Oaks Gambling Screen and modified Minnesota Impulse Disorders Interview. ResultsA higher prevalence of pathological gambling and hypersexuality was found in PD patients than in control subjects. A higher frequency of pathological gambling in our sample of young-onset PD patients was found in patients using dopamine agonists and in patients with dyskinesias lasting 5 or more years. The frequency of any ICD symptom was associated with coffee consumption, higher reported anxiety, and somatization. ICD symptoms were also related to personality characteristics in PD patients; specifically, patients who manifested any ICD symptom scored significantly higher on Self–assertive/Antisocial and Reserved/Schizoid personality styles and pathological gambling was associated with lower reported Conscientiousness. ConclusionOur results demonstrate that ICD presents a real problem in young-onset PD patients. Knowledge about the factors associated with ICD symptoms might be helpful in the proactive search for these pathological behaviours in this specific subgroup of PD patients.

Medicinal herbs Oenanthe javanica (Blume) DC., Casuarina equisetifolia L. and Sorghum bicolor (L.) Moench protect human cells from MPP+ damage via inducing FBXO7 expression

BackgroundThe F-box protein 7 (FBXO7) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD. PurposeWe screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPP+-treated cells. MethodsPromoter reporter assay in HEK-293 cells was used to examine the cis/trans elements controlling FBXO7 expression and to screen extracts of medicinal herbs enhancing FBXO7 expression. MTT assay was performed to assess cell viability of MPP+-treated HEK-293/SH-SY5Y cells. In addition, proteasome activity, mitochondrial membrane potential and FBXO7/TRAF2/GATA2 protein expression were evaluated. ResultsWe demonstrated that −202–−57 region of the FBXO7 promoter is likely to contain sequences that are bound by positive trans protein factors to activate FBXO7 expression and GATA2 is the main trans protein factor enhancing FBXO7 expression. Extracts of medicinal herbs Oenanthe javanica (Blume) DC. (Umbelliferae), Casuarina equisetifolia L. (Casuarinaceae), and Sorghum bicolor (L.) Moench (Gramineae) improved cell viability of both MPP+-treated HEK-293 and SH-SY5Y cells, rescued proteasome activity in MPP+-treated HEK-293 cells, and restored mitochondrial membrane potential in MPP+-treated SH-SY5Y cells. These protection effects of herbal extracts are acting through enhancing FBXO7 and decreasing TRAF2 expression, which is probably mediated by GATA2 induction. ConclusionCollectively, our study provides new targets, FBXO7 and its regulator GATA2, for the development of potential treatments of PD.

Reactive but not predictive locomotor adaptability is impaired in young Parkinson's disease patients

BackgroundGait and balance disorders are common in Parkinson's disease (PD) and major contributors to increased falling risk. Predictive and reactive adjustments can improve recovery performance after gait perturbations. However, these mechanisms have not been investigated in young-onset PD. ObjectiveWe aimed to investigate the effect of gait perturbations on dynamic stability control as well as predictive and reactive adaptability to repeated gait perturbations in young PD patients. MethodsFifteen healthy controls and twenty-five young patients (48±5yrs.) walked on a walkway. By means of a covered exchangeable element, the floor surface condition was altered to induce gait perturbations. The experimental protocol included a baseline on a hard surface, an unexpected trial on a soft surface and an adaptation phase with 5 soft trials to quantify the reactive adaptation. After the first and sixth soft trials, the surface was changed to hard, to examine after-effects and, thus, predictive motor control. Dynamic stability was assessed using the ‘extrapolated center of mass’ concept. ResultsPatients’ unperturbed walking was less stable than controls’ and this persisted in the perturbed trials. Both groups demonstrated after-effects directly after the first perturbation, showing similar predictive responses. However, PD patients did not improve their reactive behavior after repeated perturbations while controls showed clear locomotor adaptation. ConclusionsOur data suggest that more unstable gait patterns and a less effective reactive adaptation to perturbed walking may be a disease-related characteristic in young PD patients. These deficits were related to reduced ability to increase the base of support.

Drug-Induced Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia.

Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced dyskinesia (LID) is one of the main types of drug-induced dyskinesia, occurring in patients with Parkinson's disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into "peak-dose dyskinesia," "diphasic dyskinesia," and "wearing off" or "off-period" dyskinesia, of which peak-dose dyskinesia is the most common, followed by off-period, and then diphasic dyskinesia. Treatment strategy includes identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future.