Dyskinesia

타케시:

• Takeshi introduced the proposed mechanism of L-dopa induced dyskinesia: in advance stage DaN axon damage causes the reduced uptake of excessive dopamine, which links to the fluctuation of dopamine level. Questions exist on can we find pts at the early stage rather than advanced stage (DaT scan may be the tool to find the pts as it can detect axonal damage)? nature history of the pts from early stage to advance stage, movement scales, time frame? (Amount of levodopa dosage requirement will be helpful to see that change)

Mov Disord. 1998; 13(6): 885-894
Prog Neurobiol. 2015;132:96-168.
J Mov Disord. 2019;12:161-165

Clinical presentation of Dyskinesia in PD

{Schrag, 1998 #1701} not yet full text	1998	25- 40% after 4-6 years of levodopa therapy After a disease duration of 10 years or less, only 5% of patients were experiencing falls and 30% freezing, but all patients had developed L-dopa-related fluctuations and dyskinesias.
{Bastide, 2015 #1703}	2015	up to 80% of patients having LID within 5 years of treatment Eighty to ninety per cent of PD patients suffer from LID after 10 years of DA replacement therapy
{Martini, 2019 #1704}	2019
type		peak-dose dyskinesia (involuntary movements that coincide with the peak-action of levodopa and thus period of best anti-parkinsonian action), : most common (70%), Peak-dose dyskinesia is seen at high plasma drug level (eg. beginning 80–90 min after levodopa) OFF period dystonia (=wearing-off dyskinesia): 30% , seen when the serum level of levodopa is least, They are commonly seen in early morning diphasic dyskinesia (involuntary movements that emerge just before the DA replacement therapy turns the patient ON and that reappear at the end of the therapeutic benefit) : least common (14%), seen when serum level of levodopa is going up or down coinciding with two peaks of abnormal movements, one present at the onset of drug effect and another present at the end of drug effect.[11]

MOA of Dyskinesia

Normal	In DA nerve terminas: there are autoregulatory mechanism i) DAT ii) D2 autoreceptors, so they can buffer when DA are in excess In Serotonergic neuron: s are a another source of dopamine release in striatal synapses (AADC convert L-DOPA into dopamine), but there is no autoregulatory/buffer process
In PD	DA n terminal 은 없어 buffer 없고, 더군다나 serotonergic n 늘이 보상석으로 더 DA release 하고 있는 상태인데, When L-DOPA is administered to PD patients, synaptic dopamine levels oscillate as serotonergic neurons metabolize L-DOPA to dopamine but fail to autoregulate in response to elevated dopamine levels → ↑ LID{Martini, 2019 #1704}
PD?	levodopa therapy may sensitize the nigrostriatal system but (it alone) does not induce dyskinesia in the setting of preserved dopaminergic circuit [3]. a lack of presynaptic dopamine storage capacity, increased extracellular levodopa and pulsatile stimulation of dopamine receptors [4,5,6]. [Hattori] Dyskinesia in PRKN-PD is dominant in the lower limb, so-called dancing-feet dyskinesia. His team is trying to elucidate its mechanism by electrophysiological approach by using Prkn KO rat. Flash result suggests D1 signal is associated with dyskinesia. Prog Neurobiol. 2015;132:96-168.

Outcome Measures Dyskinesia

UDysRS		https://www.movementdisorders.org/MDS/MDS-Rating-Scales/Unified-Dyskinesia-Rating-Scale.htm
biochemical device which is under development (force plate technology)		https://clinicaltrials.gov/ct2/show/NCT00467597

Animal models of Dyskinesia

{Bastide, 2015 #1703}	Comprehensive review
In 6OHDA Rat	{Peng, 2019 #1706} In 6OHDA Rat: repeated administration of DA agonists (2-3w) → (response sensitization, ie a gradual increase in rotation or stereotype response → AIMS ; rotational locomotion, axial torsion, limb movements, and orolingual stereotypies, 평가 protocols: TABLE 1 | Current options used to induce and evaluate LID in unilateral 6-OHDA-lesioned rat models. Henry's protocol (Rotational sensitization) Cenci's protocol (AIMs rating scale) Steece-Collier's protocol MODELING PROCEDURES Lesion sites MFB MFB/striatum MFB Screening Spontaneous rotation Amphetamine-induced rotation Amphetamine-induced rotation LID inducing (drugs and dosage) Methyl L-DOPA 6.5 mg/kg/day Benserazide 25 mg/kg/day Methyl L-DOPA 6 mg/kg/day Benserazide 25 mg/kg/day Methyl L-DOPA 50 mg/kg/day Carbidopa 5 mg/kg/day LID ASSESSMENT Rating targets Rotational turns The presenting time of locomotive, axial, limb, and orolingual AIMs The presenting time and the intensity of dyskinetic movements in different parts of the body Patterns of movements scored Contralateral rotation Rotational locomotion, axial torsion, limb movements, and orolingual stereotypies Clasping of forepaw, twisting of axial musculature, torsional movements beginning in the neck region, and twisting of limbs. Monitoring styles A consecutive 120-min monitoring A disconnected 180-min monitoring with 9 turns of rating, and each rating session lasts 1 min A single-point 2-min rating 30 min after the administration of L-DOPA Rating styles Automated rotometry Human observation Human observation Pros Time-effective an objective measuring with high inter-rater consistency Good validation in pharmacological and biomarker's tests The precise recording of dyskinetic movements Cons Not supported by pharmacological validation The predictive value of rotational sensitization is controversial Relatively poor inter-rater reliability Lack of pharmacological validation Single-point sampling at the peak time cannot cover the whole time-action curve of an agent
6OHDA mouse	Cenci's group and a similar AIM rating scale for mice was built up in 2044. Compared with the rat, mouse AIMs are more rapid, have a more simplified repertoire, and present more prominent rotational locomotion with less dystonic features, i.e., axial AIMs (44, 45).
MPTP NHP
GENEtic mice

Pipeline of Dyskinesia

drug	mechanism	Clinical	Patients	Design	results
amantadine ER (Gocovri), previously known as ADS-5102	an uncompetitive antagonist at the N-methyl-D-aspartate receptor known to have benefit to relieve the symptoms of dyskinesia and currently the only available molecule for management of dyskinesia. The rationale of extended release is to provide a therapeutic level of amantadine in the blood for a longer period of time, in this case enabling once a day dosing. Two capsules are administered at bedtime to give a slow increase during sleep, peak levels in the morning and a sustained concentration during the day.	P3. EASE LID P3. EASE LID3	at least 2 on question 4.2 of the UPDRS); at least two episodes of half an hour of troublesome dyskinesia when ON; and at least 3 administrations of levodopa per day. Exclusion criteria included a history of dyskinesia that was exclusively diphasic, OFF state, myoclonic, dystonic, or akathetic without peak-dose dyskinesia	TABLE 1 – Summary of EASE LID and EASE LID 3 trial plans EASE LID EASE LID 3 Title ADS-5102 for the Treatment of Levodopa-Induced Dyskinesia (EASE LID Study) Efficacy and Safety Study of ADS-5102 in PD Participants with Levodopa-Induced Dyskinesia (EASE LID 3) Status Complete Complete clinicaltrials.gov ID NCT02136914 NCT02274766 Enrolment 121 75 Study design Randomized, double blind, placebo-controlled, multi-centre (44 sites). Randomized, double blind, placebo-controlled, multi-centre (32 sites). Primary outcome measures Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12. Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12. Key Secondary outcome measures Change from baseline in the UDysRS total score at 24 Weeks. ON time without troublesome dyskinesia (ON time without dyskinesia plus ON time with non-troublesome dyskinesia) at 12 and 24 weeks. OFF time (amount of time the PD medication is not controlling motor symptoms) at 12 and 24 weeks. Change from baseline at 12 and 24 weeks in the UPDRS score. ON time with troublesome dyskinesia. Change in the standardized PD home diary (ON time without dyskinesia, ON time with troublesome dyskinesia, OFF time) at 12 weeks. Restuls] TABLE 2 – Summary of EASE-LID and EASE-LID 3 results EASE LID; Gocovri vs placebo* EASE LID 3; Gocovri vs placebo* Change in UDysRS at week 12 -7.90 (2.30) -14.40 (3.0) Change in UDysRS at week 24 -9.30 (2.70) ND Change in ON time without troublesome dyskinesia at week 12 (hours) 2.74 (0.61) 1.90 (0.78) Change in ON time without troublesome dyskinesia at week 24 (hours) 2.22 (0.63) ND Change in ON time with troublesome dyskinesia at week 12 (hours) -1.54 (0.51) -1.13 (0.65) Change in ON time with troublesome dyskinesia at week 24 (hours) -1.45 (0.53) ND Change in OFF time at week 12 (hours) -0.9 (0.37) -1.10 (0.46) Change in OFF time at week 24 (hours) -0.81 (0.39) ND CGIC score (reported improvement) at week 12 51/63 vs 21/58 ND CGIC score (reported improvement) at week 24 43/63 vs 27/58 ND ND = not determined * Standard error values in parentheses (McFarthing, 2019 #1708)
dipraglurant	mGluR5 negative	Preclinical 2b/3	ND	Js: there seems no preclinical studies, (amantadine is an old drug) 20220627: Addex Therapeutics announced that it has terminated the Phase 2b/3 study evaluating dipraglurant (an mGluR5 negative

Uncertain Spans

location	transcription	uncertainty
Animal models of Dyskinesia / 6OHDA mouse / first bullet	built up in 2044	the year reads as 2044 on the page; this matches the OCR but is almost certainly a typo for 2014 in the source. Preserved verbatim per direct-transcription policy.
Animal models of Dyskinesia / In 6OHDA Rat / 평가 protocols heading	Korean word 평가 (evaluation) precedes the colon; visible spelling is 평가.	reads cleanly; flagged because the surrounding sentence mixes English and Korean fragments.
Pipeline / amantadine row / Restuls]	the heading above TABLE 2 reads Restuls] (sic) on the page, with the closing bracket and an apparent typo of Results. Preserved verbatim.	source typo.