Table A.7.

Quantitative evaluation of the KER

Upstream key event (KE 4)	Downstream key event (AO)	References	Comments
Rat models
45% loss of TH‐positive SNpc neurons in 7 month old rats, ca. 40% loss in 12 month old rats Striatal DA reduced from 90 ng/mg (control) down to 45 ng/mg TH pos. neuron number 18,000 (control) 10,000 (rotenone)	Bradykinesia, postural instability, rigidity observed in 50% of cases: 3 month old rats: after 12 days of rotenone 7 + 12 month old rats. After 6 days of rotenone Postural instability test: Distance required for the animal to regain postural stability: 3.5 cm (control) 5 cm (rotenone) Rearing test (rears/5 min): 10 (control 3 (rotenone) Loss of rearing performance evoked by rotenone was reversed by the DA agonist Apomorphine in 3 month old rats	Cannon et al. (2009)	Lewis rats + rotenone (3 mg/kg per day, i.p. daily)
Dopamine in the anterior and posterior striatum reduced by ca. 50%	Catalepsy test: decline from 35 s to 5 s Grid test: decline from 30 s to 4 s Distance travelled in 10 min: reduction from 37 m to 17 m Number of rearings: decline from 65 to 30 Inactivity time increased from 270 to 400 s Partial reversibility by L‐DOPA treatment: L‐DOPA: number of rearings increased from 16 to 30 L‐DOPA: inactivity time reduced from 450 to 360 s L‐DOPA: increase in the distance travelled from 12 to 16 m	Alam et al. (2004)	Rats + rotenone (2.5 mg/kg) daily over the course of 48 days
TH staining intensity reduced from 0.2 to 0.12	Rearing scores reduced from 80% (vehicle controls) to 20% (rotenone group) Increase in the average time to initiate a step from 5 to 11 s.	Fleming et al. (2004)	Rats + rotenone 2.5 mg/kg for 21 days i.v. or s.c.
Loss of striatal DA fibres by 54% Loss of DA neurons by 28.5%	Spontaneous locomotor activity after 1 week 100% (control) 55% (rotenone)	Höglinger et al. (2003)	Rats + rotenone (2.5 mg/kg per day for 28 days
Mouse models
Subacute model: Striatal DA dropped from 11 (control) to 2.5 ng/mg (MPTP) after 3 days 3H‐DA striatal uptake reduced from 2.9 (control) to 1.3 pmol/mg after 3 days of MPTP Total nigrostriatal TH cell count was not affected Chronic model: Striatal DA content reduced from 13 down to 0.5 ng/mL at 1 week after MPTP treatment 3H‐DA uptake in the striatum reduced from 3 to 1 pmol/mg 1 week after start of MPTP treatment TH staining in the nigrostriatal system reduced by ca. 50% 1 week after initiation of MPTP treatment	Subacute model: Rotarod performance reduced from 1,800 AUC (control) down to 1,500 AUC (MPTP) Chronic model: Rotarod performance reduced from 1,800 AUC (control) to 1,250 AUC (1 week after initiation of MPTP treatment)	Petroske et al. (2001)	Mouse + MPTP Subacute model: 25 mg/kg MPTP 1x days for 5 days Chronic model: MPTP (25 mg/kg + 250 mg/kg probenizid) in 3.5 day intervals for maximal 5 weeks
Reduction in TH staining intensity of at least 50% required for detectable influence on motor performance TH density in the nigrostriatal system correlated with the decline of rotarod performance (r2 = 0.87)	Rotarod performance reduced from 1,250 AUC to 200 AUC Time on rod at a speed of 20 rpm: 125 s in controls, 25 s in MPTP animals	Rozas et al. (1998)	Mouse + MPTP
Monkey models
Approx. 50% loss of TH positive neurons in the SNpc. DA content in the caudate nucleu reduced to < 10%; DA content of the putamen ca. 10% compared with control	Mean duration in the bradykinesia test increased from 3 s (day 0) to 19 s at day 15	Bezard et al. (2001)	Macaca + MPTP i.v. 0.2 mg/kg daily for 15 days
Human
18F‐dopa influx rate constants (Ki) Midbrain: Control: 0.008 Early PD: 0.008 Adv. PD: 0.006 Right putamen: Control: 0.017 Early PD: 0.006 Adv. PD: 0.0036 Left putamen: Control: 0.017 Early PD: 0.0096 Adv. PD: 0.005	Early PD: UPDRS: 9 ± 3 Adv. PD: UPDRS: 41 ± 15	Rakshi et al. (1999)	Human PD patients
Putamen influx (Ki/min) detected by 18F‐dopa control: 0.0123 asympt. PD: 0.0099 symptom. PD: 0.007	Symptom. PD patients: mean UPDRS: 15.1 ± 7.5 Correlation between total UPDRS and putamen Ki: r = −0.41	Morrish et al. (1995)	Human PD
Uptake of 18F‐DTBZ (VMAT2 tracer) reduced by: 20–36% (caudate) 45–80% (putamen) 31% (SN)	UPDRS total: 12.1 ± 7.1 Hoehn and Yahr: 1.0 ± 0.1	Lin et al. (2014)	Human PD
Caudate nucleus Ki/min Control: 0.011 PD group 3: 0.0067 Putamen Ki/min Control: 0.011 PD group 3: 0.0043	UPDRS: 50 ± 11.6 in PD group 3	Broussolle et al. (1999)	Human PD
Reduction in 18F‐CFT uptake in the posterior putamen (by 18%); in the anterior putamen (by 28%); in the caudate nucleus (by 51%)	Correlation between total motor score of the UPDRS and 18F‐CFT uptake: Posterior putamen: r = −0.62 Anterior putamen: r = −0.64 Caudate nucleus: r = −0.62	Rinne et al. (1999)	Human PD
123I‐CIT SPECT values in controls and PD cases with a Hoehn and Yahr rating of 2–2.5: Putamen (ipsilateral): Control: 6.13 PD: 1.84 Caudate (ipsilateral): Control: 6.93 PD: 3.66 Striatum (ipsilateral): Control: 6.28 PD: 2.33	Correlation coefficient between striatal 123I‐CIT binding and: Str. (ipsilateral) and Bradykinesia: r = −0.61 Str. (ipsilateral) and Rigidity: r = −0.46 Str. (ipsilateral) and UPDRS: r = −0.79	Tissingh et al. (1998)	Human PD
Binding ration striatum/cerebellum detected by 123I‐CIT/SPECT Control: 8.71 ± 1.54 PD: 4.49 ± 1.86	Correlation between 123I‐CIT binding to DAT and PD motor symptoms rated according to the Hoehn and Yahr scale: r = −0.75 Correlation according to the UPDRS: r = −0.49	Asenbaum et al. (1997)	Human PD
Uptake of 123I‐CIT in the putamen reduced to 54%; uptake into the caudate nucleus reduced to 65%	Correlation between CIT uptake in the putamen and Hoehn and Yahr stage: r = −0. 79	Rinne et al. (1995)	Human PD
Decline in nigrostriatal DAT assed by 123I‐CIT SPECT in PD patients	Correlation coefficients for 123I‐CIT uptake in the striatum and: UPDRS: r = −0.54 Bradykinesia: r = −0.5 Rigidity: r = −0.27 Tremor: r = −0.3 Correlation coefficients for 123I‐CIT uptake in the caudate and: UPDRS: r = −0.5 Bradykinesia: r = −0.43 Rigidity: r = −0.27 Tremor: r = −0.26 Correlation coefficients for 123I‐CIT uptake in the putamen and: UPDRS: r = −0.57 Bradykinesia: r = −0.53 Rigidity: r = −0.29 Tremor: r = −0.37	Benamer et al. (2000)	Human PD