EARLY ONSET PARKINSON’S DISEASE (EOPD) PROGRESSION AS MONITORED BY HYPERECHOGENICITY OF THE SUBSTANTIA NIGRA (SN)S. RAVI1, K. VENKITESWARAN1, V. SHIVKUMAR1, N. HARID1, T. GILMOUR1, C. LIEU1, R. SAADI1, D. DANG1, J.L. WANG2, Q. YANG2, T. SUBRAMANIAN1

1Neurology and Neural and Behavioral Sciences, 2Radiology, Penn State Milton S. Hershey College of Medicine, Hershey, PA.

We test the hypothesis that SN hyperechogenicity can be used as a biomarker for disease progression from stage I (unilateral parkinsonsim) to stage II (bilateral parkinsonism) in EOPD patients.

Objective

Early Onset Parkinson’s Disease (EOPD) is characterized by disease onset at ages >40 and <60 years. These patients have a high risk for treatment related complications and need close monitoring for disease progression. Substantia nigra (SN) hyperechogenicity measured by Transcranial Sonography (TCS) is an established biomarker to differentiate PD from other forms of parkinsonism. Many studies have shown that the SN hyperechogenicity remains greater >0.2 cm2 in area once this criteria is attained. However, the value of SN hyperechogenicity as a disease progression marker in stage I disease EOPD patients has not been thoroughly explored.

Methods A total of 27 EOPD patients who met UK Brain Bank criteria for PD, did not

have genetic forms of PD and were in stage I disease, as determined by MDS-UPDRS and H&Y staging by an experienced movement disorder specialist (TS), were offered this prospective single blind study. All consented patients were examined in the “off” state. Most patients were not on any medications (N=15), a few that were on meds (N=8) were evaluated after overnight medication withdrawal of all anti-PD meds. Of the 27 patients who consented, 4 patients had poor acoustic window, 2 patients dropped out, and 21 patients completed the study.

TCS was performed and evaluated by a blinded rater using a Siemens Acuson Sequoia Ultrasound system (2.5 MHz transducer). Planimetric measurements of SN hyperechogenicity > 0.2 cm2 was classified as significant on each side. Methods described by Dr. D. Berg, et. al., were utilized for the planimetric measurements and to ensure quality several random deidentified image captures were evaluated by Dr. Berg who provided training to KV. Planimetric measurements were confirmed in these random checks to ensure reliability. A full neurological exam which included MDS-UPDRS was performed at every visit following the TCS.

Patients were evaluated for the baseline measures at visit 1 (V1). Subsequently, they were evaluated at visits 2 (V2), 3 (V3), and 4 (V4), approximately 1, 1.5, and 2 years after V1,respectively. At each visit, the TCS was performed by the blinded investigator without any knowledge of the patient’s clinical condition and while they were optimally medicated several hours after the “practically defined “off” evaluation was completed. To ensure blinding, the subjects limbs were covered and conversations between the sonographer and the subject was kept to a minimum. All data was collected and stored without any personal identifiers. To date, we have completed 80% of visits in all subjects. The clinical assessor (TS) was blinded to all TCS data at every visit. Data for V1 and V2 is complete, with a few remaining V3 visits. V4 visits have been completed only for a few subjects.

Background

Conclusions

As noted earlier, the 2 assessments were done blinded such that the sonographer and the clinical assessor had no knowledge of each others findings for each patient at any visits.

In EOPD patients, who do not have any genetic forms of PD, we show that SN hyperechogenicity is a progressive phenomenon that transitions from <0.2cm2 value to >0.2cm2 value over variable lengths of time. This is the first demonstration of SN hyperechogenicity serving as a disease progression marker in any PD population.

TCS is an inexpensive, easy to use, repeatable, and safe biomarker for EOPD patients in stage I disease and could be a valuable tool to study disease modifying agents for EOPD.

Representative TCS images obtained through the right (R) and left (L) temporal acoustic bone windows showing large hyperechogenecity (encircled) on right side (contralateral) in an early onset PD patient with left hemiparkinsonism at V1 visit. Note that the ipsilateral nigra has a much smaller hyperechogenicity that did not meet the criteria of >0.2 cm2.

S. Ravi has nothing to disclose. Dr. Venkiteswaran has nothing to disclose. Dr. Shivkumar has nothing to disclose. Dr. Gilmour has nothing to disclose. Dr. Harid has nothing to disclose. Dr. Saadi has nothing to disclose. Dr. Subramanian has received personal compensation for activities with Teva Neuroscience, USMedWorld, and UCB Pharma as a speaker board member. Dr. Subramanian has received research support from Ipsen, and Allergan Inc. This research was supported in part by Charles Dana Foundation, Pennsylvania Tobacco Settlement Biomedical Research Fund, and the Penn State University Brain Research Funds. Authors acknowledge the generous help od Dr. D. Berg from Tubingen

V1 V2 V30.0000.1000.2000.3000.400

Average SN Hyperechogenicity

Contralateral_x000d_Avg.Ipsilateral _x000d_Avg.

Visit

SN e

chog

nici

ty

(cm

2)

Subject

2/Left

Subject

3/Left

Subject

4/Left

Subject

5/Left

Subject

6/Right

Subject

8/Right

Subject

9/Left

Subject

10/Right

Subject

13/Left

Subject

14/Right

Subject

15/Right

Subject

17/Right

Subject

18/Right

Subject

20/Left

Subject

21/Left

Subject

23/Left

Subject

24/Right

Subject

25/Right

Subject

26/Right

Subject

29/Right

Subject

33/Right

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5 Progression of Hyperechogenicity in the Less Affected Hemisphere

Visit 1Visit 2Visit 3

Subjects

Ipsi

late

ral H

yper

echo

geni

city

(cm

^2)

1 2 3 402468

1012141618

Average Overall UPDRS Score for Motor Examination

VisitUPD

RS S

core

0 350-450 451-550 551-650 651-75002468

1012141618202224

Progression of EOPD Patients from Stage I to Stage II PD A Kaplan-Meier Curve

As Determined by Ipsilateral TCS

As Determined by Affected Side MDS-UPDRS

Days Since Visit 1Num

ber o

f Sub

ject

s Stil

l in

stag

e I There is a clear mismatch between changes seen on TCS and the

clinician’s ability to detect parkinsonism in the less affected side during clinical evaluation despite careful and detailed examination and rigorous application of MDS-UPDRS and a multitude of bedside maneuvers designed to unmask clinical parkinsonism. This may be related to incomplete washout of anti-PD medications after overnight withdrawal or could be plastic changes induced by anti-PD treatments as noted in other studies (e.g., ELLDOPA study). Surprisingly, even in unmedicated patients, clinical detection of bilateral parkinsonism was not as quick as the development of SN hyperechogenicity.

TCS may be of value in clinical decision making for EOPD patients who seek early surgical intervention. Presence of bilateral SN hyperechogenicity in a patient previously shown to have only unilateral hyperechogenicity, may be a better candidate for such intervention.

In all patients in clinical Stage I disease, hyperechogenicity that met > 0.2 cm2 area by planimetry was only found on the contralateral SN (N=21). At V2(350-479 days post enrollment), 14 of these patients (66.66%) went onto develop >0.2 cm2 area of hyperechogenicity in the ipsilateral SN that previously did not meet this criteria. The other 7 patients progressed to meet the 0.2cm2 V3 (177-280 days post V1). V4 data collection is ongoing.

Side specific UPDRS on the unaffected side (resting tremor, alternate supination, opening and closing fist, finger taps, foot tapping and UE and LE rigidity) was zero in all enrolled subjects at V1. As expected, overall mUPDRS scores for all 21 patients gradually increased over time. However, the transition of Stage I to Stage II disease as predicted by SN hyperechogenicity did not match up with careful mUPDRS examinations at V2 or beyond in most cases. At V2, 2 patients clinically progressed from stage I to stage II. By V3, an additional 2 patients progressed to stage II.

Results