Although motor symptoms are the characteristic symptoms of Parkinson’s disease (PD) and required for the diagnosis, cognitive impairment, especially in executive function [
Transcranial sonography (TCS) of the mesencephalon has emerged as a possible diagnostic tool for PD, because of its ability to delineate hyperechogenic zones in the substantia nigra (SN) [
The aim of this analysis was to explore the association between cognitive impairment in patients with parkinsonism and echogenic features shown by TCS. We used the dataset of a large prospective cohort study on the diagnostic accuracy of TCS in early parkinsonian patients [
This study was a cross-sectional study, nested within a prospective cohort study that aimed to test the diagnostic accuracy of TCS of the SN in patients who were referred to a neurologist by their general practitioner because of recent-onset parkinsonism of unclear origin [
We considered 283 consecutive patients with parkinsonism of unknown origin, who were referred to the neurology outpatient clinic of Maastricht University Medical Centre, Maastricht, and the Orbis Medical Centre, Sittard, Netherlands, for diagnostic work-up. Patients who did not consent or those in whom a definite diagnosis could already be made at the first visit (
Eventually, we were able to obtain interpretable TCS images of the SN in 126 patients. Interpretable images of the RN and third ventricle were available for 81 and 59, respectively, of the 126 since these structures were visualized only in one center or later on in the study.
After signing informed consent, all subjects underwent a structured interview [
Within two weeks of inclusion all patients underwent a TCS, at the Department of Clinical Neurophysiology of one of the two hospitals. In the hospital in Sittard only the SN was visualized. In Maastricht University Medical Center, visualization of the RN was included in the TCS protocol from the start of the study. One year later, measurement of the third ventricle was included as well.
TCS was performed using a SONOS 5500 system (Philips, Eindhoven, Netherlands). The examination took place in a darkened room with the patient already lying on the examination table before the investigator entered the room, in order to minimize possible identification of a patient’s clinical signs. Patient and investigator were instructed not to discuss symptoms or diagnoses.
TCS was performed bilaterally through the preauricular bone window with a 2–4 MHz phased array transducer. The quality of the bone window was scored as good, moderate, or inferior.
Two different methods were applied for the evaluation of the SN. First, the presence or absence of a clearly visible SN was scored (qualitative method). Second, the SN area was encircled manually and calculated automatically (quantitative method). This was only performed when the hyperechogenicity was located within the anatomical distribution of the SN, meaning that it showed a typical oblique stripe-shaped configuration. Both the right and left SN were measured from both sides.
The RN were identified if they met the criteria of an anatomic structure equally echo-intense to the red nucleus and localized in the transverse plane of the midbrain extending uninterrupted from anterior to posterior direction. Echogenicity of the RN was rated using a visual scoring system resulting in a semiquantitative assessment. Hence, if the RN appeared as an uninterrupted relatively echo-intense structure on TCS, it was scored as hyperechogenic. We scored the RN as hypoechogenic if it was not detectable at all or if it was interrupted. The patient was scanned from both sides because of the fact that the bone window can vary in quality of visualization of the RN from right to left. We used the best possible result, meaning when the RN was absent from one side but visible from the other side, it was scored as hyperechogenic.
The transverse diameter of the third ventricle was measured from both sides on a standardized diencephalic examination plane.
Two years after inclusion, patients were reexamined by two movement disorder neurologist specialists to obtain a definite clinical diagnosis, using the official diagnostic criteria for Parkinson’s disease [
SPSS 21.0 for Windows was used for the statistical analysis. Comparing categorical variables was done by chi-square test. The two-sample
For further analyses regarding the means between groups with different diagnoses, we performed an analysis of variance (ANOVA). To analyse the influence of other variables, partial correlation analysis was used.
At follow-up, seventy-two (57%) patients were diagnosed with PD. Patients with APS included 7 patients with MSA, 4 with PSP, 4 having LBD, and 3 patients with CBD. Eighteen (14%) patients had VP and 18 (14%) were diagnosed with ET.
At inclusion, 81% of the patients did not use any medication which could have an influence on both the motor as the cognitive performance such as an antidepressant or antiepileptic medication.
The subgroups differed significantly on the total UPDRS score with patients with APS having higher UPDRS scores compared to those with PD (Table
Patient characteristics, divided into group of diagnosis.
Parkinson’s disease ( |
Atypical parkinsonism ( |
|
|
---|---|---|---|
Age years (SD) | 68.54 (9.27) | 71.85 (9.31) |
|
Men (%) | 50 (70) | 43 (80) | 0.20 |
Disease duration months mean (SD) | 29.08 (46.78) | 40.39 (41.69) | 0.16 |
UPDRS total score mean (SD) | 24.03 (10.98) | 30.26 (17.24) |
|
UPDRS motor score mean (SD) | 13.10 (6.00) | 15.63 (8.52) | 0.07 |
SCOPA-COG mean (SD) | 23.83 (5.93 |
21.41 (7.85) |
|
Presence of cognitive impairment % | 37.50 | 51.85 | 0.11 |
Hyperechogenic substantia nigra % | 41.28 | 46.30 | 0.50 |
Hypoechogenic raphe nuclei % | 21.74 | 20.00 | 0.85 |
Third-ventricle width mm (SD) | 5.78 (2.28) | 5.31 (2.38) | 0.45 |
SCOPA-COG = scales for the outcome of Parkinson’s disease cognition, UPDRS = Unified Parkinson’s Disease Rating Scale.
Fifty-five (44%) subjects of the total group had a SCOPA-COG < 22, indicating the presence of cognitive impairment. Of the 72 PD patients, 27 (37.5%) had a SCOPA-COG < 22 compared to 28 (52%) of the APS patients. The mean score on the HAMD was 5.05 (SD = 5.40) with a range of 0 up to 28.
The percentage of abnormal SN or RN echogenicity, as well as third-ventricle width, did not differ between the PD patients and the patients with APS (see Table
Patient characteristics, divided into presence or absence of cognitive impairment.
PD absence of cognitive impairment ( |
PD presence of cognitive impairment ( |
|
APS absence of cognitive impairment ( |
APS presence of cognitive impairment ( |
|
|
---|---|---|---|---|---|---|
Mean age years (SD) | 67.27 (10.10) | 70.67 (7.36) | 0.13 | 68.15 (10.53) | 75.29 (6.49) |
|
Disease duration months mean (SD) | 27.29 (53.75) | 32.07 (32.87) | 0.68 | 51.92 (50.28) | 29.68 (28.78) |
|
UPDRS total score mean (SD) | 22.31 (10.14) | 27.00 (11.90) | 0.83 | 25.27 (13.77) | 35.07 (19.05) |
|
UPDRS motor score mean (SD) | 12.56 (5.55) | 14.04 (6.73) | 0.32 | 13.31 (6.75) | 17.79 (9.50) |
|
SCOPA-COG mean (SD) | 27.40 (3.70) | 17.89 (3.79) |
|
27.54 (4.26) | 15.71 (5.87) |
|
Hyperechogenic substantia nigra % | 35.56 | 48.15 | 0.29 | 46.15 | 46.43 | 0.98 |
Hypoechogenic raphe nuclei % | 20.69 | 23.53 | 0.82 | 5.56 | 35.29 |
|
Third-ventricle width mm (SD) | 5.05 (1.84) | 6.92 (2.49) |
|
5.27 (3.02) | 5.38 (1.44) | 0.91 |
PD = Parkinson’s disease, APS = atypical parkinsonism.
Boxplot of the range of scores on the SCOPA-COG scores compared to the echogenicity of the substantia nigra.
Boxplot of the range of scores on the SCOPA-COG scores compared to the echogenicity of the raphe nuclei.
Boxplot of the range of scores on the SCOPA-COG scores compared to the diameter of the third ventricle divided in subgroups with and without cognitive impairment.
About one-third of the patients with PD and about half of the patients with APS had cognitive impairment. The echogenicity of the SN did not indicate the presence or absence of cognitive impairment, neither in PD nor in APS. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive impairment compared to the patients without cognitive impairment. Furthermore, we found a larger diameter of the third ventricle in PD patients with cognitive impairment compared to the PD patients without cognitive impairment.
The major limitation of our study is that it is a secondary analysis of a study that was not powered on the presence of cognitive impairment. Because of that, our results must be seen as exploratory and interpreted with caution. However, the prevalence of cognitive impairment in our study is comparable to that in other studies [
The important strengths of our study are that, compared to other studies, sample size is fairly large regarding the amount of visualized SN and the fact that we included newly referred patients with early signs of parkinsonism that are not yet (extensively) treated pharmacologically. This patient group is clinically the most relevant, because in daily practice you want to know the right diagnosis in the earliest stage of the disease.
A study performed in PD patients with and without cognitive impairment and in patients with LBD reported a hyperechogenic SN in almost all patients [
Hypoechogenicity of the RN has been described as a indicator for the presence of depression in various diseases [
The finding of an association between cognitive impairment and a larger diameter of the third ventricle in our studies confirms earlier studies in PD, LBD, and AD [
How can we explain that in two different diagnostic groups (PD and APS) different echo features were related to the presence of cognitive impairment? This is likely due to the different underlying pathophysiology. Earlier studies have described a pattern of brain atrophy which is similar in AD and in PD [
With regard to hypoechogenicity of the RN in APS, because these patients have a worse prognosis and faster disease progression than PD, the emphasis of the pathophysiology may lay more on neurotransmitter level than on decline through atrophy. There also seems to be a correlation between the SCOPA-COG score and the score on the UPDRS which may explain the higher frequency of cognitive problems in APS compared to PD.
The exact pathogenesis of cognitive impairment in PD is still unknown. Studies have indicated that Lewy-type pathology [
The echogenicity of the SN was not related to cognitive impairment, neither in PD nor in APS. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment compared to the PD patients without supports earlier findings that the width of the third ventricle may reflect Alzheimer like brain atrophy. Differences shown by TCS indicate that various mechanisms and pathways are involved in the pathophysiology of cognitive impairment in PD and APS.
None of the authors had conflict of interests.
Angela E. P. Bouwmans, Wim E. J. Weber, and Werner H. Mess contributed in study concept and design, Angela E. P. Bouwmans, Wim E. J. Weber, and Werner H. Mess contributed in acquisition of subjects and/or data, Angela E. P. Bouwmans, Wim E. J. Weber, Werner H. Mess, and Albert F. G. Leentjens contributed in analysis and interpretation of data, and Angela E. P. Bouwmans, Wim E. J. Weber, Werner H. Mess, and Albert F. G. Leentjens contributed in preparation of paper.