| | Vascular pathology in patients with idiopathic Parkinson's diseaseReceived 14 May 2007; received in revised form 30 January 2008; accepted 12 February 2008. Abstract To study the impact of brain vessel pathology on the clinical status of Parkinson's disease (PD), in 57 consecutive patients the clinical and neuropsychological data were compared with clinical MRI signs of vascular impairment and with the ultrasound brain vessel investigations. There was a significant correlation between clinical and cognitive status and intimomedial thickness, which is an indicator of large vessel impairment. Cognitive status was significantly related to the pulsatility index (an indicator of small vessel impairment). This study provides evidence that subclinical vascular pathology could influence the clinical status by contributing to motor and cognitive dysfunction in PD. Atherosclerotic diseases of the vessels supplying the brain and idiopathic Parkinson's disease (PD) both occur frequently in advanced age. Atherosclerotic heart disease is one of the most common causes of death in PD [1]. The high incidence of vascular pathology at the age typical for PD i.e. in the seventh and eighth decade of life leads to the assumption of frequent co-incidence of both pathologies. Ischemic brain lesions influence the clinical status of PD patients [2]. However, clinically manifest cerebrovascular disease is rather rare in PD [1]. Cerebrovascular disease (CVD) is diagnosed in autopsy as the etiological factor of parkinsonism only in 1–3.2% of cases [3], [4]. Jellinger [5], [4] found that about 2.5% of all parkinsonian syndromes were related to CVD. Cerebrovascular impairment may be in a causal relation with extrapyramidal symptoms in vascular parkinsonism syndrome [6], [7]. Nevertheless, vascular parkinsonism and PD are distinct entities; it remains largely unknown whether there is an interaction between vascular pathology and idiopathic PD. To our knowledge the impact of vascular pathology on PD has not yet been studied. In this study, we raised the question: does the vascular pathology contribute to the disease severity (motor performance, neuropsychological test performance) in PD patients? 1. Subjects and methods  A group of consecutive PD patients from the Movement Disorder Centre in Brno composed the study cohort. All patients fulfilled the Brain Bank criteria for idiopathic Parkinson's disease [8], [3]. We excluded patients with clinical signs of vascular parkinsonism syndrome (for diagnostic criteria see Refs. [6], [7]) or other unrelated cerebral pathology and patients with severe cognitive impairment. No patient was severely impaired by any other co-morbidity. Patients who had undergone DBS were also excluded. We examined 57 patients (39 men and 18 women) ages 54–84 (mean 68.2 ±6.9) years. The average duration of the disease was 9.3±5.1 years (Table 1). All patients were under antiparkinsonian drug therapy. The study cohort was representative of a patient population in a large Movement Disorders Centre. It is probable that patients in the initial and in the most advanced stages of PD were under-represented. Nevertheless, the cohort characteristics (Table 1) indicate that the patient population reflected a range of stages of disease. The Local Ethics Committee approved the study and informed consent was obtained from each patient. 1.1. Methods Clinical and neuropsychological data were compared with signs of vascular impairment, i.e. with the occurrence of stroke in the patient's personal history and in MRI, and with the results of ultrasound brain vessel investigations. Four groups composed the research team: movement disorders specialists, stroke specialists, an MR specialist, and neuropsychologists. Study PD nurses collected data about medical history. Each group was blinded toward the information of the other groups, e.g. the sonographers were not informed about clinical status and MR results. An independent statistician evaluated all data. 1.1.1. Clinical impairment Clinical impairment was classified by the severity of motor symptoms. These were measured by UPDRS III [9]; and by the general impairment scales that are largely influenced by the motor as well as non-motor symptoms: the Hoehn–Yahr scale [10], the instrumental activities of daily living scale (IADL, [11]), and the Barthel index [12]. The patients and their caregivers were questioned about occurrence of fluctuations, dyskinesias, at the time of the interview or in their medical history. 1.1.2. Neuropsychology We focused on basic orientation, visuo-spatial and constructional disabilities, auditory memory, semantic association, depression, and neuropsychiatric symptomatology. Patients were given the Mini-Mental State Examination (MMSE) [13], the Benton Temporal Orientation Test [14], [15], the clock drawing test [16], [17], [18], [19], the Verbal Fluency Test [20], [21], two subtests of the Wechsler Memory Scale III (WMS-III, third edition) [22], Word Lists I and II [23], and the Montgomery Asberg Depression Scale (MADRS) [24], [25]. The tests were administered and evaluated by specialized psychologists. The patients and their caregivers were questioned about occurrence of hallucinations, delusions, and depression, at the time of the interview or in their medical history. 1.1.3. Vascular pathology We obtained data about previous stroke and all patients underwent an MR of the brain and an ultrasonographic examination of extracranial and intracranial vessels. The intimomedial thickness of the common carotid artery (CCA-IMT), the pulsatility index (PI), and the resistance index (RI) transcranially in a. cerebri media (ACM) were measured. 1.1.3.1. Stroke The patients and their caregivers were interviewed using a structured questionnaire about the occurrence of several vascular risk factors and history of stroke, including TIA. Furthermore, the medical records of each patient at the Movements Disorder Centre were evaluated. The MRI was performed in order to display the ischemic brain lesions and to exclude any possible concomitant brain pathologies. Brain imaging was performed on a 1.5-T Siemens Magnetom Symphony scanner. T2 weighted and FLAIR anatomical images were collected. The T1 weighted images served for comparison with lesions identified by the T2 weighted images. An independent MR specialist overviewed the findings and provided a detailed description. He evaluated the volume of brain tissue and the total volume of white matter lesions in periventricular regions using “Transfer” software, version 3.0. 1.1.3.2. Ultrasonographic examination The extracranial carotid arteries were evaluated with an ultrasound Toshiba Nemio equipped with a linear transducer (7.5MHz) in duplex mode. A transcranial examination was performed with the use of a 2-MHz annular array ultrasound imaging system. The sonographers (neurologists with experience in ultrasound examination) were not provided with any clinical and radiological information about the patients. Ultrasonographic examination of extracranial vesselsThe intimomedial thickness. The intimomedial thickness of the common carotid artery (CCA-IMT) was measured in B-mode. The measurement of IMT in the CCA was made 1cm proximal to the carotid bulb on the far wall. We focused on far wall IMT in our study, because this measurement is considered more valid than near-wall measurement [26]. Maximal IMT values for right and left carotid artery were averaged to obtain the mean IMT. IMT is considered to be a useful sonographic marker of early atherosclerotic affection [27], [28], [29], [26]. Atherosclerotic (AS) plaque. The carotid arteries were evaluated for the presence of atherosclerotic lesions (plaques) by Doppler and color-flow Doppler ultrasound examination. The basic approach for the detection of AS changes in the carotid region is B-mode. We examined the common carotid artery, bifurcation and the origin of the internal and external carotid arteries bilaterally in each patient. Atherosclerotic changes are imaged as lesions of different echogenicity prominating into vessel lumen. All lesions of 1.5mm and more were evaluated as plaques; the smaller ones were considered as IMT. Potential AS plaque was examined in longitudinal and transversal sections; the residual lumen was measured; the peak systolic and end-diastolic velocities were detected using Doppler. Finally, the approximate stenosis grade was determined. Ultrasonographic examination of intracranial vesselsResistance index. Pourcelot introduced the “resistance index” (RI) as a means of characterizing peripheral resistance in cerebral circulation. This index describes the ratio of peak systolic velocity to end-diastolic velocity. For the normal common carotid artery, the RI is between 0.55 and 0.75. Arteries that supply the brain have an RI less than 0.75. Pulsatility index. Another commonly used description of Doppler waveforms is the pulsatility index (PI), introduced by Gosling in 1974. PI and RI may reflect microangiopathic changes of cerebral vessels. Vascular risk factors and clinically demonstrated vascular diseases (such as arteriolopathy) are associated with an increase in RI [30], [31]. The final RI and PI are the average values of RI and PI on both sides. Both indexes are not just functions of flow resistance; they are also influenced by vascular compliance. 1.1.4. Statistics According to our hypothesis, vascular factors influence motor performance and neuropsychological test performance. To test the hypothesis, vascular factors were correlated with demographic data and with clinical signs of PD. A univariate analysis was performed in order to assess the mutual relationship of the individual variables. The relationships among single quantities were determined using a parametrical correlation coefficient (Pearson's). Pearson's correlation analysis was used for testing continuous variables, where normal distribution can be presumed. The clinical and neuropsychological data were correlated with the results of ultrasound investigations (IMT, RI, PI) this way. Quantities that gained logical values were optimised by LOGIT regression. Logit regression is used for analyzing the relationship between one or more independent (predictor) variables with a categorical dependent (criterion) variable at two levels. This was used for correlating the main clinical and neuropsychological data (i.e. UPDRS, Hoehn–Yahr, ADL, MADRS, MMSE) with the presence of vascular risk factors and AS plaque. None of the investigated clinical variables can be attributed to a single causal factor; all of them are influenced by various factors. This was the reason for performing multiple regression analysis as the second part of the statistical evaluation. Continuous clinical data were included in this analysis (UPDRS III, Hoehn–Year, IADL, Barthel index ADL, clock test, MMSE, MMSE+clock test, Benton, VFT, MADRS, WMS-III). Factors were patient age, duration of PD, and vascular factors (IMT, RI, PI). For this analysis, data with normal distribution were needed; therefore some data were normalized using natural logarithms. 2. Results The characteristics of the investigated patients and the principal results are shown in Table 1. Further clinical data. The first manifestation of PD was rigidity/akinesia in 28 subjects, tremor in 45 subjects, and both in 16 subjects. Fluctuations occurred in 36 subjects, dyskinesias in 28 subjects, hallucinations in 13 subjects, and depression (in the personal history) in 9 subjects. The MADRS administered in this study revealed that the cohort as the whole was rather non-depressed. Vascular risk factors were present as follows: smoking in 11 subjects, diabetes in 5 subjects, arterial hypertension in 14 subjects, stroke (including TIA) in personal history in 4 subjects, and ischemic heart disease in 14 subjects. While the mean MMSE (27.3±2.8) showed a rather non-demented population, individual analysis displayed 6 demented patients (24 and less points) and 13 patients with borderline scores (27–25) indicating a mild cognitive impairment. Stroke (including TIA) in personal history was reported in four subjects. According to MR findings, a territorial stroke was present in only one patient. Except the brain atrophy and limited white matter lesions (WML), no other pathological changes were described. Specifically, no ischemic changes in the basal ganglia or tegmentum were observed. White matter lesions were present in 30 patients. The volume of ischemic changes was small in general: it exceeded 10,000mm3 (less than 1% of mean brain volume) in five patients only. AS plaque was detected in 27 patients; however, in most them of it was haemodynamically insignificant. The lumen reduction was less than 50%, with no pathological changes in flow wave pattern in 24 patients. The lumen reduction between 50 and 70% was present in three patients. Statistical evaluations. A univariate analysis was performed in order to assess the mutual relationship of individual variables. Pearson's correlation analysis and LOGIT regression were used (for more details about statistics, see above). The analyses with significant results are displayed in Table 2, Table 3. | | |  | | UPDRS III | Hoehn–Yahr | IADL | Barthel index | |
|---|
| IMT | 0.4527, p=0.003 | 0.3533, p=0.023 | −0.5213, p=0.0001 | −0.6578, p=0.0001 | | | RI | 0.124, p=0.44 | 0.131, p=0.41 | −0.213, p=0.182 | −0.217, p=0.17 | | | PI | −0.0067, p=0.97 | 0.073, p=0.65 | −0.249, p=0.12 | −0.229, p=0.15 | | | | |
| | | | | Clock test | MMSE | MMSE + clock | Benton | VFT cat. | WMS-III ts | WMS-III r | WMS-III recog. | |
|---|
| IMT | −0.4174, p=0.007 | −0.4421, p=0.004 | −0.4964, p=0.001 | 0.4163, p=0.006 | −0.3178, p=0.043 | −0.209, p=0.19 | −0.299, p=0.058 | −0.3265, p=0.037 | | | RI | −0.256, p=0.11 | −0.157, p=0.327 | −0.196, p=0.22 | 0.3238, p=0.039 | −0.102, p=0.52 | −0.022, p=0.89 | −0.066, p=0.68 | −0.079, p=0.623 | | | PI | −0.3547, p=0.023 | −0.269, p=0.09 | −0.282, p=0.07 | 0.5623, p=0.0001 | −0.348, p=0.05 | −0.158, p=0.32 | −0.4148, p=0.007 | −0.3503, p=0.025 | | | | |
Further results. (1) The occurrence of hallucinations significantly correlated with IMT (p=0.02). (2) The occurrence of AS plaque significantly correlated only with the Benton test (p=0.027). (3) The depression did not significantly correlate with the monitored parameters, neither in the personal history nor when evaluated by MADRS. The incidence of depression was low in our group of patients. (4) Neither the severity of the disease nor the cognitive deficit was significantly influenced by the presence of vascular risk factors (smoking, diabetes, hypertension, stroke, ischemic heart disease). Multiple regression analysis was then performed. No significant results were found when the following dependent variables were studied: VFT, clock test, MADRS, WMS-III cs and WMS-III r. The significant results are displayed in Table 4. | a Data were normalized using natural logarithms. |
3. Discussion Due to the high incidence of cerebrovascular disease (CVD), it is possible for CVD and idiopathic Parkinson's disease (PD) to coincide in some cases. Our attempt was to study the influence of vascular factors in an unselected PD population; consequently the cohort is in some aspects heterogeneous. We targeted the PD population under naturalistic conditions. The study group was composed of consecutive patients with various degree of impairment; severe impairment was rather infrequent (see median UPDRS III 19, median MMSE was 28). The influence of depression was found insignificant, probably because the studied population was clinically rather non-depressed. Otherwise, PD patients with major depression tend to be more cognitively impaired than non-depressed patients [32], [33], [34]. First we searched for the presence of stroke/TIA in the patient history and in the MR images. Vascular basal ganglia lesions in MRI/CT are associated with worse clinical outcome in patients with PD [35], [36]. In our patients, the rather rare occurrence of MR and clinically manifest CVD concur with results of a large epidemiological study [37] as well as with autopsy findings in a large cohort of PD patients in which the cerebral haemorrhage caused death in 2.3% and cerebral infarction in only 1.1% of the patients [1]. The incidence of CVD in PD patients differs from observations of patients with Alzheimer's disease (AD). The findings in the Nun study [38] suggest that brain infarcts and atherosclerosis may play an important role in determining the appearance and severity of clinical symptoms of AD. However, in AD patients the CVD seem to occur more frequently than in PD. Second we measured the ultrasound parameters indicating the atherosclerotic disease of the large and small brain vessels. Our study revealed a possible role of subclinical vascular impairment. The measurement of the intimomedial thickness (IMT) was significantly related to the severity of the motor as well as the cognitive impairment in our study. This suggests a possible link between atherosclerotic involvement (IMT is a marker) and impairment of PD patients. IMT is considered to be a useful sonographic marker of early atherosclerotic lesions [27], [28]. A thickening of the intimomedial complex not only reflects local alterations of examined vessel, but also corresponds to generalized atherosclerosis [29]. Measurement of CCA-IMT is also regarded as a valid index of the involvement of other arterial beds with atherosclerosis. In addition, CCA-IMT has been found to be significantly and positively associated with cardiovascular risk factors, such as systolic blood pressure, total cholesterol, LDL cholesterol, triglycerides, and blood glucose; and negatively with HDL cholesterol. The otherwise subclinical higher IMT values were associated with worse performance on gait and balance tests in unselected older subjects [39]. Cognitive decline was found to be associated with left carotid stenosis without clinically evident CVD in non-parkinsonian patients [38]. In contrast, the investigation of small vessels by means of PI and RI displayed less consistent results. No clear impact on motor status was revealed, several cognitive tests were significantly related with the pulsatility index (one of them with the resistance index). It is true that disease-related degenerative brain changes are primary causes of cognitive and motor decline in PD [40], [41], [42]; nevertheless a co-morbid hypoperfusion may contribute to their occurrence and degree. In our study, the signs of advanced PD including cognitive impairment were significantly related to the pathological changes of large vessels. In a SPECT study of PD associated with dementia, the frontal, parietal, and temporal regional blood flow was significantly less than in controls [43]. This hypoperfusion could be due to underlying atrophic process; however, it might also be a factor contributing to cognitive decline. The exact mechanism by which vascular pathology worsens PD remains rather hypothetical. Two mechanisms are probable. First, there may be an additive effect of two independent but convergent disease processes, of the neurodegenerative and of the vascular, respectively. This option cannot be excluded but an argument against it is the absence of significant clinical manifestation of the CVD in most patients. The other probable mechanism is a synergic effect of both conditions, i.e. the deleterious effect of otherwise subclinical hypoperfusion on regions made vulnerable by the degenerative process. 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