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Abstract

Background: Recent genetic and epidemiological studies have shown that there is a link between essential tremor and Parkinson’s disease (PD). However, there is a lack of data about the clinical features of PD developed from essential tremor.

Objective: To explore and describe the clinical characteristics of Parkinson’s disease developed from essential tremor (ET-PD).

Methods: Twenty-five ET-PD patients and 124 IPD controls were enrolled according to each criterion. Motor and non-motor features and dopamine transporter uptake were compared between the two groups.

Results: Rest and action tremors were more severe in ET-PD patients than in IPD patients. In addition, tremor disorder of first-degree relatives occurred more frequently in the ET-PD group than in the IPD group. A comparison between cases with ET-PD and IPD was not significant for striatal dopamine transporter uptake. Among the non-motor features, sleep disorder frequency, especially rapid-eye-movement sleep behavioral disorder, were lower in patients with ET-PD than in those with IPD, and smell identification test scores were higher in patients with ET-PD than in those with IPD. The prevalence of other non-motor symptoms did not differ between the two groups.

Conclusion: This is the first comparison of motor and non-motor features between ET-PD and IPD. ET-PD and IPD have different characteristic motor and non-motor features from the nosologic perspective.

Keywords

Parkinson’s disease essential tremor non-motor symptoms REM sleep behavior disorder olfactory dysfunction

INTRODUCTION

Essential tremor (ET) and Parkinson’s disease (PD) are the most common movement disorders in neurologic clinics. Because some clinical features overlap between ET and PD [1, 2], it is sometimes difficult to discriminate between the two disorders. Resting tremor may be present in patients with ET [3, 4], and tremor-dominant early PD may also look like ET. Some patients with ET can develop incident PD [5]. Recently, a genetic association between ET and PD has also been reported in somefamilies [1, 6].

In PD, non-motor symptoms are major features that allow diagnosis of PD in the prodromal state and discriminate it from atypical Parkinson’s disease [7]. In addition, non-motor symptoms are also reported in ET and include cognitive dysfunctions, depression, anxiety, poor sleep quality, olfactory loss, and hearing loss [8 –10]. However, several non-motor symptom domains of PD are more severe and frequent than ET, especially in terms of gastrointestinal, cardiovascular, urinary and thermoregulatory function [11, 12]. In addition, rapid-eye-movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) have been found to occur more frequently in patients with PD than in patients with ET [13, 14].

Although there is reasonable epidemiological and clinical evidence to support a link between ET and PD, it is not clear what factors predict ET patient risk for developing PD (ET-PD). Furthermore, there are few data about the clinical features of Parkinson’s disease developed from essential tremor (ET-PD). The hypothesis tested in this study was that patients in the ET-PD group have clinical features that are distinct from idiopathic PD (IPD) patients. In Korean patients with early and mild PD, we compared the motor and non-motor features of ET-PD and IPD. In addition, we also investigated striatal dopamine depletion level, which was measured by ¹⁸F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) scans.

METHODS

Patients

The study protocol was approved by the Institutional Review Board at Seoul St. Mary’s Hospital. All subjects provided informed consent for participation.

A total of 25 ET-PD patients and 124 IPD patients were enrolled from a movement disorder clinic at Seoul St. Mary Hospital between July 2014 and December 2015. Diagnosis of PD was made according to the diagnostic criteria of the UK Brain Bank Parkinson’s Disease Society [15] and the presence of appropriate dopamine transporter defects on FP-CIT PET scans. None of the patients had ever taken anti-parkinsonian medication before the enrollment period, and all responded to anti-parkinsonian medications during follow-up (more than 6 months). Criteria from the Movement Disorder Society Tremor Investigation Group were used for diagnosis of ET [16]. Patients in the ET-PD group fulfilled the above-mentioned PD diagnostic criteria and had a prior history of ET. ET was defined by the use of tremorolytic agents after prior diagnosis of ET or by having postural tremor with or without kinetic tremor lasting for more than five years on the medical record or patient’s history before the diagnosis of PD. Exclusion criteria included patients with (1) PD diagnosis before age 40 and (2) neurological abnormalities related to atypical PD or secondary Parkinsonism. In addition, patients having a history of postural or action tremors lasting for less than five years were also excluded due to diagnostic uncertainty(n = 3).

Among enrolled patients, we collected clinical information such as age, gender, disease duration (PD or ET), education duration, smoking habit, and medical history. History of tremor disorder (PD or ET) in the first-degree relatives of patients was also checked. All patients were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) and the modified Hoehn and Yahr (H & Y) stage. The UPDRS motor scores were divided into subscores that included the following: speech (UPDRS item 18), facial expression (item 19), tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23–26 and 31), and axial symptoms (items 27–30) [17]. The tremor score was also subdivided further into subscores for resting tremor (item 20) and action tremor (item 21), and the resting tremor subscore was specified according to eachbody part.

PET imaging

Subjects were given 149–259 MBq of F-18 FP-CIT (3.7 MBq/kg) intravenously. PET/CT scans were acquired 3 hours after F-18 FP-CIT injection using a Discovery STE instrument (GE Healthcare, Milwaukee, WI, USA). Data were acquired in 3D mode. Computed tomography (CT) scanning began at the vertex and progressed to the skull base (30 mAs; 140 kVp; slice 3.75 mm), and PET imaging followed immediately over the same region with a 15-min duration. The CT data were used for attenuation correction, and images were reconstructed using the standard ordered subset expectation maximization (OSEM two iterations, eight subsets) algorithm. An experienced nuclear medicine physician reviewed the PET/CT images at a workstation (Advantage Workstation version 4.3, GE Healthcare) and performed a visual analysis. For statistics, a standard set of regions of interest (ROIs) was used to sample the average standardized uptake value (SUVavg) of both the caudate and putamen and of a nonspecific reference region in the occipital cortex using the sum images of two or three transverse planes. Ratios of specific to non-specific binding (SUVr) were calculated by dividing the striatal count density by the occipital count density.

Definition of non-motor features

For sleep problems, both the patient and his/her bed partner were interviewed. The patient completed the REM sleep behavior disorder screening questionnaire (RBDSQ) [18] and Epworth Sleepiness Scale (ESS) [19], and his/her bed partner also answered question 1 of the Mayo Sleep Questionnaire (MSQ1) [20]. Probable RBD was defined as an RBDSQ score of≥5 (out of a total of 13) and positive response (“yes”) on MSQ1. If the ESS was more than 11, then the patient was considered to have EDS.

Olfactory function was assessed by the Cross-Cultural Smell Identification Test (CC-SIT) [21]. Before the CC-SIT, nasal problems that evoked olfactory dysfunction were checked by physical examination.

Orthostatic hypotension (OH) was assessed by the head-up tilt-table test using the Manumed Special Tilt1-section (ENRAF NONIUS, Rotterdam, the Netherlands). After 20 min of supine rest, the tilt test was performed. Orthostatic hypotension was defined as a drop in blood pressure (BP) of at least 20 mm Hg systolic BP and/or 10 mm Hg diastolic BP, measured from the mean supine baseline 2–5 minutes after the tilt [22, 23].

Constipation was defined as decreased intestinal activity with defecation less than three times per week [24].

Depression was defined by (i) history of or current treatment for depressive symptoms, and (ii) the unequivocal classification of depressive states according to the DSM-V diagnostic categories, as specified later. In addition, anxiety was also defined with (i) history of or current treatment for anxiety disorders, and (ii) the DSM-IV residual category of “anxiety disorder, not otherwise specified” (anxiety disorder NOS).

Cognitive status was assessed using the Seoul Neuropsychological Screening Battery, which includes attention, language, praxis, the four elements of Gerstmann syndrome, visuospatial function, verbal and visual memory, and frontal/executive functions. All quantifiable test scores were classified as abnormal when they were 1.5 standard deviations below those of age-, gender-, and education-matched controls [25]. Mild cognitive impairment (MCI) was diagnosed if at least 1 of 5 cognitive domains was abnormal [26, 27]. Patients with MCI had no history or symptoms of memory problems or other cognitive disorders according to the dementia-screening questionnaire. Dementia was diagnosed according to the proposed criteria for probable Parkinson’s disease dementia from the movement disorder society task force [28].

All questionnaires were evaluated by one-to-one interview with a movement disorder specialist. Non-motor symptoms evoked by clinical factors other than ET-PD or PD were excluded.

Statistical analysis

All statistical analyses were conducted with SPSS software version 15.0 for Windows (SPSS Incorporated, Chicago, IL, USA). Independent sample t-tests were used to compare group mean differences, Pearson’s χ² tests were used to compare frequencies for categorical variables. UPDRS part III subscores were analyzed separately. The cognitive status of each group, categorized as normal cognition, MCI, or dementia, was also compared. An analysis of covariance was used to compare FP-CIT uptake values after controlling for age, disease duration, and UPDRS motor score. Statistical significance was set as P < 0.05.

RESULTS

Among the 149 patients studied, 64 were men. The mean age (±SD) was 68.6±8.5 years. The mean disease duration was 1.4±1.5 years, and the mean education status was 9.9±5.5 years. The total UPDRS and H & Y stage scores were 24.2±15.7 and 1.6±0.8, respectively. The frequencies of each non-motor feature were as follows: constipation (n = 86, 57.7%), orthostatic hypotension (n = 55, 36.9%), RBD (n = 73, 49.0%), EDS (n = 47, 31.5%), depression (n = 65, 43.6%), anxiety (n = 40, 26.8%), and dementia (n = 20, 13.4%).

Twenty-five patients were diagnosed with ET-PD, and 124 patients were diagnosed with IPD. Table 1 shows the clinical characteristics of ET-PD and IPD. There were no significant differences in age at examination, age at PD-symptom onset, gender distribution, educational status, frequencies of hypertension, diabetes mellitus, and nonsmoking status between the two groups. PD-symptom duration was mildly longer in patients with ET-PD than in those with IPD.

Table 1

Clinical characteristics of patients with Parkinson’s disease developed from essential tremor (ET-PD) and those with idiopathic Parkinson’s disease (IPD)

	ET-PD (n = 25)	IPD (n = 124)	P
Age at examination, year	70.2±7.6	68.3±8.7	0.291
Age at PD onset	68.4±7.1	67.1±8.7	0.461
Age at ET onset	59.7±7.8	–
Male gender (%)*	13 (52.0%)	51 (41.1%)	0.316
PD duration, year	1.9±1.9	1.3±1.4	0.086
ET duration, year	10.5±2.9	–	–
Education duration, year	9.8±5.6	9.9±5.4	0.893
Hypertension (%)*	10 (40.0%)	58 (46.8%)	0.535
Diabetes mellitus (%)*	4 (16.0%)	22 (17.7%)	0.834
Never-smoker (%)*	21 (84.0%)	95 (76.6%)	0.417
Family history of any tremor disorders (%)*	11 (44.0%)	9 (7.3%)	<0.001
PD (%)	1 (9.1%)	7 (77.8%)	<0.001
ET (%)	8 (72.7%)	1 (11.1%)
Both PD and ET (%)	2 (18.2%)	1 (11.1%)
UPDRS	29.0±13.0	23.6±16.0	0.197
UPDRS part 1	2.3±1.3	2.3±2.0	0.966
UPDRS part 2	8.8±4.7	6.9±5.4	0.177
UPDRS part 3	17.9±9.4	14.4±10.3	0.202
H &Y stage	1.8±0.9	1.5±0.8	0.176

Abbreviations: PD = Parkinson’s disease, ET = essential tremor, UPDRS = Unified Parkinson’s Disease Rating Scale, H & Y = Hoehn and Yahr. Values represent the mean with standard deviation or numbers of patients (percentage). Analyses were performed by independent sample t-tests or by χ² tests*.

The UPDRS score and H & Y stage score were not different between groups. However, rest and action tremors were more severe in ET-PD than in IPD patients (Table 2). Among body parts, rest tremor scores of upper extremities were higher in ET-PD patients than in IPD patients. Other parkinsonian signs such as bradykinesia, rigidity, and axial symptoms did not show any differences between the two groups (Table 2). In addition, the striato-occipital FP-CIT uptake ratios were not significantly different between the two groups (Table 3).

Table 2

Parkinsonian motor symptom characteristics of patients with Parkinson’s disease developed from essential tremor (ET-PD) and those with idiopathic Parkinson’s disease (IPD)

	ET-PD (n = 25)	IPD (n = 124)	P
Speech	0.6±0.6	0.4±0.6	0.120
Facial expression	1.1±0.7	0.8±0.7	0.132
Tremor	4.7±2.7	2.7±2.2	0.001
Rest tremor	2.7±1.8	1.4±1.5	0.002
Head	0.4±0.6	0.2±0.5	0.156
Arms	2.2±1.6	1.0±1.0	<0.001
Legs	0.3±0.4	0.3±0.7	0.964
Action tremor	2.0±1.1	1.3±1.1	0.010
Rigidity	1.7±2.2	1.6±2.0	0.886
Bradykinesia	7.3±4.2	6.6±5.2	0.612
Axial symptoms	2.4±2.1	2.2±2.4	0.738

The Unified Parkinson’s Disease Rating Scale motor scores were divided into subscores that included the following: speech (UPDRS item 18), facial expression (item 19), tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23–26 and 31), and axial symptoms (items 27–30) [17]. The tremor score was also subdivided further into subscores for resting tremor (item 20) and action tremor (item 21), and the resting tremor subscore was specified according to each body part. Values represent the mean with standard deviation. Analyses were performed by independent sample t-tests.

Table 3

Comparison of ¹⁸F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) uptake between patients with Parkinson’s disease developed from essential tremor (ET-PD) and those with idiopathic Parkinson’s disease (IPD)

	ET-PD (n = 25)	IPD (n = 124)	F	P
Average SUVr for bilateral caudate to occipitum	4.1 (1.1)	4.1 (1.0)	0.001	0.981
Average SUVr for bilateral putamen to occipitum	3.6 (1.3)	3.4 (1.0)	0.631	0.429
Ratio of caudate to putamen	1.3 (0.3)	1.2 (0.3)	0.580	0.448

Abbreviations: PD = Parkinson’s disease, ET = essential tremor, SUVr = standardized uptake value ratio. Values represent mean with standard deviation in parentheses. Analyses were performed using analyses of covariance (ANCOVAs) controlling for age, disease duration, and UPDRS motor score.

Tremor disorder in first-degree relatives was more frequent among ET-PD patients than IPD patients (χ² = 24.169, 44.0% vs. 7.3%, P < 0.001). The ET-PD group more commonly had family history of ET (10/11), whereas the IPD group frequently had a family history of PD (8/9) (χ² = 12.735, P < 0.001).

The frequencies of non-motor symptoms are presented in Table 4. There were no significant differences between the two groups in constipation, depression, anxiety, orthostatic hypotension, and cognitive impairments. The frequencies of sleep disorders, especially RBD, were higher in patients with IPD than in those with ET-PD. Although not statistically significant, EDS was also more frequent in IPD patients than in ET-PD patients. CC-SIT scores were higher in patients with ET-PD than in those with IPD.

Table 4

The frequencies of non-motor features in patients with Parkinson’s disease developed from essential tremor (ET-PD) and in those with idiopathic Parkinson’s disease (IPD)

	ET-PD (n = 25)	IPD (n = 124)	P
Constipation (%)	15 (60.0%)	71 (57.3%)	0.800
Probable RBD (%)	7 (28.0%)	66 (53.2%)	0.021
Excessive daytime sleepiness (%)	4 (16.0%)	43 (34.7%)	0.067
Depression (%)	7 (28.0%)	58 (46.8%)	0.084
Anxiety (%)	6 (24.0%)	34 (27.4%)	0.725
Orthostatic hypotension (%)	7 (28.0%)	48 (38.7%)	0.311
CC-SIT score*	7.5±2.0	5.7±2.4	0.030
Cognitive status	0.566
Normal cognition (%)	7 (28.0%)	47 (37.9%)
Mild cognitive impairment (%)	16 (64.0%)	65 (52.4%)
Dementia (%)	2 (8.0%)	12 (9.7%)

Abbreviations: PD = Parkinson’s disease, ET = essential tremor, RBD = REM sleep behavioral disorders, CC-SIT=cross-cultural smell identification test. Values represent the mean with standard deviation or numbers of patients (percentage). Analyses were performed by independent sample t-tests* or by χ² tests.

DISCUSSION

Although ET and PD are separate diseases, clinicians have long observed that there seems to be a tendency for ET patients to develop incident PD, raising questions about a link between these two neurological diseases [5]. In addition, recent genetic, pathologic, and radiologic studies have reported details about the relationship between ET and PD. The two diseases have various characteristics in common. ET patients sometimes present with resting tremor [3] and can have decreased dopamine transporter activity [4]. However, patients who have ET with rest tremor may have different clinical, electrophysiological, and imaging features compared to those with ET without rest tremor or those with tremor-dominant PD [29 –32]. ET patients may also show non-motor features that might be caused by Lewy body pathology [33, 34]. Therefore, we asked if patients with PD from ET could manifest different clinical features from those with IPD. In this study, ET-PD patients showed more severe rest and action tremors, a more frequent family history of tremor disorders, a lower frequency of sleep-related symptoms such as RBD and EDS, and higher CC-SIT scores. Other parkinsonian signs such as bradykinesia, rigidity, axial symptoms, and striatal dopamine uptake were not between the two groups.

Tremors in both ET and PD are associated with oscillatory activities in the cerebellothalamocortical circuit [34]. However, different pathophysiological mechanisms may lead to tremor within this circuit. Tremor-related local field potentials were also recorded in a different area of the thalamus for ET and PD patients [35]. In this study, tremor severities (rest and action) were increased in patients with ET-PD compared with IPD patients. In addition, a family history of tremor disorders was more prevalent in ET-PD and might be associated with nosological characteristics of ET. Recently, it was reported that mutations in certain genes (including LINGO1, LINGO2, and HTRA2) were related to both ET and IPD [36, 37]. One meta-analysis showed a lack of association between the most common LINGO1 gene polymorphisms and PD, while another showed marginal associations between these polymorphisms and familial ET [38, 39]. Considering that tremor mechanisms are shared between ET and PD, these results may be predictive and aid in defining the relationship between ET and tremor-predominant PD.

Patients with PD developed from ET presented relatively lower frequencies of RBD and EDS and higher CC-SIT scores compared to those with IPD; however, other non-motor features such as autonomic dysfunction, mood, and cognitive dysfunction did not differ between the groups. RBD and hyposmia are related to neurodegenerative processes and can be independent prodromal factors, especially through Braak’s synucleinopathies [40, 41]. RBD and hyposmia were low in frequency in the tremor-predominant PD group [42, 43]. Recent studies have defined the RBD/OH/cognitive impairments triad for predicting poor prognosis in PD [44 –48]. Normosmic PD might be associated with a more benign course when compared with hyposmic PD [49]. Therefore, we can speculate that ET itself might be a PD prodrome, although neuropathological confirmations are needed to verify the role of ET in the developmentof PD.

Our study has some limitations. First, because we enrolled a small number of ET-PD subjects and did not perform neuropathological examinations, it is difficult to generalize the results. Second, the definition of ET-PD did not necessarily exclude patients with IPD who presented with action-postural tremor, a common occurrence. In addition, by using the 5-year criterion of the ET definition, the possible ET subgroup with a relatively short duration preceding the onset of PD was lost. This could have interfered with the interpretation of the clinical characteristics of the ET-PD group (i.e. by excluding patients with a relatively short phase preceding the onset of PD symptoms). However, we think the application of classic ET criteria [16] can help to differentiate ET-PD from tremor-dominant PD. Third, PD symptom duration was too short to distinguish PD from atypical Parkinsonism. Fourth, polysomnography was not used for the analysis of RBD and it is more specific for the diagnosis of RBD than questionnaires. However, a recent report has suggested that questionnaire-based diagnosis can generate a sensitivity of 100% and a specificity of 82.4% [50]. Last, a discrepancy in sample numbers between the two groups could have created a limitation for interpreting this study. To reduce this bias, we enrolled consecutive IPD and ET-PD patients who visited our movement disorder clinic during the same period.

Despite these limitations, this study is significant in that it is the first comparison of the motor and non-motor features of ET-PD and IPD. ET-PD patients in this study were found to show different motor and non-motor characteristics compared to IPD patients. We cannot determine what factors will lead ET patients to develop PD, but this result suggests that ET-PD can have distinct clinical features compared with IPD (from the nosologic perspective). Future multi-directional studies on the pathogenesis of ET-PD and a long-term, large-cohort study are needed to better specify the identity of ET-PD.

Conflict of interest

The authors declare no competing financialinterests.

Footnotes

ACKNOWLEDGMENTS

None.

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Clinical Characteristics of Parkinson’s Disease Developed from Essential Tremor

Abstract

Keywords

INTRODUCTION

METHODS

Patients

PET imaging

Definition of non-motor features

Statistical analysis

RESULTS

DISCUSSION

Conflict of interest

Footnotes

ACKNOWLEDGMENTS

References