Abstract
Parkinson disease (PD) is not an unambiguous entity, and there is a general consensus for the statement that an akinetic-rigid dominant type of presentation has a worse prognosis, in the follow-up. The aim of our study was to examine the differences in frontal tasks and behavior, in 2 PD naive groups: the rigid and the tremor-dominant types of presentation, according to motor scores. Our study has showed some important differences in frontal tasks and in behavior, performing more apathy, aggressiveness, and irritability in the rigid type, and more depression and anxiety in the tremor-dominant type. The former group causes the caregiver more distress and has a very rapid disease progression. It can be argued that rigid type PD presentation needs specific dedicated cares and more strong clinical attention.
Introduction
Parkinson disease (PD) is not an unambiguous entity; as a whole, it is not only a motor disease: in fact, the reduced function of the nigrostriatal dopaminergic (DA) system is associated with a mesolimbic, tuberoinfundibular, and mesocortical DA failure, which causes behavioral and cognitive dysfunctions which are very different in the different stages of PD. 1 -4
Even from the motor aspect point of view, PD is not an unequivocal entity: there are few studies in the literature, although their results are still debated, which addressed toward a possible difference among “empirical motor subtypes” of PD, both on motor and nonmotor domains. 3,5 And from a clinical point of view, the distinction between 2 (or even more) motor subgroups in PD is widely accepted in clinical practice, but it is currently debated in the literature. Classification criteria vary among studies and can imply a very specific work-up. 3,6 A very well-conducted study 3 identifies 4 clusters of patients’ profiles: the benign pure motor, which is characterized by lower bradykinesia score; the benign mixed motor–nonmotor which comes with lower bradykinesia, axial score, and progression rate, along with behavior disturbances; the nonmotor dominant type, with the lowest motor and the highest nonmotor burden; and the motor dominant, with a faster progression disease. 3
Our aim was to detect any possible differences in frontal tasks, behavior, and caregiver’s stress in 2 groups of untreated PD, not cognitive impaired, defined with operative and instrumental scores as rigid type and tremor-dominant type, with a follow-up of 3 years.
Study Design
The study is an observational cohort study. A total of 572 outpatients have been evaluated, fulfilling the criteria of idiopathic PD, 7 both men and women, not bedridden, aged between 54 and 74, recruited from January 1, 2001, to January 1, 2012. Among the 572 patients, 493 patients completed the study. The 493 patients who were recruited could be fully studied (mean age 58.1 [4.1] years, range = 54-74 years; average age at onset = 54.7 [3.1] years, and estimated range = 52-64 years). Their average educational level, represented by school years, was of 12.7 (1.1) years for group A and 12.3 (0.8) years for group B.
We decided to divide the patients, at baseline, in 2 distinctive phenotype presenting pattern groups: the rigid-dominant and the tremor-dominant. Originally, we based the clinical distinction on the classification made by Abdo et al, 8 Rajput et al, 9 and Erro et al. 3 A “tremor score” was derived as the mean of the subscores of items 20 and 21 (rest and action tremor) of Unified Parkinson’s Disease Rating Scale III (UPDRS III). A “bradykinesia score” was defined as the mean of the subscores of items 23 to 26 (finger tap, hand grip, pronosupination, and leg tap) of UPDRS III. The mean value of items 27 to 31 provided the “axial score” while the progression rate was calculated as UPDRS III/disease duration. All patients were tested in OFF state after an appropriate pharmacological washout. We implemented the data, with the employment of Movement Disorder Society (MDS)-UPDRS (MDS-UPDRS, 2003 10 ) subscores: 2.9 (turning in bed, 0-4), 2.10 (tremor, 0-4), 3.3 (rigidity of neck and 4 extremities, 0-4), 3.4 (finger taps, 0-4), 3.5 (hand movements, 0-4), 3.6 (leg agility, 0-4), 3.13 (postural tremor of hands, 0-4), 3.14 (kinetic tremor of hands, 0-4), 3.15 (rest tremor amplitude, 0-4), and 3.16 (constancy of rest tremor, 0-4). We defined as akinetic prevalent type if the average scores of 2.9, 3.3, 3.4, 3.5, and 3.6 were at more than 14, and at the same time their average scores in 2.10, 3.13, 3.14, 3.15, and 3.16 were less than 10; on the contrary, we defined as tremor prevalent type if the average scores of 2.9, 3.3, 3.4, 3.5, and 3.6 were less than 10, and at the same time their average scores in 2.10, 3.13, 3.14, 3.15, and 3.16 were more than 14.
Patients were divided into 2 groups, after a neurological examination in OFF: the former composed of patients with PD, of a rigid dominant type (called group A), including 270 cases, the latter with 223 patients with tremor dominant-type PD (called group B).
All patients responded to
Visits were scheduled every 6 months. The complete pattern of cognitive and behavior tests was performed at the beginning and at the end of the study, after 3 years of follow-up.
The study was conducted in accordance with the Declaration of Helsinki and with the Ethic Guidelines of the Institute.
Outcome Measures
Complete neurological and neuropsychological examinations have been performed for each patient. Gait and freezing have been evaluated by UPDRS. 12 Computed tomography head or magnetic resonance imaging images have been performed, in order to exclude vascular dementia. 13,14 Patients who showed radiological signs of normal pressure hydrocephalus were not included in the study.
Moreover, patients with previous psychiatric illness or central nervous system disorders and alcoholism were excluded. Additional exclusion criteria included the absence of a reliable caregiver and the neurological evidence of aphasic syndromes which might have presented an obstacle to any kind of understanding and compliance with the study.
The main outcomes of the study were: Global performance which was assessed using the Montreal Cognitive Assessment.
15
Executive functions, attention, judgment, and analogical reasoning, which were assessed by Frontal Assessment Battery (FAB)
16
and by the Stroop test.
17
Apathy which was assessed by the Clinician/Researcher Rated Version of the Apathy Evaluation Scale (AES-C) and the parallel Self-Report Version of the same instrument (AES-S).
18
Global behavioral symptoms which were assessed by the Neuropsychiatric Inventory (NPI)
19
; the symptom frequency was rated on a scale of 1 to 4 (1 = less than once a week; 2 = once a week; 3 = several times a week; and 4 = everyday), and the severity was rated on a scale of 1 to 3 (1 = mild; 2 = moderate; and 3 = severe). A composite score ranging from 1 to 12, defined as the product of frequency and severity was calculated. The caregiver’s stress which was assessed by the Relative Stress Scale (RSS).
20
Insight which was assessed by the Clinical Insight Rating Scale (CIR)
21
to provide a measure of its 4 comprising items—awareness, cognitive deficit, disease progression, and functional deficit.
Statistical Analyses
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, version 16.0). Within-group changes from baseline to 24 months were tested using the Wilcoxon Signed-Rank test.
Between-group changes from baseline were tested using the Wilcoxon 2-sample test. This was done for the overall scores for each efficacy variable.
In addition, subanalyses of Spearman Rho correlation, 2-tailed analyses were performed between the behavioral data obtained using the NPI, the FAB scores, RSS, CIR, and Stroop scores. The results are presented as mean changes from baseline with standard deviations, and P values are presented where appropriate.
Results
Patients have been divided into 2 groups according to the UPDRS III subitems and to MDS-UPDRS, as reported in Tables 1 and 2 in OFF condition. Baseline UPDRS global scores are not significantly different in the 2 groups at baseline in ON and OFF, apart from UPDRS III, as reported in Table 3. At 36 months, UPDRS global scores are worse in ON status in UPDRS III and IV, as reported in Table 4; in OFF status, group A did worse than B in all subitems (Table 4). Moreover, considering a specific subitem, group A manifested freezing when walking in ON and OFF conditions at 36 months, more evidently than group B (Table 5). The mean levodopa equivalent dosage (LEDD) did not differ at baseline (Table 6); on the contrary, group A demonstrated a higher LEDD during the 36-month follow-up, showing a more severe disease. At baseline, group A patients received the following drugs: 69 patients received dopamine agonists, 110
UPDRS III at Baseline to Divide the 2 Groups.
Abbreviation: UPDRS, Unified Parkinson’s Disease Rating Scale.
MDS-UPDRS Criteria.
Baseline Results in UPDRS, in ON and OFF.a
Abbreviations: NS, not significant; SD, standard deviation; UPDRS, Unified Parkinson’s Disease Rating Scale.
aValues are mean (SD).
Thirty-Six Months’ Results in UPDRS, in ON and OFF.a
Abbreviations: NS, not significant; SD, standard deviation; UPDRS, Unified Parkinson’s Disease Rating Scale.
aValues are mean (SD).
UPDRS for Freezing When Walking, in On and OFF (Baseline and 36 Months).a
Abbreviations: NS, not significant; SD, standard deviation; UPDRS, Unified Parkinson’s Disease Rating Scale.
aValues are mean (SD).
LEDD in the 2 Groups (Baseline and 36 Months).a
Abbreviations: LEDD, levodopa equivalent dosage; NS, not significant; SD, standard deviation.
aValues are mean (SD).
Cognitive performances (as shown in Tables 7 and 8) were different in the 2 groups. Group A did worse at baseline than group B, in the attention task, as reflected by Stroop interference task subscore (P < .01), in FAB test (FAB total score P < .05, and in the analogies, go/no-go tasks, and comprehension subscores). At 36 months, there was a general decrease of all performances in both PD groups. Nevertheless, at 36 months, group A performances were worse than the ones in group B, specifically in Stroop test interference subitems (P < .01), in FAB total score (P < .01), and in some subscores (analogies, contrast instructions, go (no-go and prehension behavior), as reported in Table 7.
Cognitive Parameters at Baseline.a
Abbreviations: FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment; NS, not significant; SD, standard deviation.
aValues are mean (SD).
Cognitive Parameters at 36 Months (in Brackets P Within Groups).a
Abbreviations: FAB, Frontal Assessment Battery; NS, not significant; SD, standard deviation.
aValues are mean (SD).
Behavioral tests comprised RSS, NPI, and CIR. Group A determined more anxiety and stress in their caregivers at baseline than group B (P < .05), but they did not show any statistical difference in NPI, as a global score, than group B and any difference in their insight (see Table 8). On the contrary, at 36 months, patients of group A did show worse NPI global score, determined more caregiver’s stress but showed more insight for their clinical situation rather than group B (Table 8).
When considering the subitems of the NPI, as shown in Table 9, there are some differences in the 2 groups: at baseline, group A showed more agitation, more irritability, and more apathy than group B; on the contrary, group B showed more depression and more anxiety than group A (Table 9). The situation remained stable in the follow-up, with a worsening of the frequency and severity of behavioral manifestations (Table 9).
Behavioral Results.a
Abbreviations: CIR, Clinical Insight Rating Scale; NPI, Neuropsychiatric Inventory; NS, not significant; RSS, Relative Stress Scale; SD, standard deviation.
aValues are mean (SD).
When examining the qualitative aspect of apathy, with a dedicated test (AES-C and S), there was a very high self- and clinically evaluated report of apathy in group A, at baseline, which was more evident than in group B (Tables 10 and 11), which maintained it stable during the follow-up.
Thirty-Six Months’ Versus Baseline NPI Results; Within Group Comparison With Baseline and Between Groups Analysis.
Abbreviations: NPI, Neuropsychiatric Inventory; NS, not significant.
Apathy Scores, AES-C and AES-S.a
Abbreviations: AES-C, Clinician Rated Apathy Evaluation Scale; AES-S, Self-Report Rated Apathy Evaluation Scale; NS, not significant; SD, standard deviation.
aValues are mean (SD).
Spearman rank correlation analyses (made at 36 months) indicated that there was a significant correlation, in both the groups, between: Gait scores (in ON) and RSS (r = .78, P < .01). Freezing and RSS (r = .71, P < .01). Gait and freezing scores and CIR (r = .75, P < .01 and r = .69, P < .01, respectively). Interference mistakes in Stroop test and FAB total score in group A (r = −.71, P < .01); and the following FAB subscores: analogies (r = .72, P < .01), go/no-go (r = .71, P < .01), and phonological fluency (r = .69, P < .05). Relative Stress Scale scores were correlated to NPI (r = .91, P < .01), CIR (r = .85, P < .01), and AES total scores (r = .91, P < .01).
Discussion
In this study, we have observed that if we considered the motor different manifestations of PD, a prevalent rigid-variant and a tremor-type variant, there are some specific differences in cognitive performances and in behavior. Rigid patients did worse in attention and executive functions than tremor-type patients, they did show much more apathy, agitation, and irritability; on the contrary, tremor-dominant patients were more depressed and anxious. Caregivers were more distressed by rigid patients, rather than by tremor-dominant patients.
These results are in line with the few studies on the topic, even if this is one of the first researches which is considering not only the motor evaluation but also frontal tasks and behavior evaluations, in a quantitative and a qualitative way. It has been reported that there are many differences between motor phenotypes, possibly related to different factors such as DA deficits and concomitant white matter disease, which indeed could be involved in cognitive and behavioral aspects of PD. 4 -6,22,23 Our study has limited the possibility of enrolling patients with white matter vascular involvement, employing specific neuroimaging instruments, and with other neuropsychiatric conditions. The differences between the clinical pattern profiles have been managed by UPDRS III3 and by our choice of MDS-UPDRS subitems. 10 We need to underline that the different aspects of motor involvement define 2 groups, a more akinetic- and axial-type presentation (that is normally not widely expressed in early phases of PD), group A, and a tremor pattern, group B. There were no other significant differences in ON/OFF evaluation at baseline in the 2 groups and that suggests that at the very beginning group A patients did not have a more severe disease, than the ones in group B. At baseline, LEDD was not significant different in the 2 groups, and there were more patients taking dopamine agonists at baseline in group B, rather than group A. The disease burden severity was higher in group A, rather than group B, and that can be detected by their motor scores and by the drastic increment of LEDD at 36 months.
The topic is not new, but our study shows somehow that, although rigid-type patients have a more severe disease during follow-up, which can be conditioning for some patterns of cognitive and behavior functions, they act differently from tremor-type patients since baseline evaluation, when UPDRS, LEDD, and drug type intake can be matched in the 2 groups. That can lead to a conclusion that the 2 variants of presentation might represent a different clinical challenge; there are some studies which showed that akinetic-rigid patients have a worse prognosis (in terms of cognitive and motor disability) and a more extensive neurodegeneration. A well-conducted study 24 demonstrated that in the tremor dominant and in the akinetic patients with PD, all subdivisions of the globus pallidus external (GPe) had significantly reduced DA levels. The DA loss was very marked (about 90%) in the classic cases, where rigidity coexists with tremor, affecting uniformly all subdivisions of the GPe. The same degree of DA loss was also present in the caudal GPe subdivisions in the akinetic/rigid group. In contrast, the rostral GPe subdivisions in the tremor-dominant cases were distinctly less affected, with the DA losses ranging between 57% and 83%. 25,26 A more recent study 27 showed a significant difference uptake of I-123 fluoropropylrcarbomethoxi-3β in 2 PD groups: tremor-dominant and akinetic-rigid. This study confirmed a reduced dopaminergic projection to the dorsal putamen in akinetic-rigid patients, whereas to the lateral putamen and to the caudate nucleus in tremor-dominant patients. 27
Several important questions still need to be elucidated. The differences in anatomical and biochemical projections might explain what has been observed. Should we simply consider our observations as a consequence of a clinical severe burden of disease? Therefore, studies with larger cohorts of patients, possibly associated with pathology findings, would be necessary to assess the neuropathological/neurochemical basis of our observations.
If our hypothesis is confirmed, a proper physiotherapy, more targeted drugs, and more defined polyvalent strategies (caregiver’s education, physiotherapy, and specific application strategies) should be applied, even at the very beginning of the history, of the akinetic-rigid disease, to improve the quality of life of these patients and of their caregivers.
Footnotes
Acknowledgment
The authors thank Ms Josephine Bates for her precious help and assistance.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.