[1] 10w Progression of Dysprosody in Parkinson's Disease Over Time-A Longitudinal Study

[1] 349w Parkinsonian speech or hypokinetic dysarthria results from a multidimensional impairment of phonation, articulation, and prosody. Although the dysprosody in Parkinson's disease (PD) is well described (alterations in speech rate and pause time, speech intensity and pitch variation), little is known about alterations of these single prosodic parameters over a longer time course. The objective of this study is to analyze changes of speech rate and pitch variation in patients with PD over time and to compare these findings with healthy controls. Patients with PD (N 5 50; 27 male and 23 female) and n 5 50 age-matched healthy controls (25 male, 25 female) were tested and retested after at least 7 months (mean: 25.02; median: 21; SD: 17.44; range: 7-79 months). In the PD group, motor impairment according to UPDRS motor score was similar at first and second visit. The participants had to accomplish a standardized four sentence reading task. The acoustical analysis was performed using a standard head-worn microphone for voice recordings and commercial audio software (WaveLab 1 ). For the determination of intonation based upon fundamental frequency (F 0 ) variation, we used a computer analysis program (Praat 1 ).Articulatory velocity was determined by measurement of syllable rate and pause ratios. In the PD group, total speech rate (syllables per second related to total speech time/TSR) and net speech rate declined from first to second examination, especially in the male patients, but showed no significant differences to the control group. The course of pitch variation revealed some gender particularities. Whereas female patients' pitch variability declined over time, male patients' intonation variability remained relatively stable. F 0 variation in male and female patients with PD were significantly reduced compared with the control group in the first examination and the follow up as well. Progression of prosodic impairment over time showed no correlation to disease duration or UPDRS motor score. Some aspects of dysprosody in PD show characteristic changes over time, but show no clear correlation with general motor impairment as assessed by UPDRS motor score. Therefore, we suspect that the underlying mechanism could be independent from dopaminergic deficits.

[1] 31w According to variance analysis, gender was shown to be an independent factor for Pinw% (P < 0.001), meanF 0 , F 0 SD, and F 0 VR (P < 0.001, respectively).

[2] 19w Therefore, we abstained from pooling our data but performed a gender-related analysis and comparison with the accordant control group.

[3] 42w Condition (PD vs. healthy control) was shown to be an independent factor with effects on meanF 0 , F 0 SD, and F 0 VR (P < 0.001, respectively), TSR (P 5 0.035), PR% (P 5 0.001), and Pinw% (P < 0.001).

[4] 19w In the PD group, UPDRS motor score and time interval between the visits showed no influence on prosodic variables.

[5] 106w Concerning speech rate parameters, TSR showed a significant reduction on the second examination compared with the first, whereas PR% and Pinw% remained stable over time. Considering speech rate variables in the course of reading, decrease of TSR in sentence 4 contributed particularly to the overall speech rate reduction. Regarding pitch variability, F 0 SD and F 0 VR showed no significant differences on the second examination compared with the first, with a tendency of F 0 VR reduction over time (P 5 0.092). RelF 0 SD and relF 0 VR showed the same behavior as F 0 SD and, since meanF 0 remained stable over time.

[6] 37w UPDRS motor scores were widely stable over time. Differences of prosodic variables between visit one and visit two showed no correlations to changes of UPDRS motor scores or to the period of time between the two visits.

[7] 37w On first examination, PR% and Pinw% were significantly diminished in male patients with PD compared with the control group, whereas TSR was elevated. F 0 SD and F 0 VR showed no significant difference between the groups.

[8] 37w On second examination, speech rate variables in male patients with PD showed no differences to the control group except for a reduced Pinw%. F 0 SD and F 0 VR showed no significant difference between the groups.

[9] 67w However, since meanF 0 on first and second examination was significantly elevated in male patients with PD when compared with the male control group, relF 0 SD and relF 0 VR showed a significant reduction in male patients with PD on first (P 5 0.003 and P 5 0.015, respectively) and second examination (P 5 0.002 and P 5 0.002, respectively) in comparison to the control group.

[10] 64w In female patients with PD, average speech rate parameters remained unchanged. Regarding pitch variability, F 0 VR and F 0 SD were significantly lower in examination two compared with the first examination. RelF 0 SD and relF 0 VR showed the same behavior as F 0 SD and F 0 VR, although meanF 0 showed a tendency to reduction over time (P 5 0.058).

[11] 36w UPDRS motor scores were widely stable over time. Differences of prosodic variables between visit one and visit two showed no correlations to changes of UPDRS motor scores or to the period of time between to visits.

[12] 44w On first examination, PR% and Pinw% were significantly diminished in female patients with PD compared with the control group, whereas TSR tended to be elevated (P 5 0.092). Moreover, all the intonation parameters were reduced in the female PD group compared with female controls.

[13] 32w On second examination, behavior of PR% and Pinw% remained unchanged compared with the first examination. Again, F 0 SD and F 0 VR were found to be diminished compared with female controls.

[14] 27w Behavior of relF 0 SD and relF 0 VR showed no difference to absolute F 0 SD and F 0 VR. Results are summarized in Table 2.

[1] 191w This study dealt with the behavior of some distinct parameters of prosody in Parkinsonian speech over time, in order to disclose the impact of disease progression on a separate functional system while general motor performance remained relatively stable over time. Speech analysis was based upon a standardized reading task in order to achieve comparable data, although it is well known from literature that the kind of speech task can exert some important influence on speech performance. For example, F 0 variability has shown to be elevated in reading or deliberately ''clear'' speech in comparison to conversational speech in patients with PD and in healthy speakers as well 14,24 indicating the influence of external cues on prosodic parameters. 25 Transferring a paradigm also being used in the description of patients with PD' motor performance, conversational speech can be interpreted as rather self-initiated procedure whereas the overt reading of an unfamiliar text reflects a ''forced'' external cued reaction. 25,26 Therefore, participants' speech performance Ratio of intra-word pauses Percentage of pauses within polysyllabic words of total pause ratio in a reading task presumably mirrors the maximum remaining prosodic ability in the bounds of PD.

[2] 349w Our study revealed a decrease of TSR in male patients with PD over time, which had to result from an increase of syllable length, as PR% remained widely stable. Although analysis of speech rate behavior in the course of reading had not been the scope of this actual study, we found reduction of average speech rate over time to be exceedingly caused by speech deceleration at the end of the reading task, leading to a convergence of previously elevated TSR and NSR to the control group's speech tempo. A similar tendency, although without statistical significance, was seen in the female patients with PD, which indicates some gender-dependent patterns of speech rate. The tendency to speech rate reduction in the course of disease in PD might serve as an explanation for the inconclusive findings in literature, probably not only caused by small sample size and neglect of gender-dependencies but also because of disregard of the stage of disease. 12,13,[19][20][21] This hypothesis is supported by our previous findings of a negative correlation between articulatory rate and disease duration in patients with PD. 27 In a previous study, we had already introduced the parameter of intraword pause fraction (Pinw%) being interpreted as articulatory undershooting with slurring of stop consonants, which again was found to be reduced in patients with PD compared with the control group in the present study but without significant changes over time. As Pinw% was negatively correlated with UPDRS motor score, 27 the constancy of Pinw% over time shown in the actual study might be a result of stability of motor performance in our PD group. Interestingly, Pinw% showed a significant difference between male and female, with reduced intraword pause fraction not only in male patients with PD but in male healthy control participants as well. In the presence of basically no gender effects on PR%, this observation implies that silent intervals are differently distributed across male and females. According to our data, females tend to have longer Pinw% whereas males tend to have longer inter-word pauses, again underlining the necessity for gender-based comparisons in the analysis of speech.

[3] 661w Intonation variability based upon F 0 SD and F 0 VR (measured in Hertz, respectively) and additionally relF 0 SD and relF 0 VR showed a significant decrease only in female patients with PD in the course of time and was reduced compared with the female control group even on first examination. Accordant to previous studies, 28 meanF 0 was found to be significantly elevated in male patients with PD only. Therefore, intonation variability merely showed a reduction when compared with the male control group when based upon relative F 0 SD and F 0 VR related to meanF 0 . Independent from this finding, male PD patients' F 0 SD and relF 0 SD remained stable over time, whereas F 0 VR and relF 0 VR showed at least a tendency to reduction from first to second examination. According to literature, these gender-related disparities might mirror the sexual dimorphism of laryngeal size with a different impact of disease specific changes on the voice apparatus in male and female patients with PD. 29 On the other hand, the lack of statistical significant changes of intonation in the male PD subgroup might be a methodological artifact attributed to the relationship between Hertz scale and audible pitch with relatively small low frequency variation leading to perceptible pitch differences, especially in male voice. But, admittedly, these pathophysiological explanations are quite speculative and have to be proven on a larger series of participants. Summarized, we were able to demonstrate a special pattern of speech rate in Parkinson's disease characterized by an articulatory acceleration in the early stages and slowing during disease progression especially in male patients with PD. Furthermore, F 0 variability showed a worsening over time, at least in female patients with PD. As motor performance according to UPDRS motor score was stable over time, the changes of prosody obviously are independent from global motor function. Therefore, progression of Parkinsonian dysprosody could be the result of an escalation of axial dysfunction too subtle to be mirrored by global UPDRS motor score. Alternatively, alterations of speech parameters could be completely independent from motor performance maybe based upon non-dopaminergic mechanisms, as it is supported by the lack of an unequivocal evidence of speech amelioration under short-time L-dopa admission. 15,[30][31][32][33] As far as we know, besides a single case report, 34 our examination is the first longitudinal study on dysprosody in Parkinson's disease. The factor of widely stable UPDRS motor score over time provides new insight into the progression of Parkinsonian dysprosody that therefore can scarcely be interpreted as a unidimensional further manifestation of motor deterioration. Our findings are supported by a previous cross-section examination on voice characteristics in patients with early stage PD compared with advanced stage patients with PD that at least confirm a worsening of pitch variability in late stage patients with PD. 35 However, our study has some limitations. The control group was not retested in a follow-up examination, and therefore we cannot exclude simple ageing effects being responsible for the prosodic changes over time as observed in the PD group. But, as there were no significant differences concerning age distri-bution between the control group and the PD group on both visits, we rather ascribe changes of Parkinsonian dysprosody to the progression of underlying disease. Furthermore, as disease duration on first examination as well as period of time between the two examinations were not standardized but lay within a wide range, we were not able to appraise if progression of dysprosody follows the tempo of motor deterioration. As mean disease duration on first examination was about 6 years, our findings seem to locate the phase of speech deterioration into a more advanced stage of disease, whereas general disease progression is thought to be more rapid in the early stages of disease. 3,4 Additionally, worsening of speech performance seem to follow an individual pace, as we did not find a correlation between changes of speech parameters and the time period passed between the visits.

[4] 23w Further longitudinal studies are warranted with standardized follow-up examinations to obtain further insight into pathophysiology and progression of speech impairment in Parkinson's disease.

[1] 164w From 2002 to 2008, 50 patients with idiopathic PD were recruited for this study. Diagnosis of PD was based upon clinical criteria, levodopa responsiveness, and the absence of symptoms suggesting atypical Parkinson syndrome. Signed informed consent was obtained of all participants. Patients' age on first examination ranged from 43 to 80 years (mean: 67.10; median: 67; SD: 6.81; 27 males, 23 females). Idiopathic Parkinson's disease had been diagnosed from 1 to 20 years prior to the first examination (mean: 6.44; median: 5; SD: 4.50). Time between first and second examination ranged from 7 to 79 months (mean, 25.02; median, 21; SD, 17.44). On both visits, each patient underwent a neurological examination, according to UPDRS Motor Scale (UPDRS t1 : mean: 19.40; median: 18.5; SD: 10.40; range: 4-57 points; UPDRS t2 : mean: 18.98; median: 17; SD: 9.68; range: 5-42 points) before performing the speech task. There were no significant differences between male and female patients regarding to age, disease duration, and UPDRS motor score.

[2] 25w At the time of the examinations, patients were in their best ''on''-state on stable dopaminergic medication since at least 4 weeks prior to the examination.

[3] 28w As control group, we tested an age-matched group of 50 healthy persons (mean age: 67.62 years; median: 68 years; SD: 6.68; range: 52-80 years; 25 males, 25 females).

[4] 62w Each participant had to perform a standardized speech task consisting of a given reading passage composed of four complex sentences. After a first test run, the second trial was taken for further analysis in order to minimize general reading problems. Speech samples were digitally recorded using a commercial audio software (Steinberg WaveLab ) and a head-set microphone (Plantronics Audio 550 DSP ).

[5] 163w Description of intonation was based upon fundamental frequency (F 0 ) measurement using a commercial software (Praat 22 ) extracting fundamental frequency from the speech sample as the lowest audio frequency with the highest intensity less harmonic contents (using an acoustic periodicity detection first described by Boersma 23 ). F 0 variation was declared both as F 0 standard deviation (F 0 SD) and F 0 variation range (F 0 VR: difference between minimum and maximum F 0 ) in Hertz (Hz). Since F 0 variation depends on overall F 0 , meanF 0 has been measured for the entire speech task and additional calculations of relative F 0 SD and F 0 VR have been performed (F 0 variation in relation to meanF 0 ). The results of the computerized pitch analysis were checked by an auditory control two times by two independent examiners to eliminate artifacts or background noises, whereas less than 0.5% of the audio material had to be abolished.

[6] 173w Analysis of speech rate was performed by measuring the length (in milliseconds/ms) of each syllable and each pause respectively based on the oscillographic sound pressure signal. Pauses were defined as a period of silence lasting for a minimum of 10 ms. Besides the conventional speech rate variables as total speech rate (TSR), net speech rate (NSR) and pause ratio (PR%), we additionally defined the percentual ratio of pauses within polysyllabic words (Pinw%) (Fig. 1). For the final analysis, we calculated the average TSR, PR%, and Pinw% of the entire reading text and ignored NSR (since NSR corresponds to TSR and PR%). Additionally, speech parameters were calculated for sentence 1 and sentence 4 separately in order to detect speech rate abnormalities only manifesting in the course of reading, although for the definite statistical analysis, we decided to condense the data to avoid redundancy, particularly as multiple testing of a too high number of parameters would have demanded Bonferroni corrections to minimize alpha error inflation. Again, the audio material was analyzed by two independent examiners.

[7] 103w Definition of speech parameters are summarized in Table 1. Blinded repeated measurement of the aforementioned speech parameters in a subgroup of participants (10 controls, 15 patients with PD) showed high intra-analyzer reliability (Spearman Rho 5 0.889, P < 0.001) and inter-analyzer reliability (Spearman Rho 5 0.8572, P < 0.001). To evaluate the test-retest reliability, 30 participants (15 controls, 15 patients with PD in their best ''on'' state) had to run consecutively through the speech task for two times. Since satisfying testretest reliability was found (Spearman Rho 5 0.858, P < 0.001), only one single speech task cycle was performed for the definite study.

[8] 30w Since the aim of the study was the obtainment of objective prosodic speech parameters, perceptual analysis or description of clinical manifestation of dysarthria in PD patient were not carried out.

[9] 97w Analyses of variance with gender and condition (PD vs. control) as between-subject factors and of time interval between the two visits and UPDRS III as intra-subject factors were performed first. Kolmogorov-Smirnov test was used to test for normal contribution. As not all the variables showed Gaussian distribution, nonparametric Wilcoxon Signed Rank Test was used for intragroup comparison of prosodic variables on first and second examination. For comparison of means between the prosodic parameters of patients with PD and controls, nonparametric Mann-Whitney test for independent sample was used. Spearman Rank Calculations were used to test for significant correlations.

[1] 211w Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons, primarily in the substantia nigra pars compacta. 1 Additionally, there is a growing body of evidence that the caudal brain stem nuclei and other nondopaminergic neurons may be affected long before the classic loss of dopaminergic neurons being responsible for a variety of nonmotor deficits in the course of the disease. 2 Several studies have suggested that the rate of progression of PD may not be linear and that the disease initially progresses more rapidly and that the rate of deterioration slows in more advanced stages of the disease. 3,4 From the clinical field of vision, motor impairment as muscular rigidity, tremor, and bradykinesia are the most ostensible dopaminergic symptoms, but the great majority of individuals with PD develop further voice and speech problems over the course of their illness, which are commonly interpreted as the manifestation of bradykinesia on the laryngopharyngeal tractus. [5][6][7] The rate of decline of motoric functions of early-stage, untreated patients with PD according to the Unified Parkinson's Disease Rating Scale (UPDRS) was estimated at about 13 units per year with a slowing of progression in advanced stages, 4 but little is known about Parkinsonian dysarthria in the course of the disease.

[2] 290w In general, speech can be defined as the ability to form reproducible sounds with certain semantic meanings. From a more operationalized point of view, the ability to speak can be subdivided into several dimensions, as speech respiration, phonation, articulation, and prosody. 8 Prosody again consists of distinct subdimensions namely speech rhythm and velocity, articulation rate and speech to pause ratio, speech intensity and pitch variation. 8,9 According to clinical experience, patients with PD can show abnormalties related to all these speech dimensions whereas dysprosody seems to be the most conspicuous feature of Parkinsonian dysarthria. [9][10][11] Previous research on prosody unequivocally indicates a significantly reduced F 0 variability in patients with PD compared with healthy controls. [12][13][14][15] Whereas monopitch speech seems to be sufficiently proven to be a characteristic feature of Parkinsonian dysprosody, findings about articulatory velocity are ambiguous. As the basal ganglia are supposed to regulate temporospatial aspects at the level of the motor cortex, speech rate abnormalities should be expected in patients with PD. 16,17 Furthermore, one would presume an altered speech rate in patients with PD caused by increased rigidity and hypokinesia of the speech production system. 18 However, the results of previous studies on the speech rate in patients with PD are inconsistent, probably as a consequence of methodological differences and small sample sizes. 12,13,[19][20][21] The aim of our longitudinal study was the analysis of speech in patients with PD in the course of time to test the hypothesis of a shared underlying pathophysiology of motor impairment on the one hand and speech alterations on the other. In our study, we emphasized the analysis of objective parameters of Parkinsonian dysprosody independent from the clinical manifestation of dysarthria and compared our findings to an age-and gender-matched control group.