Psychiatric profile of motor subtypes of de novo drug‐naïve Parkinson's disease patients

Abstract Background Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder. It is well established that different motor subtypes of PD evolve with different clinical courses and prognoses. The complete psychiatric profile underlying these different phenotypes since the very early stage of the disease is debated. Aims of the study We aimed at investigating the psychiatric profile of the three motor subtypes of PD (akinetic‐rigid, tremor‐dominant, and mixed) in de novo drug‐naïve patients with PD. Methods Sixty‐eight patients with PD, divided into 39 akinetic‐rigid (AR), seven mixed (MIX), and 22 tremor‐dominant (TD) patients underwent a complete assessment of psychiatric, cognitive, and motor symptoms. Results No significant differences were found among groups. Conclusions Our results suggest that a differentiation of the psychiatric symptoms associated with specific motor subtypes of PD is not detectable in de novo drug‐naïve patients. Previous evidence that emerges later along the disease progression may be a consequence of the dopaminergic and nondopaminergic damage increase.

The studies on patients with PD at late stages of disease showed that TD and AR presentations are characterized by different risks and severities of specific neuropsychiatric symptoms along the disease course, such as depression, apathy, and cognitive impairment. AR subjects show a more rapid clinical progression and are at increased risk of developing disability and dementia (Rajput, Voll, Rajput, Robinson, & Rajput, 2009). On the other hand, disease progression of the TD subtype is slower, associated with less cognitive decline and lower incidence of complications such as visual hallucinations and depression (Oh, Kim, Choi, Sohn, & Lee, 2009;Rajput et al., 2008). These different features are supported by pathophysiological investigations showing a more widespread reduction of pallidal and striatal dopamine levels in AR patients, when compared to TD (Rajput et al., 2008).
Whilst few studies examined cognitive domains among phenotypes in de novo drug-naïve patients with PD (Domellof, Elgh, & Forsgren, 2011;Poletti et al., 2012), characterization of psychiatric phenomenology is limited to reports of higher alexithymia in de novo AR patients (Poletti et al., 2011). Moreover, comprehensive neuropsychiatric battery and formal psychiatric diagnoses were never applied in de novo patients with PD. In light of the recent efforts of Movement Disorder Societies to dissect non-motor profiles at different disease stages (Sauerbier, Jenner, Todorova, & Chaudhuri, 2016), here we studied the psychiatric profile of the three motor subtypes in early, untreated patients with PD.

| Participants
The study was carried out on 68 consecutive antiparkinsonian de novo drug-naïve patients with PD according to international guidelines. All subjects were enrolled at the Movement Disorder  Kang et al. guidelines (Kang et al., 2005): AR (n = 39), TD (n = 22), and MIX (n = 7). Subtypes were defined according to the ratio of patient's Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III) tremor score (obtained as sum of Items 20 and 21 divided by 4) to his or her mean UPDRS akinetic/rigid score (sum of Items 22-27 and 31 divided by 15) such that (a) a ratio = 1.0 equals tremor-dominant; (b) a ratio = 0.80 equals akinetic-rigid; and (c) a ratio between 0.80 and 1.0 equals mixed (Kang et al., 2005).  (Bagby, Taylor, & Parker, 1994;Pontieri et al., 2015). In particular, the SHAPS is a self-rated instrument that consists of 14 items covering the domains of social interaction, food and drink, sensory experiences, achievement, and pastimes. The subject is requested to agree or disagree with a statement in each item on a Likert scale (definitely agree, agree, disagree, and definitely disagree). The four available answers are divided into dichotomous categories (agree = 0; disagree = 1), ranging from 0 to 14 and with a cut-off score of 2 as the best discrimination between "normal" (a score of 2 or less was categorized as hedonic) and "abnormal" (a score above 2 was categorized as anhedonic) level of hedonic tone. The TAS-20 is a self− report instrument that has good internal consistency and good reliability as well as construct and criterion validity for the measurement of alexithymic characteristics. It comprises three subscales that assess distinct facets of alexithymia: F1, difficulty identifying feelings; F2, difficulty describing feelings; and F3, an externally oriented analytic mode of thinking. To evaluate the prevalence of alexithymia, patients with a TAS-20 score greater than 60 were considered alexithymic, whereas patients ranging from 52 to 60 were considered as borderline alexithymic and those scoring less than 52 were considered non alexithymic.
Further, all participants underwent a complete neuropsychological examination (Pontieri et al., 2015) including

| Statistical analysis
The distribution of the analyzed factors was verified using the Shapiro-Wilk test. Group comparisons for sociodemographic, neurological, psychiatric, and cognitive variables were performed using ANOVA or, in the case of non-normal distributions, Kruskal-Wallis for continuous variables and chi-square tests for categorical variables, followed by Fisher's protected least significant difference (PLSD) and Fisher's exact test for post hoc comparisons when appropriate.
The level of statistical significance was defined as p < 0.05.   Table 1 shows the sociodemographic and clinical characteristics of the study populations.

| RE SULTS
Akinetic-rigid, TD, and MIX PD subgroups did not differ significantly in any of these variables.
The three groups of patients with PD did not significantly differ in scores and frequency of psychiatric diagnosis, and in any cognitive scores (Table 2). TA B L E 2 Psychiatric and neuropsychological scale scores of the study cohort interesting that our findings diverge from the few previous studies investigating this topic. In particular, our results differ from those of two reports by Poletti et al. (2012Poletti et al. ( , 2011) that partially evaluated the psychiatric characteristics (depression and alexithymia) of de novo untreated patients with PD and extensively evaluated their cognitive functioning (Poletti et al., 2012). They found that the PIGD motor subtype was associated with alexithymic features and impairment in language abilities compared to TD. A possible explanation of these discrepancies lies in the different classification of motor subtypes and in patient's disease duration, very short in our sample. In particular, we utilized the classification of Kang et al. (2005) that is the most adequate method for classifying patients in the early stage of PD. On the contrary, the classifications used by Poletti et al. (2012Poletti et al. ( , 2011  We also acknowledge our study limitations. The diagnosis of our patients has not been confirmed by pathological evidence but only by clinical examinations and positive responses to dopaminergic therapy. In fact, all patients were diagnosed by independent and very expert movement disorders specialists, both at baseline and at follow-up visits performed after 12, 24, and 36 months, when the definitive effect of dopaminergic treatment can be evaluated.

| D ISCUSS I ON
Further, we do recognize that our results are obtained in a relatively small sample size. In particular, the mixed group includes only seven patients that we have decided to keep in our classification to give a more naturalistic picture of our study cohort.
In conclusion, here we showed that in the early stage of PD, the different motor subtypes are not associated with a specific psychiatric profile, suggesting that a possible differentiation emerges only over the progression of the disease and potentially with its interaction with dopaminergic replacing therapy. Therefore, the evolution of psychiatric features is not predictable based on early motor presentation and regular follow-ups are needed to investigate their different possible progression. Further studies on larger samples and investigating at which point of the disease course the motor subtypes start to diverge are strongly needed.

ACK N OWLED G M ENTS
This work was supported by grants RC09-10-11-12-13-14/A from Italian Ministry of Health to GS and PAMINA project from Regione Lazio to FA.

CO N FLI C T O F I NTE R E S T
The authors declare that there is no conflict of interest.

AUTH O R S' CO NTR I B UTI O N S
Assogna, Pellicano, Cravello, Savini, Pierantozzi, Mercuri, Pontieri, Caltagirone, Spalletta, and Stefani substantially contributed to conception and design, acquisition of data, and analysis and interpretation of data; drafted the article or revised it critically for important intellectual content; and contributed to the final approval of the version to be submitted.