Ale-anxiety subscale; NMS: non-motor symptoms; NMS-D: non-motor domains; LEDD: Levo-dopa equivalent daily dosage. a different from group 4 (p,0.01). b different from group 1 (p,0.01). c different from all groups (p,0.01). d different from group 2 and 4 (p,0.01). e different from group 2 (p,0.01). f different from group 1 and 3 (p,0.01). g different from group 1 and 2 (p,0.01). doi:10.1371/journal.pone.0070244.tMotor (bmM-NM, group 2), Non-Motor Dominant (NMD, group 3); and Motor Dominant (MD, group 4). This roughly suggests that there are two benign subtypes (one with prevalent motor impairment and one with prevalent non-motor impairment) and two more severe subtypes of PD (once again, one with prevalent motor impairment and one with prevalent non-motor impairment). Obviously, the term “benign” might be inappropriate for such neurodegenerative diseases as PD. However, it is nowadays clear that PD patients are very heterogenous in terms of progression. For the sake of simplicity, the term “benign” should be intended to recognize those patients with a relative slow shortterm progression and possibly longer time span to reach such milestones as motor complications, falls, and dementia [35]. On the other hand, we used the term “dominant” to indicate a prevalent, but not exclusive, feature for the two more severe clusters, which otherwise show an overall higher degree of both motor and non-motor Title Loaded From File involvement than the two benign groups. Figure 1 highlights differences between clusters. Our results confirmed the existence of two clusters previously described (i.e. “young age-at-onset with mild motor impairment” and “old ageat-onset with rapid disease progression”), but further revealed thepresence of two distinct subgroups of patients, which have been profiled according to both presence and relevance of NMS. With this regard, comparisons with previously identified subtypes are not straightforward. Our results are in agreement with Title Loaded From File previous studies [1,6,8], which consistently identified a subgroup of PD patients with young onset of disease. BPM cluster showed mild motor impairment with predominance of tremor symptoms, slow rate of progression and mild cognitive deficits, as previously reported [1,6,9]. Moreover, we also showed that BPM group exhibited the lowest scores of total NMS and NMS-D. This suggests that BPM cluster manifests mild motor features with virtually absent non-motor involvement. Interestingly, prevalence of patients reporting positive familial history was similar in BPM and NMD clusters, the latter having the second youngest age at onset (57.867.6 years) and sharing with the BPM a similar pattern of motor disability. The main difference between these two groups, beyond age at onset, was represented by the NMS, being BPM the group which showed the lowest score of NMS, while NMD group the highest. Indeed, the option to subject NMS to clustering allowed the distinction of these two subgroups which, in previous studies, probably mergedThe Heterogeneity of Early Parkinson’s DiseaseTable 3. Group characteristics (baseline categorical data).Group 1- BPM (n = 21) Gender, male ( ) Onset ,55y ( ) Tremulous phenotype ( ) Positive familial history ( ) Right side at onset ( ) BIlateral involvement ( ) Digestive Domain ( ) Urinary Domain ( ) Memory Domain ( ) Depression/anxiety Domain ( ) Sleep Domain ( ) Sex Domain ( ) Miscellany ( ) Cardiovascular Domain ( ) Delusion/Hallucinations ( ) doi:10.1371/journal.pone.0070244.t003 12 (57.Ale-anxiety subscale; NMS: non-motor symptoms; NMS-D: non-motor domains; LEDD: Levo-dopa equivalent daily dosage. a different from group 4 (p,0.01). b different from group 1 (p,0.01). c different from all groups (p,0.01). d different from group 2 and 4 (p,0.01). e different from group 2 (p,0.01). f different from group 1 and 3 (p,0.01). g different from group 1 and 2 (p,0.01). doi:10.1371/journal.pone.0070244.tMotor (bmM-NM, group 2), Non-Motor Dominant (NMD, group 3); and Motor Dominant (MD, group 4). This roughly suggests that there are two benign subtypes (one with prevalent motor impairment and one with prevalent non-motor impairment) and two more severe subtypes of PD (once again, one with prevalent motor impairment and one with prevalent non-motor impairment). Obviously, the term “benign” might be inappropriate for such neurodegenerative diseases as PD. However, it is nowadays clear that PD patients are very heterogenous in terms of progression. For the sake of simplicity, the term “benign” should be intended to recognize those patients with a relative slow shortterm progression and possibly longer time span to reach such milestones as motor complications, falls, and dementia [35]. On the other hand, we used the term “dominant” to indicate a prevalent, but not exclusive, feature for the two more severe clusters, which otherwise show an overall higher degree of both motor and non-motor involvement than the two benign groups. Figure 1 highlights differences between clusters. Our results confirmed the existence of two clusters previously described (i.e. “young age-at-onset with mild motor impairment” and “old ageat-onset with rapid disease progression”), but further revealed thepresence of two distinct subgroups of patients, which have been profiled according to both presence and relevance of NMS. With this regard, comparisons with previously identified subtypes are not straightforward. Our results are in agreement with previous studies [1,6,8], which consistently identified a subgroup of PD patients with young onset of disease. BPM cluster showed mild motor impairment with predominance of tremor symptoms, slow rate of progression and mild cognitive deficits, as previously reported [1,6,9]. Moreover, we also showed that BPM group exhibited the lowest scores of total NMS and NMS-D. This suggests that BPM cluster manifests mild motor features with virtually absent non-motor involvement. Interestingly, prevalence of patients reporting positive familial history was similar in BPM and NMD clusters, the latter having the second youngest age at onset (57.867.6 years) and sharing with the BPM a similar pattern of motor disability. The main difference between these two groups, beyond age at onset, was represented by the NMS, being BPM the group which showed the lowest score of NMS, while NMD group the highest. Indeed, the option to subject NMS to clustering allowed the distinction of these two subgroups which, in previous studies, probably mergedThe Heterogeneity of Early Parkinson’s DiseaseTable 3. Group characteristics (baseline categorical data).Group 1- BPM (n = 21) Gender, male ( ) Onset ,55y ( ) Tremulous phenotype ( ) Positive familial history ( ) Right side at onset ( ) BIlateral involvement ( ) Digestive Domain ( ) Urinary Domain ( ) Memory Domain ( ) Depression/anxiety Domain ( ) Sleep Domain ( ) Sex Domain ( ) Miscellany ( ) Cardiovascular Domain ( ) Delusion/Hallucinations ( ) doi:10.1371/journal.pone.0070244.t003 12 (57.

Ale-anxiety subscale; NMS: non-motor symptoms; NMS-D: non-motor domains; LEDD: Levo-dopa equivalent

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