The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life.

Non-motor symptoms are gaining relevance in Parkinson's disease (PD) management but little is known about their progression and contribution to deterioration of quality of life. We followed prospectively 707 PD patients (62 % males) for 2 years. We assessed non-motor symptoms referred to 12 different domains, each including 1-10 specific symptoms, as well as motor state (UPDRS), general cognition, and life quality. Hoehn & Yahr (H&Y) stage was used to categorize patient status (I-II mild; III moderate; IV-V severe). We found that individual non-motor symptoms had variable evolution over the 2-year follow-up with sleep, gastrointestinal, attention/memory and skin disturbances (hyperhidrosis and seborrhea) becoming more prevalent and psychiatric, cardiovascular, and respiratory disorders becoming less prevalent. Development of symptoms in the cardiovascular, apathy, urinary, psychiatric, and fatigue domains was associated with significant life-quality worsening (p < 0.0045, alpha with Bonferroni correction). During the observation period, 123 patients (17 %) worsened clinically while 584 were rated as stable. There was a fivefold greater increase in UPDRS motor score in worse compared with stable patients over 24 months (p < 0.0001 vs. baseline both in stable and worse group). The total number of reported non-motor symptoms increased over 24 months in patients with motor worsening compared to stable ones (p < 0.001). Thirty-nine patients died (3.4 % of patients evaluable at baseline) with mean age at death of 74 years. Deceased patients were older, had significantly higher H&Y stage and motor score, and reported a greater number of non-motor symptoms at baseline. In conclusion, overall non-motor symptom progression does not follow motor deterioration, is symptom-specific, and only development of specific domains negatively impacts quality of life. These results have consequences for drug studies targeting non-motor features.

Psychosis associated to Parkinson's disease in the early stages: relevance of cognitive decline and depression.

OBJECTIVE: To evaluate the prevalence of psychosis associated with Parkinson's disease (PSY-PD) in its early stages, its incidence over a 24 month follow-up period and the association with motor and non-motor clinical features. METHODS: PRIAMO is a 2 year longitudinal observational study that has enrolled patients with parkinsonism in 55 Italian centres. A cohort of 495 patients with early disease stage PD (baseline Hoehn and Yahr score ≤ 2, disease's duration (median) 3.4 years) were followed for 2 years. PSY-PD was evaluated by means of a clinician rated questionnaire and defined as the presence of at least one of the following symptoms occurring for at least 1 month: illusions, hallucinations, jealousy ideas and persecutory ideas. Patients with and without PSY-PD were compared on several clinical variables, encompassing motor and non-motor features. RESULTS: The prevalence of PSY-PD at baseline was 3%; the incidences at 12 and 24 months were 5.2% and 7.7%, respectively. Longer disease duration and prescription of dopamine agonists at baseline were associated with the development of PSY-PD over the 24 month period. At this follow-up time, worse disease severity, decline in cognitive performances, presence of depressive symptoms and anxiety were more frequently observed in PSY-PD. CONCLUSIONS: Psychotic type symptoms may occur in the early stages of PD although less frequently than in later stages. Beyond dopaminergic treatment, there are disease related factors, such as disease severity and the occurrence of cognitive and depressive symptoms, which may underlie the onset of psychotic type symptoms from the earliest stages.

Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders.

Using data from the PRIAMO study, we investigated non-motor symptoms (NMS) versus frontal lobe dysfunction in patients with idiopathic Parkinson disease (PD); 808 patients with PD and 118 with atypical parkinsonisms (AP) were consecutively enrolled at 55 Centers in Italy. Twelve categories of NMS were investigated. Cognitive impairment was defined as a Mini-Mental Status Evaluation score ≤ 23.8 and frontal lobe dysfunction as a Frontal Assessment Battery (FAB) score ≤ 3.48. Multivariable logistic regression was used to identify predictor of frontal lobe dysfunction in 524 PD patients, and a generalized linear model was used for each of the six FAB items. Not only the total FAB scores but also the single FAB items were lower in AP versus PD (p ≤ 0.005). Age (OR = 1.05), cognitive impairment (OR = 9.54), lack of cardiovascular symptoms (OR = 3.25), attention or memory problems (OR = 0.59) and treatment with L: -DOPA (OR = 5.58) were predictors of frontal lobe dysfunction. MMSE was negatively associated with all FAB items (ß ≤ -0.16) and age with all FAB items but prehension behavior (ß ≤ -0.01). Previous use of L: -DOPA was negatively associated with verbal fluency (ß = -0.32) possibly acting as surrogate marker of disease duration. Cognitive impairment is a predictor of frontal lobe dysfunction. Among NMS, lack of attention or memory problems were negatively associated with frontal impairment. Further studies are nonetheless needed to better identify the predictors of frontal impairment in PD patients.

Multiple system atrophy is associated with changes in peripheral insulin-like growth factor system.

Insulin-like growth factors (IGF-I and IGF-II) have been shown to have several neurotrophic actions and IGF system may be impaired in neurodegenerative disorders. The aim of this study was to investigate the IGF system in patients with MSA and to evaluate correlations between this endocrine system and clinical features of the disease. Serum levels of IGF-I, IGF-II, insulin, IGF-binding protein 1 (BP1), and IGF-binding protein 3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI-matched healthy controls. Clinical status of each patient was evaluated with the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II and the Hoehn and Yahr rating scale. IGF-I levels were significantly higher in MSA (164.1 + 66.2 µg/L) than in healthy controls (111.7 + 60.3 µg/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21.9 ± 14.4 µU/mL) than in healthy controls (13.3 ± 5.1 µU/mL, p = 0.048). No significant difference was found in serum IGF-II, IGF-BP1, and IGF- BP3 levels between patients with MSA and healthy controls. There was a trend toward significantly higher IGF-II levels in MSA patients with UMSARS score <26 (1026.3 ± 442.6 µg/L) than MSA patients with UMSARS score >26 (796.1 ± 234 µg/L, p = 0.055). The results of this study demonstrated that IGF system is altered in MSA. The degenerative process in MSA could lead to a compensatory increase in IGF-I and insulin in an attempt to provide additional support to degenerating neurons.

Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study.

The PRIAMO study is a cross-sectional longitudinal observational study aimed at describing epidemiology and evolution of non-motor symptoms (NMS) in patients with different forms of parkinsonism recruited in 55 Italian centres and evaluated over 24 months. In this paper, we are reporting prevalence and clinical characteristics of NMS in patients with atypical and secondary parkinsonism. Out of 1307 consecutive patients with a diagnosis of parkinsonism, 83 patients had vascular parkinsonism (VP), 34 had multiple system atrophy (MSA), 30 had progressive supranuclear palsy (PSP), 14 had dementia with Lewy bodies (DLB) and 11 had corticobasal degeneration (CBD). MSA and DLB had the highest number of NMS domains and symptoms, respectively. Gastrointestinal symptoms, pain, urinary problems and postural instability due to orthostatic hypotension were most frequent in MSA. Sleep disturbances were also common with a prevalence of approximately 70% in all diagnostic groups but CBD (36%). Psychiatric symptoms and attention and memory impairment were frequently observed in all diagnoses but were most prevalent among DLB patients, whereas the prevalence of skin and respiratory disorders was rather low in all forms, ranging between 10 and 30%. Atypical parkinsonism patients also reported a low QoL, with no significant differences among the different forms, whereas PD and VP patients had a better QoL.

The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease.

We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales.

The arginine growth hormone stimulation test in bradykinetic-rigid parkinsonisms.

The arginine growth hormone (GH) stimulation test differentiates the Parkinsonian variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine GH stimulation test in distinguishing between PSP, MSA-P, and PD. We measured the GH response to arginine in serum samples of 26 MSA-P, 23 PSP, and 26 PD patients, and in 80 healthy controls. We used ANOVA followed by the Bonferroni test to compare GH values and peaks among groups. We used receiver operating characteristic curve analysis to establish the arginine cut-off level that best differentiated between MSA-P, PSP, and PD. The GH peak was significantly lower (P < 0.01) in MSA-P (1.46 +/- 0.29 microg/L) than in both PD (8.74 +/- 0.98 microg/L) and PSP (6.64 +/- 0.82 microg/L) patients, and controls (8.59 +/- 0.44 microg/L). Growth hormone peaked later in PSP patients than in PD patients and controls. At a cut-off level of 4 microg/L, arginine test distinguished MSA-P from PD with a sensitivity of 92% and a specificity of 96%, and MSA-P from PSP with a sensitivity of 78% and a specificity of 96%. The GH response to arginine differentiates MSA-P from PD and PSP with a good diagnostic accuracy. The neuroendocrine response to arginine of PSP patients differed from that of MSA-P patients, but was not identical to that of normal controls and PD patients. Our results suggest that the impairment of the central mechanisms modulating GH release differs between PSP and MSA-P.

Multiple system atrophy is distinguished from idiopathic Parkinson's disease by the arginine growth hormone stimulation test.

OBJECTIVE: Multiple system atrophy (MSA) may be difficult to distinguish from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine growth hormone (GH) stimulation test in distinguishing between MSA and PD in large populations of patients. METHODS: We measured the GH response to arginine in 69 MSA (43 MSAp [parkinsonism as the main motor feature] and 26 MSAc [cerebellar features predominated]) patients, 35 PD patients, and 90 healthy control subjects. We used receiver-operating curve analysis to establish the arginine cutoff value that best differentiated between MSA and PD. RESULTS: The GH response to arginine was significantly lower (p < 0.01) in MSA than in either PD patients or control subjects. At a cutoff level of 4 microg/L, arginine distinguished MSAp from PD with a sensitivity and specificity of 91% and MSAc from PD with a sensitivity of 96% and specificity of 91%. The arginine test had a positive predictive value for MSA of 95%. The GH response to arginine was not affected by disease duration or severity, MSA motor subtype, pyramidal signs, response to dopaminergic therapy, or magnetic resonance imaging findings. INTERPRETATION: The GH response to arginine differentiates MSA from PD with a high diagnostic accuracy. The results suggest an impairment of cholinergic central systems modulating GH release in MSA.